International Journal of

Molecular Sciences Review

Parkinson’s Disease: From Pathogenesis to Pharmacogenomics Ramón Cacabelos EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, 15165-Bergondo, Corunna, Spain; [email protected] Academic Editor: Sabrina Angelini Received: 5 January 2017; Accepted: 20 February 2017; Published: 4 March 2017

Abstract: Parkinson’s disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, L-DOPA, L-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics. Keywords: adrenaline; antiparkinsonian drugs; Atremorine; dopamine; genomics; growth hormone; noradrenaline; Parkinson’s disease; pharmacogenetics; prolactin

1. Introduction Since 1915, over 85,000 papers have been published on Parkinson’s disease (PD) and related disorders in the international literature. The clinical entity described by James Parkinson (1755–1824) in 1817 as “paralysis agitans” in his “Assay on the Shaking Palsy” is at present the second most important neurodegenerative disorder in the elderly population, after Alzheimer’s disease. With a prevalence ranging from 35.8 per 100,000 to 12,500 per 100,000 and annual incidence estimates ranging from 1.5 per 100,000 to 346 per 100,000 in different countries [1–3], PD is becoming a major age-related problem of health [4,5]. Meta-analysis of the worldwide data indicates a rising

Int. J. Mol. Sci. 2017, 18, 551; doi:10.3390/ijms18030551

www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2017, 18, 551

2 of 28

prevalence of PD with age (41 per 100,000 at 40–49 years; 107 at 50–59 years; 173 at 55–64 years; 428 at 60–69 years; 425 at 65–74 years; 1087 at 70–79 years; and 1903 per 100,000 at over age 80), also reflecting a characteristic distribution by geographic location (a prevalence of 1601 per 100,000 in patients from North America, Europe and Australia, and a prevalence of 646 per 100,000 in Asian patients [6]. Parkinson’s disease is more prevalent in males (1729 per 100,000, >65 years) than in females (1644 per 100,000), with a peak prevalence in the age group of ≥90 years (4633 cases per 100,000), and a mean prevalence of 1680 per 100,000 in people over 65 years of age [7]. Prevalence and incidence male/female (M/F) ratios increase by 0.05 and 0.14, respectively, per 10 years of age. Incidence is similar in men and women under 50 years (M/F ratio < 1.2), and over 1.6 times higher in men than women above 80 years [8]. Furthermore, PD coexists with dementia in over 25% of the cases and with depression in over 30% of the cases in some countries [7]. The diagnosis of PD basically relies on clinical data characterized by rigidity, resting tremor, bradykinesia and postural imbalance. Although the primary cause of neurodegenerative disorders and the pathogenic mechanisms underlying protein conformational changes and premature neurodegeneration are unknown, recent advances in genomic medicine (structural and functional genomics, epigenetics, transcriptomics, proteomics, metabolomics, pharmacogenomics) have greatly contributed to better understand the complex processes responsible for age-related neuronal death in neurodegenerative disorders [9–14]. From a therapeutic perspective, the introduction of levodopa (L-DOPA) in the 1960s represented a breakthrough in the treatment of PD, and it continues to be the most effective symptomatic therapy in Parkinsonian disorders [15]. However, the chronic administration of L-DOPA and other antiparkinsonian drugs currently causes severe side effects that deserve special attention by the medical community. In this regard, novel compounds devoid of psychomotor, biochemical, neuropsychiatric and autonomic complications are under experimental scrutiny in preclinical studies and clinical trials [16–18]. A substantial component of drug pharmacokinetics and pharmacodynamics in PD can be attributed to the pharmacogenetic profile of each patient [19] (Table 1). Pathogenic, mechanistic, metabolic, transporter and pleiotropic genes associated with the pharmacogenetic outcome are determinant in the optimization of PD therapeutics [17,18]. Important issues to take into consideration for the appropriate management of PD are the following: (i) identification of environmental factors responsible for PD-related neurotoxicity; (ii) characterization of the population at risk for developing PD with predictive biomarkers; (iii) implementation of preventive programs; (iv) optimization of therapeutics with conventional antiparkinsonian drugs; (v) development of novel compounds with specific neuroprotective effects on the dopaminergic system and devoid of severe side effects; and (vi) incorporation of pharmacogenetic procedures for a personalized treatment of PD patients [17–20].

Int. J. Mol. Sci. 2017, 18, 551

3 of 30

Int. J. Mol. Sci. 2017, 18, 551

Table 1. Pharmacogenetics of antiparkinsonian drugs.

Int. J. Mol. Sci. 2017, 18, 551

Dopamine Precursors

Drug

Table 1. Pharmacogenetics of antiparkinsonian drugs. Properties

Drug Drug

CH3

.HO 2

CH3

.HO 2

Int. J. Mol. Sci. 2017, 18, 551

Drug

Drug Drug

3 of 28 3 of 30

Pharmacogenetics Table 1. Pharmacogenetics of antiparkinsonian drugs. Name: Carbidopa; 28860-95-9; Lodosyn. Dopamine Precursors IUPAC Name: Benzenepropanoic acid, α-hydrazino-3,4Properties Pharmacogenetics Dopamine Precursors dihydroxy-α-methyl-, monohydrate,(S) Name: Carbidopa; 28860-95-9; Lodosyn. Properties Pharmacogenetics Molecular Formula: C10H14N2O4 H2O IUPAC Name: Benzenepropanoic acid, α-hydrazino-3,4Molecular 244.24 g/mol Lodosyn. Name: Weight: Carbidopa; 28860-95-9; dihydroxy-α-methyl-, monohydrate,(S) Pathogenic genes: BDNF, PARK2 IUPAC Name: Benzenepropanoic acid,decarboxylase inhibitor Mechanism: Carbidopa is a peripheral Molecular Formula: C10H14N2O4 H2O Mechanistic genes: DRD2, OPRM1 withα-hydrazino-3,4-dihydroxy-α-methyl-, little or no pharmacological activitymonohydrate,(S) when given alone in Molecular Weight: 244.24 Molecular Formula: C10g/mol H14 N2 O4 H2 O Metabolic genes: genes: BDNF, PARK2 usualMolecular doses. ItWeight: inhibits244.24 the peripheral decarboxylation of levodopa Pathogenic g/mol Pathogenic BDNF, PARK2 Mechanism: Carbidopa is a peripheral decarboxylase inhibitor Substrate:genes: COMT, DDC Mechanistic genes: DRD2, to dopamine. At the same time, reduced peripheral formation of Mechanism: Carbidopa is a peripheral decarboxylase inhibitor with little Mechanistic genes: DRD2,OPRM1 OPRM1 with little or no pharmacological activity when given alone in Pleiotropic genes: ACE, ACHE Metabolic genes: or no pharmacological activity when givennotably alone in usual doses. genes: dopamine reduces peripheral side effects, nausea or It inhibitsMetabolic usualthe doses. It inhibits the peripheral decarboxylation of levodopa peripheral decarboxylation of levodopa dopamine. At theand same Substrate: COMT, DDC Substrate: COMT, DDC vomiting, and cardiac arrhythmias, althoughtothe dyskinesias to dopamine. At the same time, reduced peripheral formation of side Pleiotropic genes: ACE, ACHE time, reduced peripheral formation of dopamine reduces peripheral Pleiotropic genes: ACE, ACHE adverse mental effects associated with levodopa therapy tend to effects,reduces notably nausea or vomiting, and cardiac arrhythmias, dopamine peripheral side effects, notably nausea oralthough the develop earlier.and adverse mental effects associated with levodopa therapy dyskinesias vomiting, and cardiac arrhythmias, although the dyskinesias and tend to develop earlier.agents. Dopamine precursors. Effect: Antiparkinsonian adverse mental effects associated levodopa therapy tend to Effect: Antiparkinsonian agents.with Dopamine precursors. Name: Levodopa; 59-92-7; Levodopa; L-DOPA; Dopar; Bendopa; develop earlier. Pathogenic genes: ANKK1, BDNF, LRRK2, PARK2 Name: Levodopa; 59-92-7; Levodopa; L -DOPA; Dopar; Dopasol; 3,4-dihydroxy-L-phenylalanine; Madopar. Bendopa; Dopasol; Effect: Antiparkinsonian agents. Dopamine precursors. Mechanistic genes: CCK, CCKAR, CCKBR, DRD1, 3,4-dihydroxyL -phenylalanine; Madopar. IUPAC Name: L-Tyrosine-3-hydroxy Pathogenic genes: ANKK1, BDNF, LRRK2, PARK2 Name: Levodopa; Levodopa; L-DOPA; Dopar; Bendopa; DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B, IUPAC Name: L59-92-7; -Tyrosine-3-hydroxy Mechanistic genes: CCK, CCKAR, DRD2, DRD3, Pathogenic genes: ANKK1, BDNF, CCKBR, LRRK2,DRD1, PARK2 Molecular Formula: C 9H11NO4 Molecular Formula: CL9 H Dopasol; 3,4-dihydroxy-phenylalanine; Madopar. 11 NO4 HCRT, HOMER1, LMO3, GRIN2B, OPRM1 DRD4, DRD5, GRIN2A, HOMER1, Mechanistic genes: CCK, CCKAR, HCRT, CCKBR, DRD1, LMO3, OPRM1 Molecular Weight: 197.19 g/mol Molecular 197.19 g/mol IUPAC Name:Weight: L-Tyrosine-3-hydroxy Metabolic genes: Metabolic genes: DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B, Mechanism: Levodopa circulatesin inthe the plasma plasma totothe Mechanism: Levodopa circulates theblood–brain–barrier, blood– Substrate: COMT, CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4, Molecular Formula:to C9H11 NO4 Substrate: COMT, CYP1A2, CYP2B6, where it crosses, converted by converted striatal enzymes to dopamine. HOMER1, LMO3, OPRM1 brain–barrier, where itbecrosses, to be by striatal enzymes HCRT, CYP3A5,CYP2D6, DBH, DDC, G6PD, MAOB, TH,DBH, UGT1A1, UGT1A9 Molecular Weight: 197.19 g/mol plasma breakdown of levodopa by CYP2C19, CYP3A4, CYP3A5, DDC, Carbidopa inhibits the peripheral Metabolic genes: to dopamine. Carbidopa inhibits the peripheral plasma Transporter genes: SLC22A1, SLC6A3 inhibitingLevodopa its carboxylation, and in thereby increases levodopa at G6PD, MAOB, TH, UGT1A1, UGT1A9 Mechanism: circulates the plasma to available the blood– Pleiotropic ACE, ACHE CYP2B6, Substrate:genes: COMT, CYP1A2, breakdown of levodopa by inhibiting its carboxylation, and the blood–brain–barrier. brain–barrier, where it crosses, to be converted by striatal enzymes Transporter genes: SLC22A1, SLC6A3 CYP2C19, CYP2D6, CYP3A4, CYP3A5, DBH, DDC, thereby increases available agents. levodopa at the blood–brain–barrier. Effect: Antiparkinsonian Dopamine precursors. to dopamine. Carbidopa inhibits the peripheral plasma 4 of 30 Pleiotropic genes: ACE, ACHE G6PD, MAOB, TH, UGT1A1, UGT1A9 Effect: Antiparkinsonian agents. Dopamine precursors. Agonists Dopaminergic breakdown of levodopa by inhibiting its carboxylation, and Transporter genes: SLC22A1, SLC6A3 Dopaminergic Agonists Name: Amantadine; 768-94-5; Amantadine; Symmetrel; PK-Merz; Properties Pharmacogenetics thereby increases available levodopa at the blood–brain–barrier. Pleiotropic genes: ACE, ACHE Properties Pharmacogenetics Amantadina. Pathogenic genes: PARK2 Effect: Antiparkinsonian agents.Amantadine; Dopamine precursors. Name: Amantadine; 768-94-5; Symmetrel; PK-Merz; IUPAC Name: Tricyclo[3.3.1.13,7]decan-1-amine, Mechanistic genes: CCR5, CXCR4, DRD1, DRD2, Amantadina. Dopaminergichydrochloride Agonists Pathogenic genes: PARK2 3,7 ]decan-1-amine, hydrochloride IUPACFormula: Name: Tricyclo[3.3.1.1 GRIN3A Molecular C10H17NHCl Properties Pharmacogenetics Mechanistic genes: CCR5, CXCR4, DRD1, DRD2, GRIN3A Molecular Formula: C10 H17 NHCl Metabolic genes: Molecular Weight: 187.71 g/mol Metabolic genes: Molecular Weight: 187.71 g/mol Substrate: COMT, CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4, Substrate: COMT, CYP1A2, CYP2B6, Mechanism: Antiparkinsonian dueto toinhibition inhibition Mechanism: Antiparkinsonianactivity activitymay may be be due of of CYP3A5, DDC, UGT1A1, UGT1A9 dopamine reuptake into presynaptic orby byincreasing increasing dopamine reuptake into presynapticneurons neurons or dopamineCYP2C19, CYP2D6, CYP3A4, CYP3A5, DDC, Transporter genes: SLC22A1 releaserelease from presynaptic fibers. UGT1A1, UGT1A9 dopamine from presynaptic fibers. Effect: Antiparkinsonian agents; Adamantanes; Dopamine agonists. Transporter genes: SLC22A1 Effect: Antiparkinsonian agents; Adamantanes; Dopamine agonists. Pathogenic genes: PARK2 Name: Apomorphine; 58-00-4; Apomorhin; Apo-go; Apofin; Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, Apokinon; Apokyn; Apomorfina. CALY, DRD1, DRD2, DRD3, DRD4, DRD5, IUPAC Name: 4H-dibenzo[de,g]quinoline-10,11-diol, 5,6,6a,7HTR1A, HTR1B, HTR1D, HTR2A, HTR2B, HTR2C tetrahydro-6-methyl-hydrochloride,hemihydrate. Metabolic genes: Molecular Formula: C17H17NO2HCl1/2H2O Substrate: COMT, CYP1A2 (minor), CYP2B6, Molecular Weight: 312.79 g/mol CYP2C9 (minor), CYP2C19 (minor), CYP2D6, Mechanism: Stimulates postsynaptic D2-type receptors within the CYP3A4 (minor), CYP3A5, DDC, UGT1A1, caudate putamen in the brain. UGT1A9 Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine Inhibitor: CYP1A2 (weak), CYP2C19 (weak), receptor agonists. CYP3A4 (weak) Name: Bromocriptine; 25614-03-3; Parlodel; Pravidel; Cycloset; Pathogenic genes: ANKK1, BDNF, GSK3B, LRRK2 Corpadel; Broman; Bromocriptina. Mechanistic genes: ABCB1, AKT1, BDNF, CCK,

Int. J. Mol. Sci. 2017, 18, 551

Int. J. Mol. Sci. 2017, 18, 551

Drug

Int. J. Mol. Sci. 2017, 18, 551

Name: Amantadine; 768-94-5; Amantadine; Symmetrel; PK-Merz; Amantadina. Name: Amantadine; 768-94-5; Amantadine; Symmetrel; PK-Merz; IUPAC Name: Tricyclo[3.3.1.13,7]decan-1-amine, hydrochloride Amantadina. 3,7]decan-1-amine, hydrochloride Molecular Formula: C10H17NHCl IUPAC Name: Tricyclo[3.3.1.1 Molecular Formula: Weight: 187.71 Molecular C10H17g/mol NHCl Mechanism: Antiparkinsonian Molecular Weight: 187.71 g/molactivity may be due to inhibition of dopamine reuptake into presynaptic neurons by to increasing Mechanism: Antiparkinsonian activity may beordue inhibition of dopamine from dopamine release reuptake intopresynaptic presynapticfibers. neurons or by increasing 1. Cont. Effect: Antiparkinsonian agents; Adamantanes; Dopamine dopamine release from presynaptic fibers. Table agonists. Effect: Antiparkinsonian agents; Adamantanes; Dopamine

4 of 30

Pathogenic genes: PARK2 Mechanistic genes:PARK2 CCR5, CXCR4, DRD1, DRD2, Pathogenic genes: GRIN3A Mechanistic genes: CCR5, CXCR4, DRD1, DRD2, Metabolic genes: GRIN3A Substrate: COMT, CYP1A2, CYP2B6, Metabolic genes: CYP2C19, CYP2D6, CYP3A4, CYP3A5, DDC, Substrate: COMT, CYP1A2, CYP2B6, UGT1A1, UGT1A9 CYP2C19, CYP2D6, CYP3A4, CYP3A5, DDC, Transporter genes: SLC22A1 UGT1A1, UGT1A9

Transporter genes: SLC22A1 Pathogenic genes: PARK2 Dopaminergic Agonists agonists. Name: Apomorphine; 58-00-4; Apomorhin; Apo-go; Apofin; Mechanistic genes:PARK2 ADRA2A, ADRA2B, ADRA2C, Pathogenic genes: Properties Pharmacogenetics Apokinon; Apokyn; Apomorfina. Name: Apomorphine; 58-00-4; Apomorhin; Apo-go; Apofin; CALY, DRD1, DRD2, DRD3, DRD4, DRD5, Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, Name: Apomorphine; 58-00-4; Apomorhin; Apo-go; Apofin; Apokinon; IUPAC Name: 4H-dibenzo[de,g]quinoline-10,11-diol, 5,6,6a,7Apokinon; Apokyn; Apomorfina. Pathogenic genes: PARK2 HTR1A, HTR1B, HTR1D, HTR2A, HTR2B, CALY, DRD1, DRD2, DRD3, DRD4, DRD5,HTR2C Apokyn; Apomorfina. tetrahydro-6-methyl-hydrochloride,hemihydrate. IUPAC Name: 4H-dibenzo[de,g]quinoline-10,11-diol, 5,6,6a,7Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, Metabolic genes: HTR1D, HTR2A, HTR2B, HTR2CCALY, DRD1, IUPAC Name: 4H-dibenzo[de,g]quinoline-10,11-diol, HTR1A, DRD2,HTR1B, DRD3, DRD4, DRD5, HTR1A, HTR1B, HTR1D, HTR2A, Molecular Formula: C17H17NO2HCl1/2H2O tetrahydro-6-methyl-hydrochloride,hemihydrate. 5,6,6a,7-tetrahydro-6-methyl-hydrochloride,hemihydrate. Substrate: COMT, CYP1A2 (minor), CYP2B6, Metabolic genes: HTR2B, HTR2C Molecular Weight: 312.79 Molecular Formula: C17CH1717g/mol NO 2HCl1/2H 2O2 O Molecular Formula: H 17 NO 2 HCl1/2H CYP2C9 (minor), CYP2C19 (minor), CYP2D6, Metabolic genes: Substrate: COMT, CYP1A2 (minor), CYP2B6, Mechanism: Stimulates postsynaptic D2-type receptors within the Molecular Weight: 312.79 g/mol Molecular Weight: 312.79 g/mol Substrate: COMT, CYP1A2 (minor), CYP2B6, CYP2C9 (minor), CYP3A4 (minor), CYP3A5, DDC, UGT1A1, CYP2C9 (minor), CYP2C19 (minor), CYP2D6, Mechanism: Stimulates postsynaptic D -type receptors within the caudate 2 caudate putamen in the brain. Mechanism: Stimulates postsynaptic D2-type receptors within the CYP2C19 (minor), CYP2D6, CYP3A4 (minor), CYP3A5, DDC, UGT1A9 putamen in the brain. CYP3A4 (minor), CYP3A5, DDC, UGT1A1, Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine UGT1A1, UGT1A9 caudate putamen in the brain. Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine Inhibitor: CYP1A2 (weak), CYP2C19 (weak), UGT1A9 Inhibitor: CYP1A2 (weak), CYP2C19 (weak), CYP3A4 (weak) receptor agonists. Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine receptor agonists. CYP3A4 (weak)CYP1A2 (weak), CYP2C19 (weak), Inhibitor: receptor agonists. Name: Bromocriptine; 25614-03-3;Parlodel; Parlodel; Pravidel; Pravidel; Cycloset; Corpadel; Name: Bromocriptine; 25614-03-3; Cycloset; CYP3A4 (weak) Pathogenic genes: ANKK1, BDNF, GSK3B, LRRK2 Broman; Bromocriptina. Corpadel; Broman; Bromocriptina. Name: Bromocriptine; 25614-03-3; Parlodel; Pravidel; Cycloset; Mechanisticgenes: genes:ANKK1, ABCB1, BDNF, AKT1, BDNF, IUPAC Name: Ergotaman-30 -60 -18-trione, 2-bromo-120 -hydroxyPathogenic GSK3B,CCK, LRRK2 IUPAC Name: Ergotaman-3′-6′-18-trione, 2-bromo-12′-hydroxy-2′0 -(2-methylpropyl),monomethanesulfonate,(50 α). Corpadel; Broman; Bromocriptina. Pathogenic genes: ANKK1, BDNF, GSK3B, LRRK2 20 -(1-methylethyl)-5 CCKAR, CCKBR, CNR1, DRD1, DRD2, DRD3, Mechanistic genes: ABCB1, AKT1, BDNF, CCK, (1-methylethyl)-5′-(2-methylpropyl),monomethanesulfonate,(5′α). Mechanistic genes: ABCB1, AKT1, BDNF, CCK, CCKAR, CCKBR, Molecular C32 H40 BrN5 O5 CH4 SO IUPAC Name:Formula: Ergotaman-3′-6′-18-trione, 2-bromo-12′-hydroxy-2′3 DRD4, DRD5, GRIN2A, GRIN2B, GSK3B, HCRT, CCKAR, CNR1,DRD3, DRD1, DRD2, DRD3, CNR1,CCKBR, DRD1, DRD2, DRD4, DRD5, GRIN2A, GRIN2B, Molecular Weight:C750.70 g/mol Molecular Formula: 32H40BrN 5O5CH4SO3 (1-methylethyl)-5′-(2-methylpropyl),monomethanesulfonate,(5′α). HOMER1, LMO3, OPRM1 DRD4, DRD5, GRIN2A, GRIN2B, GSK3B, HCRT, GSK3B, HCRT, HOMER1, LMO3, OPRM1 Mechanism: Semisynthetic ergot alkaloid derivative and dopamine Molecular Weight: 750.70 Molecular Formula: C32H40g/mol BrN5O5CH4SO3 genes: Metabolic genes:OPRM1 receptor agonist which activates postsynaptic dopamine receptors in theMetabolic HOMER1, LMO3, 5 of 30 Mechanism: Semisynthetic ergot alkaloid derivative and Molecular Weight: 750.70 g/mol Substrate: COMT, CYP1A2, CY22B6, CYP2C19, CYP2D6, CYP3A4 tuberoinfundibular (inhibiting pituitary prolactin secrection) and Substrate: COMT, CYP1A2, CY22B6, Metabolic genes: dopamine receptor agonist which activates postsynaptic Mechanism: Semisynthetic ergot alkaloid derivative (major), CYP2D6, CYP3A5, DDC, MAOB, UGT1A1, UGT1A9 nigrostriatal pathways (enhancing coordinated motorand control). Causes CYP2C19, CYP3A4 (major), CYP3A5, growth hormone secretion in acromegaly. Dysregulation of brain Substrate: COMT, CYP1A2, CY22B6, dopamine receptors ininthe tuberoinfundibular (inhibiting pituitary transient increases growth hormone secretion in individuals with Inhibitor: CYP1A2 (weak), CYP3A4 (moderate) dopamine receptor agonist which activates postsynaptic DDC, MAOB, UGT1A1, UGT1A9 serotonine activity may also occur. CYP2D6, normal growth hormone concentrations. Paradoxically causes sustained CYP2C19, Transporter genes:CYP3A4 SLC22A1,(major), SLC6A3CYP3A5, prolactin secrection) and pathways (enhancing dopamine receptors in thenigrostriatal tuberoinfundibular (inhibiting pituitary Inhibitor: CYP1A2 (weak), Effect: Antiparkinsonian agents; Ergot-derivative dopamine Pleiotropic ACE, APOECYP3A4 (moderate) suppression of growth hormone secretion in acromegaly. Dysregulation ofDDC, MAOB, genes: UGT1A1, UGT1A9 coordinated motor control). Causes transient increases in growth prolactin secrection) and nigrostriatal pathways (enhancing brainagonists. serotonine activity may also occur. Transporter genes: SLC22A1, receptor Inhibitor: CYP1A2 (weak),SLC6A3 CYP3A4 (moderate) hormone individuals with normalincreases growth hormone coordinated motor in control). Causes transient in growth Effect:secretion Antiparkinsonian agents; Ergot-derivative dopamine Pleiotropic genes: ACE, APOESLC6A3 Transporter genes: SLC22A1, Name: Cabergoline; 81409-90-7; Cabergoline; Dostinex, Cabaser; concentrations. Paradoxically causes sustained suppression of receptor agonists. hormone secretion in individuals with normal growth hormone Pleiotropic genes: ACE, APOE Cabergolinum; Cabaseril; Cabergolina. concentrations. Paradoxically causes sustained suppression of Name: Cabergoline; 81409-90-7; Cabergoline; Dostinex, Cabaser; IUPAC Name: Ergoline-8β-carboxamide, N-[3Cabergolinum; Cabaseril; Cabergolina. Pathogenic genes: BDNF, GSK3B (dimethylamino)propyl]-N-[(ethylamino)carbonil]-6-(2-propenyl) IUPAC Name: Ergoline-8β-carboxamide, Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, Molecular Formula: C26H37N5O2 N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonil]-6-(2-propenyl) Pathogenic genes: BDNF, GSK3B AKT1, BDNF, CNR1, DRD1, DRD2, DRD3, DRD4, Molecular Formula: C26g/mol H37 N5 O2 Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, AKT1, BDNF, Molecular Weight: 451.60 DRD5, GSK3B, HTR1B, HTR1D, HTR2A, Molecular Weight: 451.60 g/mol CNR1, DRD1,HTR1A, DRD2, DRD3, DRD4, DRD5, GSK3B, HTR1A, HTR1B, Mechanism: A long-acting dopamine receptor agonist. Has high Mechanism: A long-acting dopamine receptor agonist. Has high bindingHTR2B, HTR1D, HTR2A, HTR2B, HTR2C, HTR7 HTR2C, HTR7 binding affinity for dopamine D 2-receptors and lesser affinity for affinity for dopamine D2 -receptors and lesser affinity for D1 , α1 - and Metabolic genes: Metabolic genes: D1, αα1-2 -adrenergic, and α2-adrenergic, and serotonin and 5-HTReduces 2) and serotonin (5-HT1 and(5-HT 5-HT2 1) receptors. serum Substrate: COMT, CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4 Substrate: COMT, CYP1A2, CYP2B6, prolactin concentrations by inhibiting release of prolactin from the anterior (minor), CYP3A5, DDC receptors. Reduces serum prolactin concentrations by inhibiting CYP2C19, CYP2D6, CYP3A4 (minor), CYP3A5, pituitary gland (agonist activity at Dpituitary 2 receptors). release of prolactin from the anterior gland (agonist DDC Effect: Antiparkinsonian agents; Ergot-derivative dopamine activity at D 2 receptors). receptor agonists. Effect: Antiparkinsonian agents; Ergot-derivative dopamine receptor agonists. Name: Lisuride; 18016-80-3; Dopergin; Arolac; Dopergine; Dipergon; Lysenyl; Lisurida. IUPAC Name: 3-(9,10-didehydro-6-methylergolin-8α-yl)Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, 1,1-diethylurea DRD1, DRD2, DRD3, DRD4, DRD5, HTR1A, Molecular Formula: C20H26N4O HTR1B, HTR1D, HTR2A, HTR2B, HTR2C Molecular Weight: 338.45 g/mol Metabolic genes: Mechanism: Displays dopaminergic, and consequently Substrate: COMT, CYP1A2, CY22B6, prolacting-reducing properties. Active substance lisuride has CYP2C19, CYP2D6 (major), CYP3A4 (major), pronounced affinity for dopamine receptors in striatum and CYP3A5, DDC, UGT1A1, UGT1A9 pituitary.

4 of 28

Int. J. Mol. Sci. 2017, 18, 551

Drug

Int. J. Mol. Sci. 2017, 18, 551

Int. J. Mol. Sci. 2017, 18, 551

IUPAC Name: Ergoline-8β-carboxamide, N-[3Pathogenic genes: BDNF, GSK3B (dimethylamino)propyl]-N-[(ethylamino)carbonil]-6-(2-propenyl) Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, Molecular Formula: C26H37N5O2 AKT1, BDNF, CNR1, DRD1, DRD2, DRD3, DRD4, Molecular Weight: 451.60 g/mol DRD5, GSK3B, HTR1A, HTR1B, HTR1D, HTR2A, Mechanism: A long-acting dopamine receptor agonist. Has high HTR2B, HTR2C, HTR7 binding affinity for dopamine D2-receptors and lesser affinity for Metabolic genes: D1, α1- and α2-adrenergic, and serotonin (5-HT1 and 5-HT2) Substrate: COMT, CYP1A2, CYP2B6, receptors. Reduces serum prolactin concentrations by inhibiting CYP2C19, CYP2D6, CYP3A4 (minor), CYP3A5, release of prolactin from the anterior pituitary gland (agonist DDC Table 1. Cont. activity at D2 receptors). Effect: Antiparkinsonian agents; Ergot-derivative dopamine receptor agonists. Dopaminergic Agonists Name: Lisuride; 18016-80-3; Dopergin; Arolac; Dopergine; Properties Pharmacogenetics Dipergon; Lysenyl; Lisurida. Name: Lisuride; 18016-80-3; Dopergin; Arolac; Dopergine; Dipergon; IUPAC Name: 3-(9,10-didehydro-6-methylergolin-8α-yl)Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, Lysenyl; Lisurida. 1,1-diethylurea 6 of 30 IUPAC Name: 3-(9,10-didehydro-6-methylergolin-8α-yl)-1,1-diethylureaDRD1, Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, DRD1, DRD2, DRD2, DRD3, DRD4, DRD5, HTR1A, Molecular Formula: C20CH2026H N264O DRD3, DRD4, DRD5, HTR1A, HTR1B, HTR1D, HTR2A, HTR2B, Molecular Formula: N4 O HTR1B, HTR1D, HTR2A, HTR2B, HTR2C Name: Pergolide; 66104-22-1; Pergolide; Permax; Pergolida; Molecular Weight: 338.45 g/mol HTR2C Molecular Weight: 338.45 g/mol Metabolic genes: Metabolic genes: Mechanism: Displays dopaminergic,and and consequently consequently Pergolidum. Mechanism: Displays dopaminergic, Substrate: COMT, CYP1A2, CY22B6, prolacting-reducing properties. Active substance lisuride has pronounced Substrate: COMT, CYP1A2, CY22B6, CYP2C19, CYP2D6 (major), 6 of 30 IUPAC Name: Ergoline,8-[(methylthio)methyl]-6prolacting-reducing properties. Active substance lisuride has affinity for dopamine receptors in striatum and pituitary. CYP3A4CYP2D6 (major), CYP3A5, UGT1A1, UGT1A9 CYP2C19, (major), DDC, CYP3A4 (major), monomethenesulfonate Mechanistic genes: ADRA1A, ADRA1B, ADRA1D, pronounced affinity for dopamine receptors in striatum and Effect: Antiparkinsonian agents; Ergot-derivative Name: Pergolide; 66104-22-1; Pergolide; Permax; dopamine Pergolida;receptor CYP3A5, DDC, UGT1A1, UGT1A9 Molecular Formula: C19H26agents. ADRA2A, ADRA2B, ADRA2C, DRD1, DRD2, N2SCHMiscellaneous. 4O3S pituitary. agonists. Antimigraine Pergolidum. DRD3, DRD4, DRD5, HTR1A, HTR1B, HTR1D, Molecular Weight: 410.59 agents; g/mol Ergot-derivative dopamine Effect: Antiparkinsonian IUPAC Name: Ergoline,8-[(methylthio)methyl]-6Name: Pergolide; 66104-22-1; Pergolide; Permax; Pergolida; Pergolidum. HTR2A, HTR2B, HTR2C Mechanism: A dopamin receptoragents. agonist.Miscellaneous. Relieves symptoms of receptor agonists. Antimigraine IUPAC Name: Ergoline,8-[(methylthio)methyl]-6-monomethenesulfonateMechanistic genes: ADRA1A, ADRA1B, ADRA1D, monomethenesulfonate Metabolic genes: parkinsonism, presumably directly postsynaptic Molecular Formula: C19 Hby N SCH4 Ostimulating S 26 2 3 Molecular Formula: C19H26N2SCH4O3S ADRA2A, ADRA2B, ADRA2C, DRD1, DRD2, Substrate: COMT, CYP1A2,ADRA1B, CY22B6,ADRA1D, ADRA2A, dopamine receptors in410.59 corpus striatum. Reduces serum prolactine Molecular Weight: g/mol Mechanistic genes: ADRA1A, DRD3, DRD4, DRD5, DRD1, HTR1A, HTR1B, HTR1D, Molecular Weight: 410.59 g/mol Mechanism: dopamin receptor Relieves symptoms ADRA2B, ADRA2C, DRD2, DRD3, DRD4, DRD5, HTR1A, CYP2C19, CYP2D6, CYP3A4 (major), CYP3A5, concentrations byAinhibiting releaseagonist. of prolactin from anteriorof HTR2A, HTR2B, HTR2C Mechanism: A dopamin receptor agonist. Relievespostsynaptic symptomsdopamine of parkinsonism, presumably by directly stimulating HTR1B, HTR1D, HTR2A, HTR2B, HTR2C DDC, UGT1A1, UGT1A9 pituitary gland. Causes transient increase in serum somatotropin receptors inpresumably corpus striatum. Reduces serum prolactine concentrations byMetabolic Metabolic genes: genes: parkinsonism, by directly stimulating postsynaptic Transporter genes: SLC6A4 (growth hormone) concentrations and decreases in serum inhibiting release of from anterior pituitary gland. Causes Substrate: COMT, CYP1A2, CY22B6, CYP2C19, CYP2D6, CYP3A4 Substrate: COMT, CYP1A2, CY22B6, dopamine receptors in prolactin corpus striatum. Reduces serum prolactine luteinizing hormone transient increase concentrations. in serum somatotropin (growth hormone) (major), CYP3A5, DDC, UGT1A1, UGT1A9 CYP2C19, CYP2D6, CYP3A4 (major), CYP3A5, concentrations by and inhibiting release of prolactin from anterior concentrations decreases serum luteinizingdopamine hormone Transporter genes: SLC6A4 Effect: Antiparkinsonian agents;inErgot-derivative DDC, UGT1A1, UGT1A9 pituitary gland. Causes transient increase in serum somatotropin concentrations. receptor agonists. Effect: Antiparkinsonian agents; Ergot-derivative dopamine Transporter genes: SLC6A4 (growth hormone) concentrations and decreases in serum Name: Pramipexole; 104632-26-0; Pramipexole; Pramipexol; Pathogenic genes: ANKK1, BDNF, LRRK2 receptorhormone agonists. concentrations. luteinizing Parmital; Mirapex; Mirapexin; Sifrol Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, Effect: Antiparkinsonian agents; Ergot-derivative dopamine Name: Pramipexole; 104632-26-0; Pramipexole; Pramipexol; Parmital; 6IUPAC Name: 2,6-benzothiazolediamine, 4,5,6,7-tetrahydro-N CCK,Pathogenic CCKAR, CCKBR, DRD1,BDNF, DRD2, DRD3, genes: ANKK1, LRRK2 Mechanistic genes: receptor agonists. Mirapex; Mirapexin; Sifrol ADRA2A, CCKAR, CCKBR, DRD1, DRD2, DRD4, DRD5,ADRA2B, GRIN2A,ADRA2C, GRIN2B,CCK, HCRT, propyl-,(S) 6 -propyl-,(S) IUPAC Name: 2,6-benzothiazolediamine, 4,5,6,7-tetrahydro-N Name: Pramipexole; 104632-26-0; Pramipexole; Pramipexol; Pathogenic genes: ANKK1, BDNF, LRRK2 DRD3, DRD4, DRD5, GRIN2A, GRIN2B, HCRT, HOMER1, HTR1A, HOMER1, HTR1A, HTR1B, HTR1D, HTR2A, Molecular Formula: C10H 17N 3SN S Molecular Formula: C10 H17 3 HTR1B, HTR1D, HTR2B, HTR2C,ADRA2C, LMO3, OPRM1 Parmital; Mirapex; Mirapexin; Sifrol Mechanistic genes:HTR2A, ADRA2A, ADRA2B, HTR2B, HTR2C, LMO3, OPRM1 Molecular Weight: 211.33 g/mol Molecular Weight: 211.33 g/mol Metabolic 6IUPAC Name: 2,6-benzothiazolediamine, 4,5,6,7-tetrahydro-N CCK, CCKAR,genes: CCKBR, DRD1, DRD2, DRD3, Mechanism: By binding to2 D dopamine receptor, and 2 subfamily Mechanism: By binding to D subfamily dopamine receptor, andto D3 , Metabolic genes: Substrate: COMT, CYP1A2, CY22B6, CYP2C19, CYP2D6, CYP3A4, propyl-,(S) it is though that Pramipexole can stimulate dopamine DRD4, DRD5, GRIN2A, GRIN2B, HCRT, 4 receptors, to D3,and Substrate: COMT, CYP1A2, CY22B6, andDD 4 receptors, it is though that Pramipexole can CYP3A5, DDC, MAOB, UGT1A1, UGT1A9 activityFormula: on nervesC of10striatum HOMER1, HTR1A, HTR1B, HTR1D, Molecular H17N3S and substantia nigra. Transporter genes:CYP3A4, SLC22A1, SLC6A3HTR2A, CYP2C19, CYP2D6, CYP3A5, DDC, stimulate activityagents; on nerves of striatum anddopamine Effect:dopamine Antiparkinsonian Non-ergot-derivative HTR2B, HTR2C, LMO3, Molecular Weight: 211.33 g/mol Pleiotropic genes: ACE,OPRM1 APOE MAOB, UGT1A1, UGT1A9 substantia nigra. receptor agonists. Mechanism: By binding to D2 subfamily dopamine receptor, and Metabolic genes: Transporter genes: SLC22A1, SLC6A3 Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine to D3, and D4 receptors, it is though that Pramipexole can Substrate: COMT, CYP1A2, CY22B6, receptor agonists. Pleiotropic genes: ACE, APOE CYP2C19, CYP2D6, CYP3A4, CYP3A5, DDC, stimulate dopamine activity on nerves of striatum and MAOB, UGT1A1, UGT1A9 substantia nigra. Transporter genes: SLC22A1, SLC6A3 Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine receptor agonists. Pleiotropic genes: ACE, APOE

5 of 28

Int. J. Mol. Sci. 2017, 18, 551

Int. J. Mol. Sci. 2017, 18, 551

Int. J. Mol. Sci. 2017, 18, 551

Drug

H3C

H3C

Drug

Drug

7 of 30

Name: Ropinirole; 91374-21-9; Ropinirole; ReQuip; Ropinirol; Table 1. Cont. Ropinilorum; ReQuip CR Pathogenic genes: ANKK1, BDNF, LRRK2 7 of 30 IUPAC Name: 2-H-Indol-2-one 4-[2-(dipropylamino)ethyl]-1,3Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, Dopaminergic Agonists dihydro-, monohydrochloride Name: Ropinirole; 91374-21-9; Ropinirole; ReQuip; Ropinirol; CCK, CCKAR, CCKBR, DRD1, DRD2, DRD3, Molecular Formula: C16H24N2O Properties Pharmacogenetics Ropinilorum; ReQuip CR DRD4, DRD5, GRIN2A, GRIN2B, HCRT, Pathogenic genes: ANKK1, BDNF, LRRK2 Molecular Weight: 296.84 g/mol Ropinirole; ReQuip; Ropinirol; Name: Ropinirole; 91374-21-9; IUPAC Name: 2-H-Indol-2-one 4-[2-(dipropylamino)ethyl]-1,3HOMER1, HTR1A, HTR1B, HTR1D, HTR2A, Mechanistic genes: ADRA2A, ADRA2B, ADRA2C, Mechanism: Has ReQuip high relative in vitro specificity and full intrinsic Ropinilorum; CR dihydro-, monohydrochloride HTR2B, HTR2C, LMO3, OPRM1 IUPAC 2-H-Indol-2-one 4-[2-(dipropylamino)ethyl]-1,3-dihydro-, CCK, CCKAR, CCKBR, DRD1, DRD2, DRD3, activity at DName: 2 and D 3 dopamine receptor subtypes, binding with Pathogenic genes: ANKK1, BDNF, LRRK2 Molecular Formula: C 16H24N2O Metabolic genes: monohydrochloride DRD4, DRD5, GRIN2A, GRIN2B, HCRT,ADRA2C, CCK, CCKAR, higher affinity to D3 than to D2 and D4 receptor subtypes. Mechanistic ADRA2A, Molecular Weight: 296.84 Substrate: genes: COMT, CYP1A2ADRA2B, (major), CY22B6, Molecular Formula: C16g/mol H24 N2 O HOMER1, HTR1B, HTR1D, CCKBR, HTR1A, DRD1, DRD2, DRD3, DRD4,HTR2A, DRD5, GRIN2A, GRIN2B, Although precise mechanism of action unknown, it is believed to Molecular Weight: g/mol Mechanism: Has high296.84 relative in vitro specificity and full intrinsic CYP2C19, CYP2D6,HTR1A, CYP3A4 (minor), CYP3A5, HCRT, HOMER1, HTR1B, HTR1D, HTR2A, HTR2B, HTR2C, HTR2B, HTR2C, LMO3, OPRM1 be due to stimulation of postsynaptic dopamine D 2 -type receptors Mechanism: Has high relative in vitro specificity and full intrinsic activity activity at D2 and D3 dopamine receptor subtypes, binding with DDC, MAOB, UGT1A1, UGT1A9 LMO3, OPRM1 at D dopamineinreceptor binding within caudate brain. subtypes, Mechanism of with higher affinity toMetabolic genes: 2 and D3putamen Metabolic higher affinity to D3 than to D2 and D4 receptor subtypes. Inhibitor:genes: CYP1A2 (moderate), CYP2D6 D3 than to D2 andpostural D4 receptor subtypes. Although mechanism of Substrate: COMT, CYP1A2 (major), CY22B6, Ropinirole-induced hypotension believedprecise to be due to Substrate: COMT, CYP1A2 (major), CY22B6, CYP2C19, CYP2D6, Although mechanism of to action unknown, it is believed to (moderate), CYP3A4 (moderate) action precise unknown, it is believed be due to stimulation of postsynaptic CYP2C19, CYP3A4DDC, (minor), CYP3A5, D2-mediated blunting of noradrenergic response to standing and CYP3A4CYP2D6, (minor), CYP3A5, MAOB, UGT1A1, UGT1A9 dopamine D2 -type of receptors within caudate putamen in brain. be due to stimulation postsynaptic dopamine D2-type receptors Transporter genes: SLC22A1, SLC6A3 Inhibitor: (moderate), CYP2D6 (moderate), CYP3A4 (moderate) MAOB,CYP1A2 UGT1A1, UGT1A9 subsequent decrease in peripheral vascular Mechanism of Ropinirole-induced postural resistance. hypotension believed to be DDC, within caudate putamen in brain. Mechanism of Pleiotropic genes: ACE, APOESLC6A3 Transporter genes: SLC22A1, Inhibitor: CYP1A2 (moderate), CYP2D6 Effect: Antiparkinsonian agents;ofNon-ergot-derivative due to D2 -mediated blunting noradrenergic response dopamine to standing and Ropinirole-induced postural hypotension believed to be due to Pleiotropic genes: ACE, APOE subsequent decrease in peripheral vascular resistance. (moderate), CYP3A4 (moderate) receptor agonists. D2-mediated blunting of noradrenergic response to standing and Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine Transporter genes: SLC22A1, SLC6A3 Name: Rotigotine; 99755-59-6; Rotigotine; Rotigotina; Neupro subsequent receptordecrease agonists. in peripheral vascular resistance. Pleiotropic genes: ACE, APOE IUPAC Name: 1-Naphthalenol, 5,6,7,8-tetrahydro-6-[propyl[2-(2Effect: Antiparkinsonian agents;Rotigotine; Non-ergot-derivative dopamine Name: Rotigotine; 99755-59-6; Rotigotina; Neupro thienyl)ethyl]amino]-6S receptor agonists. IUPAC Name: 1-Naphthalenol, Molecular Formula: C19H25NOs Pathogenic genes: ANKK1, BDNF, LRRK2 5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino]-6S Name: Rotigotine; 99755-59-6; Rotigotine; Rotigotina; Neupro Molecular Weight: 315.47 Mechanistic CCKAR, Molecular Formula: C19g/mol H25 NOs Pathogenicgenes: genes:CCK, ANKK1, BDNF,CCKBR, LRRK2 DRD1, IUPAC Name: 1-Naphthalenol, 5,6,7,8-tetrahydro-6-[propyl[2-(2MolecularAWeight: 315.47 g/mol receptor agonist with Mechanistic genes: CCK, CCKAR, CCKBR, DRD1, DRD2, DRD3, Mechanism: non-ergot dopamine DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B, thienyl)ethyl]amino]-6S Mechanism: A non-ergot dopamine receptor agonist with specificity for DRD4, DRD5, GRIN2A, GRIN2B, HCRT, HOMER1, LMO3, OPRM1 specificity for D3-, D2-, and D1-dopamine receptors. Although HCRT, HOMER1, LMO3, OPRM1 Molecular C19H25NOs D3 -, D2Formula: -, and D1 -dopamine receptors. Although precise mechanism of Pathogenic Metabolicgenes: genes:ANKK1, BDNF, LRRK2 Metabolic genes: precise mechanism of action unknown of Rotigotine, it is believed action unknown of Rotigotine, Substrate: COMT,CCK, MAOB Molecular Weight: 315.47 g/mol it is believed to be due to stimulation of Mechanistic genes: CCKAR, CCKBR, DRD1, Substrate: COMT, MAOBSLC6A3 to bepostsynaptic due to stimulation ofDpostsynaptic dopamine D2substantia -type autonigra in Transporter dopamine receptors within 2 -type auto Mechanism: A non-ergot dopamine receptor agonist with DRD2, DRD3, genes: DRD4,SLC22A1, DRD5, GRIN2A, GRIN2B, brain, leading to improved dopaminergic transmission in motor areas in Pleiotropic genes: ACE, APOE Transporter genes: SLC22A1, SLC6A3 receptors within substantia nigra in brain, leading to improved specificity for D3-,notably HCRT, HOMER1, LMO3, OPRM1 D2-, and D1-dopamine receptors. Although basal ganglia, caudate nucleus/putamen regions. Pleiotropic genes: ACE, APOE dopaminergic transmission in motor areas in basal ganglia, Metabolic genes: precise mechanism of actionagents; unknown of Rotigotine, itdopamine is believed Effect: Antiparkinsonian Non-ergot-derivative notably caudate nucleus/putamen regions. agonists. Substrate: COMT, MAOB to bereceptor due to stimulation of postsynaptic dopamine D2-type auto Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine Transporter genes: SLC22A1, SLC6A3 receptors within substantia nigra in brain, leading to improved receptor agonists. Pleiotropic genes: ACE, APOE dopaminergic transmission in motor areas in basal ganglia, Monoamine Oxidase B (MOB) Inhibitors notably caudate nucleus/putamen regions. Properties Pharmacogenetics Effect: Antiparkinsonian agents; Non-ergot-derivative dopamine receptor agonists. Monoamine Oxidase B (MOB) Inhibitors Properties Pharmacogenetics

6 of 28

Int. J. Mol. Sci. 2017, Int. J.18, Mol.551 Sci. 2017, 18, 551

Int. J. Mol. Sci. 2017, 18, 551

Drug

Drug

Drug

8 of 30

Pathogenic genes: ANKK1, BDNF, LRRK2 Name: Selegiline; 14611-51-9; Selegiline; Selegilina; L-Deprenalin; Mechanistic genes: CCK, CCKAR, CCKBR, DRD1, Table 1. Cont. Emsam; Jumex; Eldepryl; Carbex DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B, 8 of 30 IUPAC Name: Benzeneethanamine,N,α-dimethyl-N-2-propynylHCRT, HOMER1, LMO3, OPRM1 ,hydrochloride,(R) Monoamine Oxidase B (MOB) Inhibitors Pathogenic genes: ANKK1, BDNF, LRRK2 Metabolic genes: L -Deprenalin; Name: Selegiline; 14611-51-9; Selegiline; Selegilina; Molecular Formula: C31H17NHCl Properties Mechanistic genes: CCK, CCKAR, CCKBR,(minor), DRD1, Pharmacogenetics Substrate: COMT, CYP1A1, CYP1A2 Emsam; Jumex; Eldepryl; Molecular Weight: 223.74 Carbex g/mol DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B, Name: Selegiline; 14611-51-9; Selegiline; Selegilina; L-Deprenalin; Emsam; CYP1B1, CYP2A6 (minor), CYP2B6 (major), IUPAC Name: Benzeneethanamine,N,α-dimethyl-N-2-propynylMechanism: Potent, irreversible inhibitor of the monoamine Pathogenic genes: ANKK1, BDNF, CYP2D6 LRRK2 Jumex; Eldepryl; Carbex HCRT, HOMER1, LMO3, OPRM1 CYP2C8 (minor), CYP2C19 (major), ,hydrochloride,(R) oxidase (MAO). IUPAC Name:Plasma concentrations achieved via Mechanistic genes: CCK, CCKAR, CCKBR, DRD1, DRD2, DRD3, Metabolic genes: (minor), CYP2E1 (minor), CYP3A4 (minor), Molecular Formula: C31dosage H17NHCl DRD4, DRD5, GRIN2A, GRIN2B, HCRT, HOMER1, LMO3, OPRM1 Benzeneethanamine,N,α-dimethyl-N-2-propynyl-,hydrochloride,(R) administration of oral forms in recommended doses confer Substrate: COMT, CYP1A1, CYP1A2 (minor), CYP3A5, CYP19A1, Metabolic genes: DDC, MAOA, MAOB, Molecular Formula: C31MAO H17 NHCl Molecular Weight: 223.74 g/mol selective inhibition of the type B, which plays a major role in CYP1B1, CYP2A6 (minor), CYP2B6 (major), UGT1A1, UGT1A9 Substrate: COMT, CYP1A1, CYP1A2 (minor), CYP1B1, CYP2A6 Molecular Weight:irreversible 223.74 g/mol Mechanism: Potent, inhibitor of the monoamine metabolism of dopamine. Selegiline may also increase CYP2C8 (minor), CYP2C19 (major), CYP2D6 Mechanism: Potent, irreversible inhibitor of the monoamine oxidase (minor), CYP2B6 (major), CYP2C8 (minor), CYP2C19 (major), CYP2D6 Inhibitor: CYP1A2 (weak), CYP2A6 (weak), oxidase (MAO). Plasma concentrations achieved via dopaminergic activity by interfering withvia dopamine reuptake (MAO). Plasma concentrations achieved administration of oral dosage (minor), CYP2E1 (minor),CYP3A4 CYP3A4 (minor), (minor), CYP3A5, CYP19A1, DDC, (minor), CYP2E1 (minor), CYP2C9 (weak), CYP2C19 (weak), CYP2D6 (weak), administration of oral dosage forms recommended forms in recommended doses conferinselective inhibitiondoses of theconfer MAO type MAOA, MAOB, UGT1A1, UGT1A9MAOB, at synapse. CYP3A5, CYP19A1, DDC,(weak), MAOA, CYP2E1 (weak), CYP3A4 MAOB B, which plays a major role in metabolism of dopamine. Selegiline may Inhibitor: CYP1A2 (weak), CYP2A6 (weak), CYP2C9 (weak), CYP2C19 selective inhibition of the MAO type B, which plays a major role in Effect: Antidepressants. Monoamine oxidase inhibitors. UGT1A1, Transporter genes:(weak), SLC22A1, SLC6A3 also increase dopaminergic activitymay by interfering with dopamine (weak), UGT1A9 CYP2D6 CYP2E1 (weak), CYP3A4 (weak), MAOB metabolism of dopamine. Selegiline also increase Antiparkinsonian agents. Monoamine oxidase B inhibitors. Inhibitor: CYP1A2 (weak), CYP2A6 (weak), reuptake at synapse. Transporter genes: SLC22A1, Pleiotropic genes: ACE, APOESLC6A3 dopaminergic activity by interfering with dopamine reuptake Effect: Antidepressants. Monoamine oxidase inhibitors. Antiparkinsonian Pleiotropic genes: ACE, APOE CYP2C9 (weak), CYP2C19 (weak), CYP2D6 (weak), Name: Rasagiline; 136236-51-6; Azilet; Elbrux; Rasagilina; Raxac. at synapse. agents. Monoamine oxidase B inhibitors. CYP2E1 (weak), CYP3A4 (weak), MAOB IUPACAntidepressants. Name: 1H-Inden-1-amine, 2,3-dihydro-N-2-propynyl-,(R)-, Effect: Monoamine oxidase inhibitors. Pathogenic genes: BDNF, LRRK2, PARK2 Name: Rasagiline; 136236-51-6; Azilet; Elbrux; Rasagilina; Raxac. Transporter genes:ANKK1, SLC22A1, SLC6A3 methanesulfonate Antiparkinsonian agents. Monoamine oxidase B inhibitors. IUPAC Name: 1H-Inden-1-amine, 2,3-dihydro-N-2-propynyl-,(R)-, Mechanisticgenes: genes:ACE, BLC2, CCK, CCKAR, CCKBR, Pleiotropic APOE Pathogenic genes: ANKK1, BDNF, LRRK2, PARK2 Molecular Formula: C12H13NCH4O3S methanesulfonate DRD1, DRD2, DRD3, DRD4, DRD5, GRIN2A, Mechanistic genes: BLC2, CCK, CCKAR, CCKBR, DRD1, DRD2, Name: Rasagiline; 136236-51-6; Azilet; Elbrux; Rasagilina; Raxac. Molecular Weight: 267.34 Molecular Formula: C12g/mol H13 NCH 4 O3 S DRD3,HCRT, DRD4, HOMER1, DRD5, GRIN2A, GRIN2B, HCRT, HOMER1, LMO3, GRIN2B, LMO3, OPRM1 IUPAC Name: 1H-Inden-1-amine, 2,3-dihydro-N-2-propynyl-,(R)-, Molecular Weight:irreversible 267.34 g/mol Mechanism: Potent, inhibitor of the MAO type B, Pathogenic genes: ANKK1, BDNF, LRRK2, PARK2 OPRM1genes: Metabolic Mechanism: Potent, irreversible inhibitor of the MAO type B, which plays methanesulfonate which plays a major role in catabolism of dopamine. Inhibition of Metabolicgenes: genes: BLC2, CCK, CCKAR, CCKBR, Mechanistic Substrate: COMT, CYP1A2 (major), CYP2B6, a majorFormula: role in catabolism of dopamine. Inhibition of dopamine depletion Molecular 13NCH 4O3S of brain reduces Substrate: COMT, CYP1A2 (major), CYP2B6, CYP2C19, CYP2D6, dopamine depletion C in12H striatal region DRD1, DRD2, DRD3, DRD4, DRD5, GRIN2A, in striatal region of brain reduces symptomatic motor deficits of CYP2C19, CYP2D6, CYP3A4, CYP3A5, DDC, CYP3A4, CYP3A5, DDC, MAOB, UGT1A1, UGT1A9 Molecular Weight: 267.34 g/mol symptomatic motor deficits Disease. There also Parkinson’s Disease. ThereofisParkinson’s also experimental evidence of is Rasagiline GRIN2B, HCRT, HOMER1, LMO3, OPRM1 MAOB, UGT1A1, UGT1A9 Inhibitor: MAOB Mechanism: Potent, irreversible inhibitor of theantiapoptotic), MAO type B,which may conferring neuroprotective effects (antioxidant, experimental evidence of Rasagiline conferring neuroprotective Metabolic genes: Transporter genes: SLC22A1, SLC6A3 Inhibitor: MAOB delay onset of symptoms and progression of neuronal deterioration. which plays a major role in catabolism of dopamine. effects (antioxidant, antiapoptotic), which may delay Inhibition onset of of Pleiotropic genes: ACE, APOE Substrate: COMT, CYP1A2 (major), CYP2B6, Transporter genes: SLC22A1, SLC6A3 Effect: Antidepressants. Monoamine oxidase inhibitors. Antiparkinsonian dopamine in striatal region of deterioration. brain reduces symptoms depletion and progression of neuronal CYP2C19, CYP2D6, CYP3A4, Agents. Monoamine oxidase B inhibitors. Pleiotropic genes: ACE, APOECYP3A5, DDC, symptomatic motor deficits of Parkinson’s Disease. There is also Effect: Antidepressants. Monoamine oxidase inhibitors. MAOB, UGT1A1, UGT1A9 experimental evidence of Rasagiline conferring neuroprotective Antiparkinsonian Agents. Monoamine oxidase B inhibitors. Inhibitor: MAOB effects (antioxidant, antiapoptotic), which may delay(COMT) onset ofInhibitors Catecol-O-methyltransferase Transporter genes: SLC22A1, SLC6A3 symptoms and progression of neuronal deterioration. Properties Pharmacogenetics Pleiotropic genes: ACE, APOE Effect: Antidepressants. Monoamine oxidase inhibitors. Antiparkinsonian Agents. Monoamine oxidase B inhibitors. Catecol-O-methyltransferase (COMT) Inhibitors Properties Pharmacogenetics

7 of 28

Int. J. Mol. Sci. 2017, 18, 551

9 of 30

Int. J. Mol. Sci. 2017, 18, 551

8 of 28

Pathogenic genes: ANKK1, BDNF, LRRK2, PARK2 Mechanistic genes: CCK, CCKAR, CCKBR, DRD1, Name: Entacapone; 130929-57-6; Comtan; Comtess; Entacapona. Table 1. Cont. DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B, 9 of 30 IUPAC Name: E-α-cyano-N,N-diethyl-3,4-dihydroxy-5Int. J. Mol. Sci. 2017, 18, 551 HCRT, HOMER1, LMO3, OPRM1 nitrocinnamamida CH Pathogenicgenes: genes: ANKK1, BDNF, LRRK2, PARK2 Molecular Formula: C14H15N3OCatecol-O-methyltransferase 5 Metabolic (COMT) Inhibitors CH Mechanistic genes: CCK, CCKAR, CCKBR, DRD1, Name: Entacapone; 130929-57-6; Molecular Weight: 305.29 g/mol Comtan; Substrate: COMT, CYP1A2, CYP2B6, Drug PropertiesComtess; Entacapona. Pharmacogenetics DRD2, DRD3, DRD4, DRD5, GRIN2A, IUPAC Name: Mechanism: A E-α-cyano-N,N-diethyl-3,4-dihydroxy-5selective and selective inhibitor of COMT. When CYP2C19, CYP2D6, CYP3A4, CYP3A5, GRIN2B, DDC, Pathogenic genes: ANKK1, BDNF, LRRK2, PARK2 HCRT, HOMER1, LMO3, nitrocinnamamida entacapona is taken with levodopa,Comtan; the pharmacokinetics are MAOB, UGT1A1, UGT1A3, UGT1A4, UGT1A6, CH Mechanistic genes: CCK,OPRM1 CCKAR, CCKBR, DRD1, DRD2, DRD3, Name: Entacapone; 130929-57-6; Comtess; Entacapona. Molecular Formula: C14H15sustained N3O5 Metabolic genes: GRIN2A, IUPAC Name: in E-α-cyano-N,N-diethyl-3,4-dihydroxy-5-nitrocinnamamida DRD4,UGT2B7, DRD5, GRIN2B, HCRT, HOMER1, LMO3, OPRM1 altered, resulting more levodopa serum levels UGT1A9, UGT2B15 CH Metabolic Molecular Formula: C14g/mol H15 N3 O5 Molecular Weight: 305.29 Substrate: COMT, CYP1A2 CYP1A2,(weak), CYP2B6, compared to levodopa Inhibitor:genes: COMT, CYP2A6 Substrate: COMT,CYP3A4, CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4, Molecular Weight: 305.29 g/mol Mechanism: CYP2C19, CYP2D6, CYP3A5, taken alone. A selective and selective inhibitor of COMT. When (weak), CYP2C9 (weak), CYP2C19 (weak),DDC, CYP2D6 Mechanism: A selective and selective inhibitor of COMT. When CYP3A5, DDC, MAOB, UGT1A1, UGT1A3, UGT1A4, UGT1A6, entacapona is taken with levodopa, the arealtered, (weak), MAOB, UGT1A1, UGT1A3, UGT1A4, Effect: Antiparkinsonian agents. Catechol-O-methyltransferase CYP2E1 (weak), CYP3A4 (weak)UGT1A6, entacapona is taken with levodopa, thepharmacokinetics pharmacokinetics are UGT1A9, UGT2B7, UGT2B15 altered, resulting in more sustained levodopa serum levels to levodopa UGT1A9, UGT2B7, UGT2B15 inhibitors. Transporter genes: SLC6A3 resulting in more sustained levodopa serum levels compared Inhibitor: COMT,SLC22A1, CYP1A2 (weak), CYP2A6 (weak), CYP2C9 (weak), taken alone. CYP2C19 (weak), CYP2D6 (weak), CYP2E1 (weak), CYP3A4 (weak) compared to levodopa Inhibitor: COMT, CYP1A2 (weak), CYP2A6 Pleiotropic genes: ACE, ACHE, APOE Transporter genes: SLC22A1, SLC6A3 Antiparkinsonian agents. Catechol-O-methyltransferase inhibitors. takenEffect: alone. (weak), CYP2C9 (weak), CYP2C19 (weak), CYP2D6 Name: Tolcapone; 134308-13-7; Tolcapona; Tasmar. Pathogenic genes: ANKK1, BDNF, LRRK2, PARK2 Pleiotropic genes: ACE, ACHE, APOE Effect: Antiparkinsonian agents. Catechol-O-methyltransferase (weak), CYP2E1 (weak), CYP3A4 IUPAC Name: Methanone, (3,4-hydroxy-5-nitrophenyl)(4Mechanistic genes: AKT1, CCK, (weak) CCKAR, CCKBR, Name: Tolcapone; 134308-13-7; Tolcapona; Tasmar. Pathogenic genes: ANKK1, LRRK2, inhibitors. Transporter genes: SLC22A1, SLC6A3 methylphenyl) CNR1, DRD1, DRD2, DRD3,BDNF, DRD4, DRD5,PARK2 GPT, IUPAC Name: Methanone, (3,4-hydroxy-5-nitrophenyl)(4-methylphenyl)Pleiotropic Mechanistic genes: AKT1, CCK,APOE CCKAR, CCKBR, CNR1, DRD1, genes: ACE, ACHE, Molecular Formula: C14H11NO5 GRIN2A, GRIN2B, GSK3B, HCRT, HOMER1, Molecular Formula: C14 H11 NO5 DRD2, DRD3, DRD4, DRD5, GPT, GRIN2A, GRIN2B, GSK3B, HCRT, Name: Tolcapone; 134308-13-7; Tolcapona; Tasmar. Pathogenic genes: ANKK1, LMO3, OPRM1 Molecular Weight: 273.24 g/mol Molecular Weight: 273.24 g/mol HOMER1, LMO3, OPRM1BDNF, LRRK2, PARK2 IUPAC Name: (3,4-hydroxy-5-nitrophenyl)(4Mechanistic genes: Metabolic genes: Mechanism: A Methanone, selective and selective of (COMT. (COMT.InInthethe Mechanism: A selective and selectiveinhibitor inhibitor of presence Metabolic genes: AKT1, CCK, CCKAR, CCKBR, of a decarboxylase inhibitor (e.g., carbidopa), COMT is the majoris Substrate: CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, methylphenyl) CNR1, DRD1,COMT, DRD2, DRD3, DRD4, DRD5, GPT, Substrate: COMT, CYP1A2, CYP2B6, CYP2C9, presence of a decarboxylase inhibitor (e.g., carbidopa), COMT degradation pathway levodopa. Inhibition of COMT leads to more GRIN2A, CYP3A4, CYP3A5, DDC, MAOB, UGT1A1, UGT1A3, UGT1A4, Molecular Formula: C14pathway GRIN2B, GSK3B, HCRT, HOMER1, Hfor 11NO5 for levodopa. Inhibition of COMT CYP2C19, CYP2D6, CYP3A4, CYP3A5, DDC, the major degradation sustained plasma levels of levodopa and enhanced central dopaminergic UGT1A6, UGT1A9, UGT2B7, UGT2B15 LMO3, OPRM1 Molecular Weight: 273.24plasma g/mol levels of levodopa and enhanced MAOB, UGT1A1, UGT1A3, UGT1A4, leadsactivity. to more sustained Transporter genes: SLC22A1, SLC6A3 UGT1A6, CH Metabolic genes: Mechanism: A selective andagents. selective inhibitor of (COMT. In the UGT1A9, UGT2B7, central dopaminergic activity. Effect: Antiparkinsonian Catechol-O-methyltransferase inhibitors. Pleiotropic genes:UGT2B15 ACE, APOE Substrate: COMT, CYP1A2, CYP2B6, CYP2C9, presence of a decarboxylase inhibitor (e.g., carbidopa), COMT is Transporter genes: SLC22A1, SLC6A3 Effect: Antiparkinsonian agents. Catechol-O-methyltransferase ABCB1: ATP binding cassette subfamily B member 1; ACE: Angiotensin I converting enzyme; ACHE: Acetylcholinesterase; ADCY7: Adenylate cyclase 7; ADRA1A: Adrenoceptor α1A; CYP2C19, CYP2D6, CYP3A4, the major degradation pathway for levodopa. Inhibition of COMT inhibitors. Pleiotropic genes: ACE, APOECYP3A5, DDC, ADRA1B: Adrenoceptor α1B; ADRA1D: Adrenoceptor α1D; ADRA2A: Adrenoceptor α2A; ADRA2B: Adrenoceptor α2B; ADRA2C: Adrenoceptor α2C; AKT1: v-Akt murine thymoma MAOB, UGT1A1, UGT1A3, UGT1A4, UGT1A6, to more sustained plasma levels Iofconverting levodopaenzyme; and enhanced ABCB1: ATP binding cassette leads subfamily member 1; ACE: Angiotensin ACHE: Acetylcholinesterase; ADCY7: Adenylate cyclase 7; ADRA1A: viral oncogene homolog 1; ANKK1: Ankyrin repeat Band kinase domain containing 1; APOE: Apolipoprotein E; BDNF: Brain-derived neurotrophic factor; BLC2: B-cell chronic lymphocytic CH UGT1A9, UGT2B7, UGT2B15 central dopaminergic Adrenoceptor α1A; ADRA1B: Adrenoceptor α1B; activity. ADRA1D: Adrenoceptor α1D; ADRA2A: Adrenoceptor α2A; ADRA2B: Adrenoceptor α2B; ADRA2C: leukemia (CLL)/lymphoma 2; CALY: Calcyon neuron specific vesicular protein; CCK: Cholecystokinin, CCKAR: Cholecystokinin A receptor; CCKBR: Cholecystokinin B receptor; Transporter genes: SLC22A1, SLC6A3 Effect: Antiparkinsonian agents. Catechol-O-methyltransferase Adrenoceptor AKT1: 5v-Akt murine thymoma viral oncogene homolog 1; ANKK1: AnkyrinCNR1: repeat and kinase domain containing 1; APOE: Apolipoprotein E; CCR5: C–C motif chemokineα2C; receptor (gene/pseudogene); CHAT: Choline O-acetyltransferase; Cannabinoid receptor 1 (brain); COMT: Catechol-O-methyltransferase; CREB1: inhibitors. genes: ACE, BDNF: Brain-derived BLC2: B-cell chronic lymphocytic receptor leukemia (CLL)/lymphoma 2; Pleiotropic CALY: Calcyon neuron specific vesicular CCK: cAMP responsive element bindingneurotrophic protein 1; factor; CXCR4: C–X–C motif chemokine 4; CYP1A1: Cytochrome P450 family 1APOE subfamily Aprotein; member 1; CYP1A2: Cytochrome P450 3

3

3

3

3

3

Cholecystokinin, CCKAR: Cholecystokinin A receptor; CCKBR: Cholecystokinin B receptor; CCR5: C–C motif chemokine receptor (gene/pseudogene); CHAT: ABCB1: ATP binding cassette subfamily B member ACE: Angiotensin I converting enzyme; ACHE: Acetylcholinesterase; cyclase ADRA1A: family 1 subfamily A member 2; CYP1B1: Cytochrome P4501; family 1 subfamily B member 1; CYP2A6: Cytochrome P450ADCY7: familyAdenylate 25 subfamily A 7; member 6; CYP2B6: Cytochrome P450 Choline O-acetyltransferase; CNR1: Cannabinoid receptor 1 (brain); COMT: Catechol-O-methyltransferase; CREB1: cAMP responsive element binding protein 1; Adrenoceptor α1A; ADRA1B: Adrenoceptor α1B; ADRA1D: ADRA2A: Adrenoceptor α2A; ADRA2B: Adrenoceptor α2B; ADRA2C: family 2 subfamily B member 6; CYP2C19: Cytochrome P450 family 2 Adrenoceptor subfamily Cα1D; member 19; CYP2C9: Cytochrome P450 family 2 subfamily C member 9; CYP2D6: Cytochrome CXCR4: C–X–C motif chemokine receptor 4; CYP1A1: Cytochrome P450 family 1 subfamily A member 1;and CYP1A2: Cytochrome P450 family subfamily AA member Adrenoceptor α2C; AKT1: murine thymoma viral oncogene 1; ANKK1: Ankyrin kinase domain containing 1; APOE: Apolipoprotein E; P450 family 2 subfamily D member 6; v-Akt CYP2E1: Cytochrome P450 familyhomolog 2 subfamily E member 1;repeat CYP3A4: Cytochrome P450 family 31 subfamily member 4; CYP3A5: Cytochrome 2; CYP1B1: family 1 Cytochrome subfamily B member 1; lymphocytic CYP2A6: Cytochrome P450 family1; 2 subfamily A Calcyon memberβ-hydroxylase; 6; CYP2B6: Cytochrome P450 family BDNF: Brain-derived neurotrophic factor; BLC2: B-cell chronic leukemiaA(CLL)/lymphoma 2; CALY: neuron specific vesicular protein; CCK:2 P450 family 3 subfamily ACytochrome member 5;P450 CYP19A1: P450 family 19 subfamily member DBH: Dopamine DDC: DOPA decarboxylase; DRD1: Dopamine receptor D1; DRD2: DopamineCCKAR: receptorCholecystokinin D2; DRD3: Dopamine D3; DRD4: Dopamine receptor D4; motif DRD5: Dopamine receptor D5; G6PD: Glucose-6-phosphate dehydrogenase; Cholecystokinin, A receptor;receptor CCKBR: Cholecystokinin B receptor; CCR5: C–C chemokine receptor 5 (gene/pseudogene); CHAT: GPT: Glutamic-pyruvate transaminase (alanine aminotransferase); GRIN2A: Glutamate ionotropic receptor N-methylD -aspartate (NMDA) type subunit 2A; GRIN2B: Glutamate Choline O-acetyltransferase; CNR1: Cannabinoid receptor 1 (brain); COMT: Catechol-O-methyltransferase; CREB1: cAMP responsive element binding protein 1; ionotropic receptor NMDA 2B;receptor GRIN3A: Glutamate ionotropic receptor NMDAAtype subunit 3A; GSK3B: Glycogen synthase kinase 3 beta; HCRT: Hypocretin (orexin) CXCR4: C–X–Ctype motifsubunit chemokine 4; CYP1A1: Cytochrome P450 family 1 subfamily member 1; CYP1A2: Cytochrome P450 family 1 subfamily A member neuropeptide precursor; scaffolding protein 1; HRH1: Histamine receptor H1; HTR1A: 5-Hydroxytryptamine receptor 1A; HTR1B: 5-Hydroxytryptamine receptor 1B; 2; CYP1B1:HOMER1: CytochromeHomer P450 family 1 subfamily B member 1; CYP2A6: Cytochrome P450 family 2 subfamily A member 6; CYP2B6: Cytochrome P450 family 2 HTR1D: 5-Hydroxytryptamine receptor 1D; HTR2A: 5-Hydroxytryptamine receptor 2A; HTR2B: 5-Hydroxytryptamine receptor 2B; HTR2C: 5-Hydroxytryptamine receptor 2C; HTR7: 5-Hydroxytryptamine receptor 7; LMO3: LIM domain only 3; LRRK2: Leucine-rich repeat kinase 2; MAOA: Monoamine oxidase A; MAOB: Monoamine oxidase B; OPRM1: Opioid receptor mu 1; PAH: phenylalanine hydroxylase; PARK2: Parkin RBR E3 ubiquitin protein ligase; SLC22A1: Solute carrier family 22 member 1; SLC6A3: Solute carrier family 6 member 3; SLC6A4: Solute carrier family 6 member 4; SST: Somatostatin; TH: Tyrosine hydroxylase; TSPO: Translocator protein; UGT1A1: UDP glucuronosyltransferase family 1 member A1; UGT1A3: UDP glucuronosyltransferase family 1 member A3; UGT1A4: UDP glucuronosyltransferase family 1 member A4; UGT1A6: UDP glucuronosyltransferase family 1 member A6; UGT1A9: UDP glucuronosyltransferase family 1 member A9; UGT2B7: UDP glucuronosyltransferase family 2 member B7; UGT2B15: UDP glucuronosyltransferase family 2 member B15. (Source: R. Cacabelos et al., [17,19]). IUPAC: International Union of Pure and Applied Chemistry.

Int. J. Mol. Sci. 2017, 18, 551

9 of 28

2. Pathogenic Mechanisms As in other prevalent age-related neurodegenerative disorders, it is plausible that the confluence of genomic vulnerability with diverse environmental factors may be responsible for the growing impact of PD in our society. Parkinson’s disease-related neurodegeneration is likely to occur several decades before the onset of the motor symptoms [20]. Associated with different potentially pathogenic risk factors (toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, genomic defects), PD neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta and Lewy body deposition, with widespread involvement of other CNS structures and peripheral tissues [21–23]. Parkinson’s disease is a form of multisystemic α-synucleinopathy with Lewy bodies deposited in the midbrain. Descriptive phenomena to explain in part this neuropathological phenotype include the following: (i) genomic factors; (ii) epigenetic changes; (iii) toxic factors; (iv) oxidative stress anomalies; (v) neuroimmune/neuroinflammatory reactions; (vi) hypoxic-ischemic conditions; (vii) metabolic deficiencies; and (viii) ubiquitin–proteasome system dysfunction [19,23–29]; all these conditions leading to protein misfolding and aggregation and premature neuronal death. Recent evidence also suggests that PD might be a prion-like disease [30]. Telomere shortening as a result of the inability to fully replicate the ends of linear chromosomes is one of the hallmarks of aging which might also contribute to PD pathology [31]. Mutations in a series of primary genes are known to cause autosomal dominant and recessive forms of PD [28–38]. Mutations in some genes—e.g., α-Synuclein (SNCA), Parkin 2 (PARK2), PTEN-induced putative kinase 1 (PINK1), PARK7, Leucine-rich repeat kinase 2 (LRRK2), Bone narrow stromal cell antigen 1 (BST1), Microtubule-associated protein tau (MAPT)—might be causative in familial forms of PD whereas diverse genetic defects in other loci might represent susceptibility loci associated with sporadic PD without family history [28,34–39]. Mendelian variants with high penetrance (e.g., SNCA, LRRK2, PINK1, PARK7 genes) explain less than 10% of familial PD [40]. For the past decade several genome-wide association studies (GWAS) have contributed to clarify the contribution of genetic factors to the pathogenesis of PD in the Caucasian population and in other ethnic groups [41–51]. In a recent meta-analysis of PD GWAS with over 7 million variants, 26 loci have shown significant association with PD. Replication studies confirmed 24 single nucleotide polymorphisms (SNPs), and conditional analyses within loci showed four loci —β-Glucocerebrosidase (GBA); Diacylglycerol kinase θ, 110kD (GAK-DGKQ); SNCA; Human leukocyte antigen (HLA)—with a secondary independent risk variant [52]. Significant associations at different loci—Discs large homolog of 2 (DLG2), Sipa1-like protein (SIPA1L2), Serine/Theonine kinase 39 (STK39), Vacuolar protein sorting 13 homolog C (VPS13C), Ric-like protein without CAAX motif 2 (RIT2), BST1, PARK16—have been found in Asians vs. Europeans, together with allelic heterogeneity at LRRK2 and at six other loci including MAPT and GBA-SYT11 [50]. Some other candidate genes have been recently reported to be associated with PD in different cohorts (i.e., RAD51B [39], DYRK1A [53], CHCHD2 [54], VPS35 [55], RAB39B [56], TMEM230 [57]). In addition to the mutations of primary genes responsible for PD-related synucleopathy, most defective loci identified so far are linked to pathogenic pathways leading to premature neurodegeneration in PD [51]. α-Synuclein accumulation, mitochondrial dysfunction, autophagic impairment, and oxidative and endoplasmic reticulum stress are common findings in the PD pathogenic cascade. The SNCA (α-synuclein) gene encodes a presynaptic protein that tends to misfold and is subsequently found to be a major component of Lewy bodies, a histological hallmark of the PD brain. Point mutations in the SNCA gene cause rare familial forms of PD. Duplication/triplication of the wild type SNCA gene also causes a form of PD, indicating that increased levels of the normal α-synuclein protein are sufficient to cause the disease. Several SNPs in the SNCA gene are associated with an increased risk of developing sporadic PD. A GWAS has identified a novel SNP rs356182 at SNCA that can modulate the risk of PD in Caucasian ancestry and in the Chinese population [58]. Glucocerebrosidase 1 (GBA1) mutations, resulting in misfolded glucocerebrosidase (GCase), affect the functioning of endoplasmic reticulum (ER), lysosomes, and mitochondria. Misfolded

Int. J. Mol. Sci. 2017, 18, 551

10 of 28

GCase trapped in the ER leads to an increase in both the ubiquitin–proteasome system (UPS) and the ER stress. The presence of ER stress triggers the unfolded protein response (UPR) and/or ER-associated degradation, with subsequent increase in apoptosis. The presence of misfolded GCase in the lysosomes together with a reduction in wild type GCase levels leads to a retardation of α-synuclein degradation via chaperone-mediated autophagy, which results in α-synuclein accumulation and aggregation. Impaired lysosomal functioning also causes a decrease in the clearance of autophagosomes, and accumulation of this cellular detritus. GBA1 mutations perturb normal mitochondria functioning by increasing the generation of free radical species (ROS) and decreasing ATP production, oxygen consumption, and membrane potential [59]. Furthermore, heterozygous GBA1 mutations alter the lysosomal enzyme that converts glucosyl-ceramides into ceramide, and increase the risk of developing PD [60]. Defects in ceramide metabolism have been recognized in PD. Altered sphingolipid composition in Lrrk2−/− mouse brains has been observed in lipidomic studies. Ceramide levels are increased in Lrrk2−/− mice with effects on GBA1 [60]. Oxidative stress plays a central role in the progress of PD (i) affecting nucleic acid stability by oxidizing RNA, increasing mitochondrial DNA (mtDNA) mutation, and launching translesion synthesis (TLS); (ii) disturbing protein homeostasis by accelerating α-synuclein aggregation, parkin aggregation, and proteasome dissociation; (iii) modulating dopamine release by activating ATP-sensitive potassium channels (KATP ) and inactivating neuronal nicotinic acetylcholine receptors (nAChRs); and (iv) influencing cellular self-defenses by promoting the cytoprotective effects of oncogene DJ1(DJ-1) and phosphatase and tensin homolog PINK1 while inducing Akt dysregulation [53,61,62]. Elevated levels of oxidative or nitrative stresses have been implicated in α-synuclein-related toxicity. Phosphorylation of α-synuclein on serine 129 (S129) modulates autophagic clearance of inclusions and is prominently found in Lewy bodies [63]. Mutations in the LRRK2 gene associated with PD also cause autophagy dysregulation [64]. Some studies delineating the pathways involved in parkin/PINK1-mediated mitophagy also contributed to the renaissance of the “mitochondrial theory of PD” [65,66]. Dysfunction of the mitochondria caused by bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations linked to mitochondria, and changes in dynamics of the mitochondria such as fusion or fission, changes in size and morphology, alterations in trafficking or transport, altered movement of mitochondria, impairment of transcription, and the presence of mutated proteins associated with mitochondria are implicated in PD [66]. The “proteasome theory of PD” is based on the fact that several genes with polymorphic variants associated with different forms of PD encode proteins which are integrated in the machinery of the proteasome system. Parkin is a unique, multifunctional ubiquitin ligase whose various roles in the cell, particularly in neurons, are widely thought to be protective. Parkin dysfunction represents a predominant cause of familial parkinsonism and also a formal risk factor for the sporadic form of PD. Parkin exerts housekeeping protein quality control roles, and regulates mitochondrial homeostasis and stress-related signaling. Parkin functions as an E2-dependent ubiquitin ligase associated with the UPS, a major intracellular protein degradation machinery. Parkin is also a key mammalian regulator of mitochondrial autophagy (mitophagy). Neurodegeneration in PD patients harboring homozygous loss-of-function mutations in the PARK2 gene may result from unbalanced levels of ROS, which are mostly produced in mitochondria and can irreparably damage macromolecules and trigger apoptosis [67]. Mutations in genes encoding proteins that interact with parkin in the UPS may also contribute to PD. Mutations in PINK1 cause early onset familial PD. PINK1 accumulates on the outer membrane of damaged mitochondria followed by recruiting parkin to promote mitophagy [65]. Mutations in the FBX07 (F-box protein 7) gene, encoding an adaptor protein in Skp–Cullin–F-box (SCF) SCF(FBXO7) ubiquitin E3 ligase complex, to recognize substrates and mediate substrate ubiquitination by SCF(FBXO7) E3 ligase, are also associated with PD. Parkinson’s disease-linked FBXO7 can recruit parkin into damaged mitochondria and facilitate its aggregation [68]. Point mutations within FBXO7 map within specific functional domains, including near its F-box domain and its substrate recruiting domains, suggesting that deficiencies in SCFFbxo7/PARK15 ubiquitin ligase activity are mechanistically

Int. J. Mol. Sci. 2017, 18, 551

11 of 28

linked to early-onset PD. FBXO7 negatively regulates glycogen synthase kinase 3 β (GSK3β) activity. FBXO7 ubiquitinates translocase of outer mitochondrial membrane 20 (Tomm20), and its levels correlate with Fbxo7 expression, indicating a stabilizing effect [69]. DJ-1, the product of the causative gene of a familial form of PD, plays a significant role in anti-oxidative defense to protect cells from oxidative stress. DJ-1 undergoes preferential oxidation at the cysteine residue at position 106 (Cys106) under oxidative stress. oxDJ-1 is transformed into dimer and polymer forms that interact with 20S proteasome [70]. Proteasome subunits (PSMB) and transporter associated with antigen processing (TAP) loci located in the HLA class II region play important roles in immune response and protein degradation in neurodegenerative diseases. Immune dysregulation, which was associated with the major histocompatibility complex (MHC) class I pathway, may be involved in PD pathogenesis. Proteasome subunits and TAP genes are responsible for immune activity and protein degradation in MHC class I pathway. The classical MHC class molecules, HLA-DRB, represent the antigens for immune effector cells associated with PD. The PSMB and TAP genes are adjacent to HLA-DR within the HLA class II region. PSMB9 and PSMB8 encode β1i (low molecular weight protein 2) and β2i (low molecular weight protein 7) subunits of immunoproteasome, and replace the proteasome subunits in the ubiquitin–proteasome system as “immune” subunits. PSMB and TAP genes may be involved in α-synuclein degradation with more genetic susceptibility to PD by regulation of immunoproteasome in dopaminergic neurons [71]. Defects in genes responsible for pesticide metabolism (PON1), transport across the blood–brain barrier (ABCB1), pesticides interfering with or depending on dopamine transporter activity (DAT/SLC6A3) and dopamine metabolism (ALDH2), impacting mitochondrial function via oxidative/nitrosative stress (NOS1) or proteasome inhibition (SKP1), and contributing to immune dysregulation (HLA-DR), may also represent additional risk factors for PD [22]. Parkinson’s disease-related pathogenic and susceptibility genes are under the influence of the epigenetic machinery (DNA methylation, chromatin remodeling, histone modifications, miRNA regulation) that regulates their expression in different tissues and may contribute to selective nigrostriatal dopaminergic neurodegeneration. Epigenetic changes in PD-related genes also contribute to PD pathogenesis and epigenetic drugs might constitute a potential therapeutic option in the future [26,34,35,72–77]. 3. Conventional Treatments Classical therapeutic interventions for the symptomatic treatment of psychomotor dysfunction in PD include pharmacotherapy, deep brain stimulation, and physiotherapy [78]. In addition to dopamine precursors (L-DOPA), other symptomatic treatments for PD include dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone) [9,15,17,19] (Table 1). The initial complication of long-term L-DOPA therapy is the “wearing-off” phenomenon [79,80], together with motor fluctuations and dyskinesia, which develop during the use of both L-DOPA and dopamine agonists [15,81]. Diverse dopaminergic and nondopaminergic pharmacological approaches have been developed to manage such complications, including novel L-DOPA formulations, COMT inhibitors (opicapone), dopamine agonists, adenosine A2A antagonists (istradefylline, preladenant, tozadenant), glutamatergic N-methyl-D-aspartate (NMDA) antagonists, serotonergic agents (eltoprazine), and metabotropic glutamate receptor 5 (mGluR5) modulators (mavoglurant), with controversial results [82,83]. Polypharmacy with antidepressants, antipsychotics, urological drugs, analgesics, antihistaminics and cholinesterase inhibitors also contributes to severe complications associated with the anticholinergic burden in PD [84]. Furthermore, gastrointestinal complications (constipation, sialorrhea, dysphagia, difficulty in mastication, choking/aspiration) [85,86], cardiovascular problems [87,88], neuroendocrine changes and psychiatric disorders are frequent in PD patients chronically treated with conventional

Int. J. Mol. Sci. 2017, 18, 551

12 of 28

antiparkinsonian drugs [9,85]. An additional complication is the Pisa syndrome, defined as a reversible lateral bending of the trunk with a tendency to lean to one side [89]. It is common to administer atypical neuroleptics (e.g., quetiapine) when PD patients develop psychotic symptoms. This pharmacological intervention should be avoided due to the fact that most neuroleptics display an antidopaminergic effect which may neutralize or reduce the pharmacological action of antiparkinsonian drugs, contributing to additional psychomotor deficits. 4. Pharmacogenomics Pharmacogenomics accounts for 60%–90% variability in the pharmacokinetics and pharmacodynamics of antiparkinsonian drugs. Genes involved in the pharmacogenetic network include pathogenic, mechanistic, metabolic, transporter and pleiotropic genes [9–14] (Table 1), and all these genes are also under the influence of epigenetic modifications (DNA methylation, histone/chromatin remodeling, mRNA regulation) [12–14]. In recent years novel evidence has demonstrated the impact of pharmacogenetics on antiparkinsonian drug efficacy and safety [9,17,90–93] (Table 1). In the particular case of L-DOPA, the ANKK1, BDNF, LRRK2, and PARK2 genes are pathogenic genes potentially involved in its effects. The CCK, CCKAR, CCKBR, DRD1, DRD2, DRD3, DRD4, DRD5, GRIN2A, GRIN2B, HCRT, HOMER1, LMO3, and OPRM1 genes are mechanistic genes whose products influence L-DOPA efficacy and safety. L-DOPA is a substrate of enzymes encoded by the COMT, CYP1A2, CYP2B6, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DBH, DDC, G6PD, MAOB, TH, UGT1A1, and UGT1A9 genes responsible for its metabolism. Solute carrier family 6 member 3 (SLC6A3) is the major transporter of L-DOPA and ACE, ACHE and APOE are pleiotropic players in L-DOPA efficacy and safety [9] (Table 1). ADORA2A SNPs and HOMER1 variants may be associated with L-DOPA-induced dyskinesia and psychotic symptoms [94,95]. A haplotype integrating −141C Ins/Del, rs2283265, rs1076560, C957T, TaqIA and rs2734849 polymorphisms at the DRD2/ANKK1 gene region might also be associated with L-DOPA-induced motor dysfunction [96]. SLC6A3 is a genetic modifier of the treatment response to L-DOPA in PD [97]. The multidrug resistance gene (MDR1) C1236T polymorphism may also influence PD pharmacotherapy [98] as well as SNPs in genes encoding the dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2) [99]. Consequently, the personalized treatment of PD patients requires the implementation of pharmacogenetic procedures in order to optimize therapeutics (improving efficacy and safety) [9]. 5. Novel Treatments The unsatisfactory effects of conventional antiparkinsonian drugs have prompted the search for novel alternatives. Some attempts have been made with novel compounds (alternative and complementary medicines) for PD in recent times [17–19,100,101]. The revival of some classic and novel natural products (i.e., Vicia faba, Mucuna pruriens, Siegesbeckia pubescens, Sophora flavescens, Carthamus tinctorius, Curcuma longa, Huperzia selago, Diphasiastrum complanatum, Erythrina velutina, Gynostemma pentaphyllum, Echinacoside, Centella asiatica, Sulforaphane, Oleuropein, flavonoids, Ginsenosides, cyanidin-3-O-glucoside, caffeine, Resveratrol, and other polyphenols) has also been proposed; and new applications have been submitted to the USA and European Patent Offices in this regard. Some of these natural products with potential efficacy in PD show selective dopaminergic neuroprotection to prevent neuronal death, with additional benefits such as antioxidant, anti-inflammatory, and neurotrophic effects. An example of this is E-PodoFavalin-15999 (Atremorine), a novel biopharmaceutical compound, obtained by means of non-denaturing biotechnological procedures from structural components of Vicia faba L., for the prevention and treatment of PD [17–19,101,102]. Preclinical studies (in vitro) revealed that Atremorine is a powerful neuroprotectant in (i) cell cultures of human neuroblastoma SH-SY5Y cells; (ii) hippocampal slices in conditions of oxygen and glucose deprivation; and (iii) striatal slices under conditions of neurotoxicity induced by 6-hydroxydopamine (6-OHDA). In vivo studies showed that Atremorine (i) protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Int. J. Mol. Sci. 2017, 18, 551

13 of 28

(MPTP)-induced dopaminergic neurodegeneration; (ii) inhibits MPTP-induced microglia activation and neurotoxicity in the substantia nigra; and (iii) improves motor function in mice with MPTP-induced neurodegeneration [17–19,101,102] (Figure 1). Int. J. Mol. Sci. 2017, 18, 551

15 of 30

Figure 1. Effect of Atremorine (AT) treatment against dopaminergic degeneration. Comparative

Figure 1. Effect of Atremorine (AT) treatment against dopaminergic degeneration. Comparative photomicrographs of tyrosine hydroxylase (TH) immunoreactivity were taken in the substantia nigra photomicrographs of tyrosine hydroxylase (TH) immunoreactivity were taken in the substantia (SN) of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, nigrauntreated (SN) of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced (E) and treated with L-DOPA (C,D) or Atremorine (A,B). Note the remarkableneurotoxicity, effect of untreated (E) and treated with L-DOPA (C,D) effect or Atremorine (A,B). Note the neurons. remarkable Atremorine (A,B) in reversing the neurotoxic of MPTP on dopaminergic (A–F)effect Atremorine; (A,B) (J–L) Atremorine + L-DOPA; (M–O) Untreated; Controlon + Atremorine. Scale neurons. bar: of Atremorine in reversing the neurotoxic effect (P–R) of MPTP dopaminergic µm. Adapted withAtremorine permission from Carrera et (M–O) al. [101]. Untreated; (P–R) Control + Atremorine. (A–F)100 Atremorine; (J–L) + L-DOPA; Scale bar: 100 µm. Adapted with permission from Carrera et al. [101].

Int. J. Mol. Sci. 2017, 18, 551 Int. J. Mol. Sci. 2017, 18, 551

14 of 28 16 of 30

Clinical studies ininuntreated untreatedpatients patients who receive Atremorine forfirst thetime first(never time treated (never Clinical studies who receive Atremorine for the treated before with antiparkinsonian drugs) revealed that Atremorine enhances dopaminergic before with antiparkinsonian drugs) revealed that Atremorine enhances dopaminergic neurotransmission andincreases increases plasma dopamine by 200–500-fold [17]2).(Figure 2). neurotransmission and plasma dopamine levelslevels by 200–500-fold [17] (Figure In patients In patients chronically with -DOPA or other antiparkinsonian drugs, Atremorine induces chronically treated withtreated L-DOPA or Lother antiparkinsonian drugs, Atremorine induces a dopamine aresponse dopamine similar magnitude to that observed in previously untreated patients. of response similar of magnitude to that observed in previously untreated patients. This This pro-dopaminergic attributed richcontent contentofof natural natural L-DOPA (average pro-dopaminergic effecteffect can can be be attributed to to thetherich (average concentration the composition composition of Atremorine. However, the neuroprotective concentration20 20mg/g) mg/g) in the neuroprotective effect effect of of this this nutraceutical nutraceutical product on dopaminergic dopaminergic neurons, as demonstrated in in vitro vitro studies studies and and in in animal animal models models of of PD PD [17,101,102], [17,101,102], cannot cannot be be attributed attributed to to LL-DOPA -DOPA alone, alone, but but to to other other intrinsic intrinsic constituents constituents (selective (selective neurotrophic neurotrophicfactors) factors)of ofthe the compound compound [17]. [17]. One One hundred hundred percent percent ofUntreated ofUntreated PD PD patients patients exhibit dramatic hypodopaminemia, hypodopaminemia,with withplasma plasmalevels levels dopamine (DA) below 20 pg/mL, exhibit a dramatic of of dopamine (DA) below 20 pg/mL, and and PD patients under long-term treatment L -DOPA and/or conventional antiparkinsonian PD patients under long-term treatment with with L-DOPA and/or conventional antiparkinsonian drugs drugs experience a hyperdopaminemic status which might be responsible for (i)improvement the clinical experience a hyperdopaminemic status which might be responsible for (i) the clinical improvement PD cardinal in the(ii) short (ii) the “wearing-off” phenomenon of PD cardinalofsymptoms insymptoms the short term; theterm; “wearing-off” phenomenon [79,80]; (iii)[79,80]; motor (iii) motor fluctuations and dyskinesia systemic complications(gastrointestinal (gastrointestinal disorders, fluctuations and dyskinesia [15,81];[15,81]; (iv) (iv) systemic complications cardiovascular cardiovascular problems, problems, hormonal hormonal dysregulation) dysregulation) [85–87]; [85–87]; and (v) (v) neuropsychiatric neuropsychiatric disorders disorders (depression, (depression, anxiety, anxiety,toxic toxicpsychosis) psychosis)[9,103]. [9,103].

Figure 2.2.Atremorine-induced Atremorine-induceddopamine dopamine (DA) response in patients Parkinsonian disorders. Figure (DA) response in patients with with Parkinsonian disorders. DAb: DAb: Basal dopamine levels; DAt: Plasma dopamine levels one hour after Atremorine administration Basal dopamine levels; DAt: Plasma dopamine levels one hour after Atremorine administration (5 g, (5 g, p.o.). Adapted with permission Cacabelos et al. [18]. p.o.). Adapted with permission from from Cacabelos et al. [18].

Atremorine is an option to minimize the “wearing-off” phenomenon, extending the therapeutic Atremorine is an option to minimize the “wearing-off” phenomenon, extending the therapeutic effect of conventional antiparkinsonian drugs, and reducing potential side effects, since the effect of conventional antiparkinsonian drugs, and reducing potential side effects, since the co-administration of Atremorine with other antiparkinsonian drugs allows a dose reduction of co-administration of Atremorine with other antiparkinsonian drugs allows a dose reduction of conventional drugs by 25%–50% with enhancement of clinical benefits and reduction of short- and conventional drugs by 25%–50% with enhancement of clinical benefits and reduction of short- and long-term adverse drug reactions [19]. long-term adverse drug reactions [19]. Atremorine is a powerful enhancer of plasma catecholamines (noradrenaline, adrenaline, Atremorine is a powerful enhancer of plasma catecholamines (noradrenaline, adrenaline, dopamine), with no apparent effect on serotonin [18]. Catecholamines are processed by three main dopamine), with no apparent effect on serotonin [18]. Catecholamines are processed by three main nuclei (A8-retrobulbal, A9-substantia nigra pars compacta, A10-ventral tegmental area) arranged in nuclei (A8-retrobulbal, A9-substantia nigra pars compacta, A10-ventral tegmental area) arranged the mesencephalic region where the mesostriatal, mesolimbic and mesocortical pathways are organized [104,105]. Midbrain dopaminergic neurons in the ventral tegmental area and

Int. J. Mol. Sci. 2017, 18, 551

15 of 28

in the mesencephalic region where the mesostriatal, mesolimbic and mesocortical pathways are organized [104,105]. Midbrain dopaminergic neurons in the ventral tegmental area and noradrenergic neurons in the locus coeruleus are major sources of dopamine and noradrenaline to the prefrontal cortex, where these amines regulate cognition, behavior, and psychomotor function [106,107]. Noradrenaline, adrenaline, dopamine and serotonin play a central role in CNS and gut pathophysiology. Dopamine and noradrenaline are involved in the chemical structure of neuromelanins in the substantia nigra and the locus coeruleus, respectively. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), 3,4-dihydroxyphenylethanol (DOPE), and 3,4-dihydroxyphenylalanine (DOPA) are mainly responsible for the structure of neuromelanin from substantia nigra, while noradrenaline, 3,4-dihydroxymandelic acid (DOMA), and 3,4-dihydroxyphenylethylene glycol (DOPEG) are responsible for the structure of neuromelanin from locus coeruleus [108]. Deficiencies in these monoamines are currently found in PD [109,110]. Monoamine transporters (MATs) that facilitate the reuptake of noradrenaline, dopamine, and serotonin are sodium-coupled transport proteins belonging to the neurotransmitter/Na+ symporter (NSS) family, which have also been implicated in PD [111,112]. Hypoactivity of the dopaminergic and noradrenergic systems in the brain stem are related to non-motor and motor symptoms in PD [113,114]. Dysregulation of these neurotransmitters is also involved in a variety of gastrointestinal symptoms in PD [115], and all of them appear to contribute to neurotransmitter and autonomic dysfunctions in PD [113], including mechanisms of L-DOPA-induced dyskinesia [115,116] and cardiovascular dysautonomia [117]. Therefore, appropriate doses of Atremorine alone or in combination with low doses of conventional antiparkinsonian drugs [118] may benefit PD patients in whom the biosynthetic apparatus of the catecholaminergic system is damaged, including tyrosine hydroxylase (TH), the tetrahydrobiopterin (BH4) cofactor of TH, and the activity of the BH4-synthesizing enzyme, GTP cyclohydrolase I (GCHI), as well as the activities of aromatic L-amino acid decarboxylase (AADC, DOPA decarboxylase), DBH, and phenylethanolamine N-methyltransferase (PNMT), which synthesize dopamine, noradrenaline, and adrenaline, respectively [119]. Atremorine may also neutralize the apoptosis of nigrostriatal dopamine neurons which, in post-mortem studies, show increased levels of pro-inflammatory cytokines—tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)—, increased levels of apoptosis-related factors—p 55, soluble Fas, B-cell lymphoma 2 (Bcl-2), caspases 1-2—, and decreased levels of neurotrophins (BDNF) [119]. The increase in noradrenaline induced by Atremorine may contribute to clinical improvement and neuroprotection, since noradrenergic neuronal loss in the locus coeruleus is exacerbated in PD. Lewy pathology in the locus coeruleus, the brain’s main source of noradrenaline, precedes that of the substantia nigra and may be one of the very first pathogenic events in PD. Oxidized noradrenaline exerts a neuroprotective effect and may even prevent the formation of toxic and higher molecular weight α-synuclein oligomers associated with PD. Noradrenergic neurons innervate the substantia nigra. The locus coeruleus orchestrates the other major catecholaminergic nuclei, such as the substantia nigra and raphe nuclei. In this regard, it has been suggested that neuronal loss in the locus coeruleus and the accompanying noradrenergic deficiency constitute an important pharmacological target for the treatment of PD [120]. Noradrenaline exerts critical effects in the modulation of different types of behavior (sleep-wakefulness cycle, depression, anxiety), psychomotor function, anti-inflammatory responses in glial cells, neurotrophic activity, and neuroprotection against oxidative stress-related free radical formation [121,122]. Preclinical studies showed that Atremorine displays powerful antioxidant, anti-inflammatory, and neuroprotective effects [102], some of which might be associated with its effect as a noradrenergic enhancer. Since premature noradrenaline deficiency resulting from selective degeneration of neurons of the locus coeruleus and sympathetic ganglia may be a praecox event in PD [123,124], the noradrenergic effects of Atremorine may also explain, in part, its clinical and biochemical benefits [17,18].

Int. J. Mol. Sci. 2017, 18, 551

16 of 28

The midbrain dopaminergic system is regulated by the central adrenergic system [125]. The moderate increase in adrenaline levels observed after Atremorine administration may also contribute to enhancing dopaminergic neurotransmission in PD [18]. Neuroendocrine dysfunction and alterations in circadian rhythms are frequently seen in patients with PD, but most results are contradictory, with no clear definition between basal conditions and drug-induced modifications in hypothalamus-pituitary neuropeptides and hormones [126–128]. Furthermore, prolactin and growth hormone (GH) secretion are directly regulated by hypothalamic and supra-hypothalamic dopaminergic mechanisms [129–131]. Some studies reported higher levels of prolactin and GH in PD patients as compared with controls [128,132]. In patients with multiple system atrophy, in whom there is a reported loss of hypothalamic dopamine, basal prolactin levels are elevated, L-DOPA increases GH secretion, and the neuroendocrine response to L-DOPA is unclear [133], differing from endocrine responses in PD patients [134,135]. 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a BH4 deficiency with hyperphenylalaninemia, which is treated with L-DOPA/Carbidopa, 5-hydroxytryptophan (5-HTP) and BH4. In these patients, serum prolactin levels are elevated due to their hypodopaminergic condition, and the administration of L-DOPA reduces prolactin secretion [136]. In healthy subjects, acute L-DOPA and exercise release GH, but in PD patients this response is delayed [137]. In animal studies, L-DOPA causes a decrease in prolactin response, whereas cortisol levels tend to increase [138]. It has also been postulated that peripheral noradrenergic terminals may contribute to regulating prolactin secretion [139]. Atremorine induces a significant decrease in prolactin, GH, and cortisol levels [18]. The prolactin and GH response to Atremorine can be directly attributed to the effect of L-DOPA on dopamine and noradrenaline synthesis and release, with the consequent increase in central and peripheral dopamine and noradrenaline levels. In contrast, the effect on cortisol might be primarily influenced by a direct effect of dopamine, noradrenaline and adrenaline on the adrenal gland, and secondarily by pituitary and/or hypothalamic regulation of adrenocorticotropic hormone (ACTH), which in plasma did not show any significant changes. Neuroendocrine function in PD is still poorly understood, and the investigation of differences in PD-related basal neuroendocrine conditions vs antiparkinsonian drug-induced neuroendocrine changes deserves further studies. Other non-motor symptoms present in PD, such as constipation and other alterations in gastrointestinal motility mediated via catecholaminergic mechanisms [80,140], might also be alleviated by Atremorine. However, further investigation is needed on the central and peripheral effects of Atremorine, especially taking into account that the effects of Atremorine are genotype-related, involving both pathogenic genes associated with neurodegeneration, and genes of the cytochrome P450 family associated with drug metabolism [17,19]. All these data together clearly indicate that Atremorine is a very safe bioproduct in PD, with a powerful effect on catecholamines, especially dopamine and, to a lesser extent, noradrenaline. The effect of Atremorine on adrenaline is very modest, and no effect on serotonin levels can be detected one hour after oral administration. The effect of Atremorine on prolactin and GH is likely to result from the primary consequence of hypothalamic regulation mediated via dopaminergic and noradrenergic neurotransmission, and secondarily as a direct effect on the pituitary gland. In contrast, the effect on cortisol might result primarily from a direct effect on the adrenal gland, and secondarily from the hypothalamus–hypophyseal regulation of ACTH. According to these results, Atremorine may help to optimize neuroendocrine function in PD, especially in those patients with somatotropinergic, lactotropinergic and corticotropinergic dysregulation. The effects of Atremorine on plasma catecholamines might also be beneficial for PD patients with cardiovascular dysautonomia. However, although the dopaminergic surge induced by Atremorine is proportional to basal DA levels in PD patients, with a potential 200–500-fold increase over basal levels, its real potency and pharmacodynamic and pharmacokinetic properties are highly influenced by genetic and pharmacogenetic factors [17] (Figures 3–6). The condition of extensive (EM), intermediate (IM), poor (PM) or ultra-rapid metabolizer (UM) associated with different CYP variants, and the inheritance

Int. J. Mol. Sci. 2017, 18, 551

17 of 28

of the APOE-4 allele as well, influence the Atremorine-induced dopamine response in PD patients [17]. Although practically 100% of the patients respond to Atremorine, the magnitude of the response is modulated by the pharmacogenetic profile of each patient. For instance, in absolute values, CYP2D6-PMs exhibit the lowest basal dopamine levels and a response to Atremorine which is lower than that of CYP2D6-EMs or IMs; however, CYP2D6-UMs show the highest basal dopamine levels and the most spectacular response to Atremorine [17] (Figure 3). The three major CYP2C19 genophenotypes J. Mol. Sci. 2017, 18, 551 19 of 30 show aInt. similar response to Atremorine (Figure 4); in contrast, comparatively, CYP2C9-IMs (Figure 5) and CYP3A4/5-IMs (Figure 6) are the best responders and CYP2C9-PMs and CYP3A4/5-RMs are CYP2C9-IMs (Figure 5) and CYP3A4/5-IMs (Figure 6) are the best responders and CYP2C9-PMs and the worst respondersare to the Atremorine, though genophenotypes with a respond significant in CYP3A4/5-RMs worst responders to all Atremorine, though allrespond genophenotypes withsurge a dopamine levels one hour after Atremorine administration (5 g, p.o.) [17]. significant surge in dopamine levels one hour after Atremorine administration (5 g, p.o.) [17].

Figure 3. CYP2D6-related Atremorine-induced dopamine response. Basal (DAb) and Atremorine-

Figure 3. CYP2D6-related Atremorine-induced dopamine response. Basal (DAb) and Atremorineinduced dopamine response (DAt) in CYP2D6 extensive (EM), intermediate (IM), poor (PM), and induced dopamine response (DAt) in CYP2D6 extensive (EM), intermediate (IM), poor (PM), ultra-rapid metabolizers (UM). Adapted with permission from Cacabelos et al. [17]. and ultra-rapid metabolizers (UM). Adapted with permission from Cacabelos et al. [17].

Int. J. Mol. Sci. 2017, 18, 551 Int. J. Mol. Sci. 2017, 18, 551

18 of 28 20 of 30

Figure CYP2C19-relatedAtremorine-induced Atremorine-induced dopamine dopamine response. and AtremorineFigure 4. 4. CYP2C19-related response.Basal Basal(DAb) (DAb) and Atremorineinduced dopamine response (DAt) in CYP2C19 extensive (EM), Intermediate (IM), and Ultra-rapid induced dopamine response (DAt) in CYP2C19 extensive (EM), Intermediate (IM), and Ultra-rapid metabolizers (UM). Adapted with permission from Cacabelos et al. [17]. metabolizers (UM). Adapted with permission from Cacabelos et al. [17].

Int. J. Mol. Sci. 2017, 18, 551 Int. J. Mol. Sci. 2017, 18, 551

19 of 28 21 of 30

Figure 5. CYP2C9-related Atremorine-induced dopamine response. Basaland (DAb) and Figure 5. CYP2C9-related Atremorine-induced dopamine response. Basal (DAb) AtremorineAtremorine-induced dopamine response (DAt) in CYP2C9 extensive (EM), Intermediate (IM), and induced dopamine response (DAt) in CYP2C9 extensive (EM), Intermediate (IM), and Poor metabolizers Poor metabolizers (PM). Adapted with permission from (PM). Adapted with permission from Cacabelos et al. [17].Cacabelos et al. [17].

Int. J. Mol. Sci. 2017, 18, 551 Int. J. Mol. Sci. 2017, 18, 551

20 of 28 22 of 30

Figure CYP3A4/5-relatedAtremorine-induced Atremorine-induced dopamine (DAb) and AtremorineFigure 6. 6. CYP3A4/5-related dopamineresponse. response.Basal Basal (DAb) and Atremorineinduced dopamine response (DAt) in CYP3A4/5 extensive (EM), intermediate (IM), induced dopamine response (DAt) in CYP3A4/5 extensive (EM), intermediate (IM),and andrapid rapid metabolizers (RM). Adapted with permission from Cacabelos et al. [17]. metabolizers (RM). Adapted with permission from Cacabelos et al. [17].

6. Further Considerations 6. Further Considerations Cardiovascular dysfunction is a common finding in PD patients. When PD patients are stratified Cardiovascular dysfunction is a common finding in PD patients. When PD patients are stratified by their cardiovascular function, as assessed with electrocardiogram (EKG), 39.50% show an by their cardiovascular function, as assessed with electrocardiogram (EKG), 39.50% show an abnormal abnormal EKG, 19.32% are borderline, and 41.18% exhibit a normal EKG [141]. EKG, 19.32% are borderline, and 41.18% exhibit a normal EKG [141]. Cardiac parasympathetic dysfunction occurs in the early phase of PD, but not necessarily in Cardiac parasympathetic dysfunction occurs in the early phase of PD, but not necessarily in parallel with cardiac sympathetic dysfunction [88]. Low plasma levels of noradrenaline and parallel with cardiac sympathetic dysfunction [88]. Low plasma levels of noradrenaline and adrenaline,

Int. J. Mol. Sci. 2017, 18, 551

21 of 28

secondary to the loss of catecholaminergic neurons in the rostral ventrolateral medulla, together with loss of nigral dopaminergic neurons, may be responsible for reduced sympathetic activity [142] and cardiovascular dysautonomia in PD [117]. Parkinson’s disease patients with abnormal EKG have lower levels of dopamine, and the basal levels of noradrenaline are substantially different between cases with abnormal vs normal EKG [18,141]. The administration of Atremorine tends to increase the plasma levels of the three catecholamines, with the highest impact on dopamine levels, and a minimum effect on adrenaline levels [18]. Basal biochemical conditions and cardiovascular function have been evaluated in PD patients without any treatment at the moment of their first diagnosis, and in PD patients chronically treated with antiparkinsonian drugs for more than one year. Both groups exhibited substantial biochemical and cardiovascular differences. In addition to changes in blood biochemical (i.e., urea, creatinine, phosphorous, alkaline phosphatase, folate, cyanocobalamin) and hematological parameters (neutrophils, basophils) [17], the most significant differences were found in plasma neurotransmitters and hormones. For instance, as expected, basal dopamine levels in untreated patients were below 20 pg/mL (11.22 ± 0.29 pg/mL; mean ± standard error (SE)) whereas basal dopamine levels in treated patients ranged from 21 to 30,000 pg/mL (2139.23 ± 804.72 pg/mL; mean ± SE) (p < 0.001) [17,18]. Chronic treatment with antiparkinsonian drugs reduces the levels of plasma serotonin, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estrogen, and tends to increase the levels of adrenaline, histamine, ACTH, cortisol, and testosterone in a non-significant mode [18]. Changes in neurotransmitters and endocrine parameters are highly influenced by the genomic profile of each patient [17–19]. Since PD patients undergo long-term periods of treatment with different antiparkinsonian drugs, which chronically alter neurotransmitter levels and hormonal regulation, some reflections are pertinent: (i) it is likely that the chronic overstimulation of the dopaminergic system at central and peripheral levels may become deleterious for cardio-cerebrovascular function and hormonal regulation; (ii) since the central dopaminergic dysfunction precedes the clinical onset of the disease by several decades, it is urgent to identify predictive biomarkers to protect the population at risk of suffering PD; (iii) the progression of PD over the past 50 years, in terms of gradual increase in prevalence and incidence rates, indicates that environmental toxicity may contribute to accelerating selective dopaminergic neurodegeneration; therefore, a better scrutiny of environmental risk factors is necessary to implement preventive programs in susceptible persons; (iv) most post-mortem neurochemical studies might be contaminated by chronic polypharmacy; (v) novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration rather than dopaminergic overstimulation; and (vi) since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics [16]. Modern neuroscience must embrace the idea that most brain disorders require more neuroprotection and fewer symptomatic repressors. Unfortunately, the history of neuropsychopharmacology is a history of chemical symptomatic repression with delayed consequences for patients and society in terms of chronic disability, family burden, and health costs. In the particular case of Parkinson’s disease, future challenges are (i) a better insight into the pathogenesis of premature dopaminergic neurodegeneration; (ii) the identification of biomarkers for an early diagnosis; (iii) the implementation of preventive programs to halt disease progression at pre-symptomatic stages; (iv) the development of novel antiparkinsonian drugs with specific neuroprotective effects on the dopaminergic system; and (v) the personalized treatment of PD patients. Conflicts of Interest: The author is President of EuroEspes.

Int. J. Mol. Sci. 2017, 18, 551

22 of 28

References 1.

2.

3. 4. 5. 6. 7.

8.

9. 10. 11. 12. 13. 14. 15. 16. 17.

18.

19. 20. 21.

22.

Von Campenhausen, S.; Bornschein, B.; Wick, R.; Bötzel, K.; Sampaio, C.; Poewe, W.; Oertel, W.; Siebert, U.; Berger, K.; Dodel, R. Prevalence and incidence of Parkinson’s disease in Europe. Eur. Neuropsychopharmacol. 2005, 15, 473–490. [CrossRef] [PubMed] Zou, Y.M.; Liu, J.; Tian, Z.Y.; Lu, D.; Zhou, Y.Y. Systematic review of the prevalence and incidence of Parkinson’s disease in the People’s Republic of China. Neuropsychiatr. Dis. Treat. 2015, 15, 1467–1472. [CrossRef] [PubMed] Muangpaisan, W.; Hori, H.; Brayne, C. Systematic review of the prevalence and incidence of Parkinson’s disease in Asia. J. Epidemiol. 2009, 19, 281–293. [CrossRef] [PubMed] Hirsch, L.; Jette, N.; Frolkis, A.; Steeves, T.; Pringsheim, T. The Incidence of Parkinson’s Disease: A Systematic Review and Meta-Analysis. Neuroepidemiology 2016, 46, 292–300. [CrossRef] [PubMed] Savica, R.; Grossardt, B.R.; Bower, J.H.; Ahlskog, J.E.; Rocca, W.A. Time Trends in the Incidence of Parkinson Disease. JAMA Neurol. 2016, 73, 981–989. [CrossRef] [PubMed] Pringsheim, T.; Jette, N.; Frolkis, A.; Steeves, T.D. The prevalence of Parkinson’s disease: A systematic review and meta-analysis. Mov. Disord. 2014, 29, 1583–1590. [CrossRef] [PubMed] Riedel, O.; Bitters, D.; Amann, U.; Garbe, E.; Langner, I. Estimating the prevalence of Parkinson’s disease (PD) and proportions of patients with associated dementia and depression among the older adults based on secondary claims data. Int. J. Geriatr. Psychiatry 2016, 31, 938–943. [CrossRef] [PubMed] Moisan, F.; Kab, S.; Mohamed, F.; Canonico, M.; le Guern, M.; Quintin, C.; Carcaillon, L.; Nicolau, J.; Duport, N.; Singh-Manoux, A.; et al. Parkinson disease male-to-female ratios increase with age: French nationwide study and meta-analysis. J. Neurol. Neurosurg. Psychiatry 2016, 87, 952–957. [CrossRef] [PubMed] Cacabelos, R. World Guide for Drug Use and Pharmacogenomics; EuroEspes Publishing: Corunna, Spain, 2012. Cacabelos, R.; Cacabelos, P.; Torrellas, C.; Tellado, I.; Carril, J.C. Pharmacogenomics of Alzheimer’s disease: Novel therapeutic strategies for drug development. Methods Mol. Biol. 2014, 1175, 323–556. [PubMed] Cacabelos, R.; Torrellas, C.; Carrera, I. Opportunities in Pharmacogenomics for the treatment of Alzheimer’s Disease. Future Neurol. 2015, 10, 229–252. [CrossRef] Cacabelos, R.; Torrellas, C. Epigenetic drug discovery for Alzheimer's disease. Expert Opin. Drug Discov. 2014, 9, 1059–1086. [CrossRef] [PubMed] Cacabelos, R.; Torrellas, C. Epigenetics of aging and Alzheimer’s disease: Implications for pharmacogenomics and drug response. Int. J. Mol. Sci. 2015, 16, 30483–30543. [CrossRef] [PubMed] Cacabelos, R.; Torrellas, C.; Teijido, O.; Carril, J.C. Pharmacogenetic considerations in the treatment of Alzheimer’s disease. Pharmacogenomics 2016, 17, 1041–1074. [CrossRef] [PubMed] Katzenschlager, R.; Lees, A.J. Treatment of Parkinson’s disease: Levodopa as the first choice. J. Neurol. 2002, 249, II19–II24. [CrossRef] [PubMed] Cacabelos, R. Parkinson’s disease: Old concepts and new challenges. Sci. Pages Alzheimers Dis. Dement. 2016, 1, 001. Cacabelos, R.; Fernández-Novoa, L.; Alejo, R.; Corzo, L.; Alcaraz, M.; Nebril, L.; Cacabelos, P.; Fraile, C.; Carrera, I.; Carril, J.C. E-PodoFavalin-15999 (Atremorine® )-induced dopamine response in Parkinson’s Disease: Pharmacogenetics-related effects. J. Genom. Med. Pharmacogenom. 2016, 1, 1–26. Cacabelos, R.; Fernández-Novoa, L.; Alejo, R.; Corzo, L.; Rodríguez, S.; Alcaraz, M.; Nebril, L.; Cacabelos, P.; Fraile, C.; Carrera, I.; et al. E-PodoFavalin-15999 (Atremorine® )-induced neurotransmitter and hormonal response in Parkinson’s Disease. J. Exp. Res. Pharmacol. 2016, 1, 1–12. Cacabelos, R.; Carrera, I.; Fernández-Novoa, L.; Alejo, R.; Corzo, L.; Rodríguez, S.; Alcaraz, M.; Nebril, L.; Casas, A.; Fraile, C.; et al. Parkinson’s Disease: New solutions to old problems. EuroEspes J. 2017, 11, 74–96. Miller, D.B.; O’Callaghan, J.P. Biomarkers of Parkinson’s disease: Present and future. Metabolism 2015, 64, S40–S46. [CrossRef] [PubMed] Naughton, C.; O’Toole, D.; Kirik, D.; Dowd, E. Interaction between subclinical doses of the Parkinson’s disease associated gene, α-synuclein, and the pesticide, rotenone, precipitates motor dysfunction and nigrostriatal neurodegeneration in rats. Behav. Brain Res. 2017, 316, 160–168. [CrossRef] [PubMed] Ritz, B.R.; Paul, K.C.; Bronstein, J.M. Of Pesticides and Men: A California Story of Genes and Environment in Parkinson’s Disease. Curr. Environ. Health Rep. 2016, 3, 40–52. [CrossRef] [PubMed]

Int. J. Mol. Sci. 2017, 18, 551

23.

24.

25.

26.

27. 28. 29.

30. 31.

32. 33.

34.

35. 36. 37.

38. 39.

40. 41.

42.

23 of 28

Rokad, D.; Ghaisas, S.; Harischandra, D.S.; Jin, H.; Anantharam, V.; Kanthasamy, A.; Kanthasamy, A.G. Role of Neurotoxicants and Traumatic Brain Injury in α-Synuclein Protein Misfolding and Aggregation. Brain Res. Bull. 2016. [CrossRef] [PubMed] Toledo, J.B.; Arnold, S.E.; Raible, K.; Brettschneider, J.; Xie, S.X.; Grossman, M.; Monsell, S.E.; Kukull, W.A.; Trojanowski, J.Q. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain 2013, 136, 2697–2706. [CrossRef] Irwin, D.J.; Grossman, M.; Weintraub, D.; Hurtig, H.I.; Duda, J.E.; Xie, S.X.; Lee, E.B.; van Deerlin, V.M.; Lopez, O.L.; Kofler, J.K.; et al. Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: A retrospective analysis. Lancet Neurol. 2017, 16, 55–65. [CrossRef] Wen, K.X.; Miliç, J.; El-Khodor, B.; Dhana, K.; Nano, J.; Pulido, T.; Kraja, B.; Zaciragic, A.; Bramer, W.M.; Troup, J.; et al. The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review. PLoS ONE 2016, 11, e0167201. [CrossRef] [PubMed] Nussbaum, R.L. Genentics of synucleopathies. Cold Spring Harb. Perspect. Med. 2017. [CrossRef] [PubMed] Lill, C.M. Genetics of Parkinson’s disease. Mol. Cell. Probes 2016, 30, 386–396. [CrossRef] [PubMed] Xie, Y.; Feng, H.; Peng, S.; Xiao, J.; Zhang, J. Association of plasma homocysteine, vitamin B12 and folate levels with cognitive function in Parkinson’s disease: A meta-analysis. Neurosci. Lett. 2017, 636, 190–195. [CrossRef] [PubMed] Olanow, C.W.; Brundin, P. Parkinson’s disease and alpha synuclein: Is Parkinson’s disease a prion-like disorder? Mov. Disord. 2013, 28, 31–40. [CrossRef] [PubMed] Scheffold, A.; Holtman, I.R.; Dieni, S.; Brouwer, N.; Katz, S.F.; Jebaraj, B.M.; Kahle, P.J.; Hengerer, B.; Lechel, A.; Stilgenbauer, S.; et al. Telomere shortening leads to an acceleration of synucleinopathy and impaired microglia response in a genetic mouse model. Acta Neuropathol. Commun. 2016, 4, 87. [CrossRef] [PubMed] Olszewska, D.A.; Fearon, C.; Lynch, T. Novel gene (TMEM230) linked to Parkinson’s disease. J. Clin. Mov. Disord. 2016, 3, 17. [CrossRef] [PubMed] Nuytemans, K.; Theuns, J.; Cruts, M.; van Broeckhoven, C. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: A mutation update. Hum. Mutat. 2010, 31, 763–780. [CrossRef] [PubMed] Lardenoije, R.; Iatrou, A.; Kenis, G.; Kompotis, K.; Steinbusch, H.W.; Mastroeni, D.; Coleman, P.; Lemere, C.A.; Hof, P.R.; van den Hove, D.L.; et al. The epigenetics of aging and neurodegeneration. Prog. Neurobiol. 2015, 131, 21–64. [CrossRef] [PubMed] Coppedè, F. Genetics and epigenetics of Parkinson’s disease. Sci. World J. 2012. [CrossRef] [PubMed] Hernandez, D.G.; Reed, X.; Singleton, A.B. Genetics in Parkinson’s disease: Mendelian versus non-Mendelian inheritance. J. Neurochem. 2016, 139, 59–74. [CrossRef] [PubMed] Hill-Burns, E.M.; Ross, O.A.; Wissemann, W.T.; Soto-Ortolaza, A.I.; Zareparsi, S.; Siuda, J.; Lynch, T.; Wszolek, Z.K.; Silburn, P.A.; Mellick, G.D.; et al. Identification of genetic modifiers of age-at-onset for familial Parkinson’s disease. Hum. Mol. Genet. 2016, 25, 3849–3862. [CrossRef] [PubMed] Chen, Y.; Xu, R. Phenome-based gene discovery provides information about Parkinson’s disease drug targets. BMC Genom. 2016, 17, 493. [CrossRef] [PubMed] Sandor, C.; Honti, F.; Haerty, W.; Szewczyk-Krolikowski, K.; Tomlinson, P.; Evetts, S.; Millin, S.; Keane, T.; McCarthy, S.A.; Durbin, R.; et al. Whole-exome sequencing of 228 patients with sporadic Parkinson’s disease. Sci. Rep. 2017, 7, 41188. [CrossRef] [PubMed] Verstraeten, A.; Theuns, J.; van Broeckhoven, C. Progress in unraveling the genetic etiology of Parkinson disease in a genomic era. Trends Genet. 2015, 31, 140–149. [CrossRef] [PubMed] Lill, C.M.; Roehr, J.T.; McQueen, M.B.; Kavvoura, F.K.; Bagade, S.; Schjeide, B.M.; Schjeide, L.M.; Meissner, E.; Zauft, U.; Allen, N.C.; et al. Comprehensive research synopsis and systematic meta-analyses in Parkinson’s disease genetics: The PDGene database. PLoS Genet. 2012, 8, e1002548. [CrossRef] [PubMed] Do, C.B.; Tung, J.Y.; Dorfman, E.; Kiefer, A.K.; Drabant, E.M.; Francke, U.; Mountain, J.L.; Goldman, S.M.; Tanner, C.M.; Langston, J.W.; et al. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson’s disease. PLoS Genet. 2011, 7, e1002141. [CrossRef] [PubMed]

Int. J. Mol. Sci. 2017, 18, 551

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55. 56.

57.

58. 59. 60.

24 of 28

International Parkinson Disease Genomics Consortium; Nalls, M.A.; Plagnol, V.; Hernandez, D.G.; Sharma, M.; Sheerin, U.M.; Saad, M.; Simón-Sánchez, J.; Schulte, C.; Lesage, S.; et al. Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: A meta-analysis of genome-wide association studies. Lancet 2011, 377, 641–649. Edwards, T.L.; Scott, W.K.; Almonte, C.; Burt, A.; Powell, E.H.; Beecham, G.W.; Wang, L.; Züchner, S.; Konidari, I.; Wang, G.; et al. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann. Hum. Genet. 2010, 74, 97–109. [CrossRef] [PubMed] Pankratz, N.; Wilk, J.B.; Latourelle, J.C.; DeStefano, A.L.; Halter, C.; Pugh, E.W.; Doheny, K.F.; Gusella, J.F.; Nichols, W.C.; Foroud, T.; et al. Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum. Genet. 2009, 124, 593–605. [CrossRef] [PubMed] Pankratz, N.; Beecham, G.W.; de Stefano, A.L.; Dawson, T.M.; Doheny, K.F.; Factor, S.A.; Hamza, T.H.; Hung, A.Y.; Hyman, B.T.; Ivinson, A.J.; et al. Meta-analysis of Parkinson’s disease: Identification of a novel locus, RIT2. Ann. Neurol. 2012, 71, 370–384. [CrossRef] [PubMed] Simón-Sánchez, J.; van Hilten, J.J.; van de Warrenburg, B.; Post, B.; Berendse, H.W.; Arepalli, S.; Hernandez, D.G.; de Bie, R.M.; Velseboer, D.; Scheffer, H.; et al. Genome-wide association study confirms extant PD risk loci among the Dutch. Eur. J. Hum. Genet. 2011, 19, 655–661. [CrossRef] [PubMed] Liu, X.; Cheng, R.; Verbitsky, M.; Kisselev, S.; Browne, A.; Mejia-Sanatana, H.; Louis, E.D.; Cote, L.J.; Andrews, H.; Waters, C.; et al. Genome-wide association study identifies candidate genes for Parkinson’s disease in an Ashkenazi Jewish population. BMC Med. Genet. 2011, 12, 104. [CrossRef] [PubMed] Hernandez, D.G.; Nalls, M.A.; Ylikotila, P.; Keller, M.; Hardy, J.A.; Majamaa, K.; Singleton, A.B. Genome wide assessment of young onset Parkinson’s disease from Finland. PLoS ONE 2012, 7, e41859. [CrossRef] [PubMed] Foo, J.N.; Tan, L.C.; Irwan, I.D.; Au, W.L.; Low, H.Q.; Prakash, K.M.; Ahmad-Annuar, A.; Bei, J.; Chan, A.Y.; Chen, C.M.; et al. Genome-wide association study of Parkinson’s disease in East Asians. Hum. Mol. Genet. 2016. [CrossRef] [PubMed] Zhang, M.; Mu, H.; Shang, Z.; Kang, K.; Lv, H.; Duan, L.; Li, J.; Chen, X.; Teng, Y.; Jiang, Y.; et al. Genome-wide pathway-based association analysis identifies risk pathways associated with Parkinson’s disease. Neuroscience 2017, 340, 398–410. [CrossRef] [PubMed] Nalls, M.A.; Pankratz, N.; Lill, C.M.; Do, C.B.; Hernandez, D.G.; Saad, M.; DeStefano, A.L.; Kara, E.; Bras, J.; Sharma, M.; et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat. Genet. 2014, 46, 989–993. [CrossRef] [PubMed] Cen, L.; Xiao, Y.; Wei, L.; Mo, M.; Chen, X.; Li, S.; Yang, X.; Huang, Q.; Qu, S.; Pei, Z.; et al. Association of DYRK1A polymorphisms with sporadic Parkinson’s disease in Chinese Han population. Neurosci. Lett. 2016, 632, 39–43. [CrossRef] [PubMed] Funayama, M.; Ohe, K.; Amo, T.; Furuya, N.; Yamaguchi, J.; Saiki, S.; Li, Y.; Ogaki, K.; Ando, M.; Yoshino, H.; et al. CHCHD2 mutations in autosomal dominant late-onset Parkinson’s disease: A genome-wide linkage and sequencing study. Lancet Neurol. 2015, 14, 274–282. [CrossRef] Mohan, M.; Mellick, G.D. Role of the VPS35 D620N mutation in Parkinson’s disease. Park. Relat. Disord. 2016. [CrossRef] [PubMed] Shi, C.H.; Zhang, S.Y.; Yang, Z.H.; Yang, J.; Shang, D.D.; Mao, C.Y.; Liu, H.; Hou, H.M.; Shi, MM.; Wu, J.; et al. A novel RAB39B gene mutation in X-linked juvenile Parkinsonism with basal ganglia calcification. Mov. Disord. 2016, 31, 1905–1909. [CrossRef] [PubMed] Deng, H.X.; Shi, Y.; Yang, Y.; Ahmeti, K.B.; Miller, N.; Huang, C.; Cheng, L.; Zhai, H.; Deng, S.; Nuytemans, K.; et al. Identification of TMEM230 mutations in familial Parkinson’s disease. Nat. Genet. 2016, 48, 733–739. [CrossRef] [PubMed] Cheng, L.; Wang, L.; Li, N.N.; Yu, W.J.; Sun, X.Y.; Li, J.Y.; Zhou, D.; Peng, R. SNCA rs356182 variant increases risk of sporadic Parkinson’s disease in ethnic Chinese. J. Neurol. Sci. 2016, 368, 231–234. [CrossRef] [PubMed] Migdalska-Richards, A.; Schapira, A.H. The relationship between glucocerebrosidase mutations and Parkinson disease. J. Neurochem. 2016, 139, 77–90. [CrossRef] [PubMed] Ferrazza, R.; Cogo, S.; Melrose, H.; Bubacco, L.; Greggio, E.; Guella, G.; Civiero, L.; Plotegher, N. LRRK2 deficiency impacts ceramide metabolism in brain. Biochem. Biophys. Res. Commun. 2016, 478, 1141–1146. [CrossRef] [PubMed]

Int. J. Mol. Sci. 2017, 18, 551

61.

62. 63.

64. 65. 66. 67. 68. 69.

70.

71.

72. 73. 74.

75. 76. 77.

78. 79. 80.

81.

82.

25 of 28

Chen, L.; Mo, M.; Li, G.; Cen, L.; Wei, L.; Xiao, Y.; Chen, X.; Li, S.; Yang, X.; Qu, S.; et al. The biomarkers of immune dysregulation and inflammation response in Parkinson disease. Transl. Neurodegener. 2016. [CrossRef] [PubMed] Zhao, J.; Yu, S.; Zheng, Y.; Yang, H.; Zhang, J. Oxidative Modification and Its Implications for the Neurodegeneration of Parkinson’s Disease. Mol. Neurobiol. 2017, 54, 1404–1418. [CrossRef] [PubMed] Kleinknecht, A.; Popova, B.; Lázaro, D.F.; Pinho, R.; Valerius, O.; Outeiro, T.F.; Braus, G.H. C-Terminal Tyrosine Residue Modifications Modulate the Protective Phosphorylation of Serine 129 of α-Synuclein in a Yeast Model of Parkinson’s Disease. PLoS Genet. 2016, 12, e1006098. [CrossRef] [PubMed] Bang, Y.; Kim, K.S.; Seol, W.; Choi, H.J. LRRK2 interferes with aggresome formation for autophagic clearance. Mol. Cell. Neurosci. 2016, 75, 71–80. [CrossRef] Zhang, C.W.; Hang, L.; Yao, T.P.; Lim, K.L. Parkin Regulation and Neurodegenerative Disorders. Front. Aging Neurosci. 2016, 7, 248. [CrossRef] [PubMed] Bose, A.; Beal, M.F. Mitochondrial dysfunction in Parkinson’s disease. J. Neurochem. 2016, 1802, 29–44. [CrossRef] [PubMed] Buhlman, L.M. Parkin loss-of-function pathology: Premature neuronal senescence induced by high levels of reactive oxygen species? Mech. Ageing Dev. 2016, 161, 112–120. [CrossRef] [PubMed] Zhou, Z.D.; Sathiyamoorthy, S.; Angeles, D.C.; Tan, E.K. Linking F-box protein 7 and parkin to neuronal degeneration in Parkinson’s disease (PD). Mol. Brain 2016, 9, 41. [CrossRef] [PubMed] Teixeira, F.R.; Randle, S.J.; Patel, S.P.; Mevissen, T.E.; Zenkeviciute, G.; Koide, T.; Komander, D.; Laman, H. Gsk3β and Tomm20 are substrates of the SCFFbxo7/PARK15 ubiquitin ligase associated with Parkinson’s disease. Biochem. J. 2016, 473, 3563–3580. [CrossRef] [PubMed] Saito, Y.; Akazawa-Ogawa, Y.; Matsumura, A.; Saigoh, K.; Itoh, S.; Sutou, K.; Kobayashi, M.; Mita, Y.; Shichiri, M.; Hisahara, S.; et al. Oxidation and interaction of DJ-1 with 20S proteasome in the erythrocytes of early stage Parkinson’s disease patients. Sci. Rep. 2016, 6. [CrossRef] Mo, M.S.; Huang, W.; Sun, C.C.; Zhang, L.M.; Cen, L.; Xiao, Y.S.; Li, G.F.; Yang, X.L.; Qu, S.G.; Xu, P.Y. Association Analysis of Proteasome Subunits and Transporter Associated with Antigen Processing on Chinese Patients with Parkinson’s Disease. Chin. Med. J. 2016, 129, 1053–1058. [PubMed] Pihlstrøm, L.; Berge, V.; Rengmark, A.; Toft, M. Parkinson’s disease correlates with promoter methylation in the α-synuclein gene. Mov. Disord. 2015, 30, 577–580. [CrossRef] [PubMed] Ammal Kaidery, N.; Tarannum, S.; Thomas, B. Epigenetic landscape of Parkinson’s disease: Emerging role in disease mechanisms and therapeutic modalities. Neurotherapeutics 2013, 10, 698–708. [CrossRef] [PubMed] Masliah, E.; Dumaop, W.; Galasko, D.; Desplats, P. Distinctive patterns of DNA methylation associated with Parkinson disease: Identification of concordant epigenetic changes in brain and peripheral blood leukocytes. Epigenetics 2013, 8, 1030–1038. [CrossRef] [PubMed] Moore, K.; McKnight, A.J.; Craig, D.; O’Neill, F. Epigenome-wide association study for Parkinson’s disease. Neuromol. Med. 2014, 16, 845–855. [CrossRef] [PubMed] Cacabelos, R.; Torrellas, C.; Carril, J.C.; Aliev, G.; Teijido, O. Epigenomics and proteomics of brain disorders. Curr. Genom. 2017, in press. Mo, M.; Xiao, Y.; Huang, S.; Cen, L.; Chen, X.; Zhang, L.; Luo, Q.; Li, S.; Yang, X.; Lin, X.; et al. MicroRNA expressing profiles in A53T mutant alpha-synuclein transgenic mice and Parkinsonian. Oncotarget 2016. [CrossRef] [PubMed] Oertel, W.; Schulz, J.B. Current and experimental treatments of Parkinson disease: A guide for neuroscientists. J. Neurochem. 2016, 139, 325–337. [CrossRef] [PubMed] Pahwa, R.; Lyons, K.E. Levodopa-related wearing-off in Parkinson’s disease: Identification and management. Curr. Med. Res. Opin. 2009, 25, 841–849. [CrossRef] [PubMed] Bhidayasiri, R.; Hattori, N.; Jeon, B.; Chen, R.S.; Lee, M.K.; Bajwa, J.A.; Mok, V.C.; Zhang, B.; Syamsudin, T.; Tan, L.C.; et al. Asian perspectives on the recognition and management of levodopa ‘wearing-off’ in Parkinson’s disease. Expert Rev. Neurother. 2015, 15, 1285–1297. [CrossRef] [PubMed] Haaxma, C.A.; Horstink, M.W.; Zijlmans, J.C.; Lemmens, W.A.; Bloem, B.R.; Borm, G.F. Risk of disabling response fluctuations and dyskinesias for dopamine agonists versus Levodopa in Parkinson’s disease. J. Parkinsons Dis. 2015, 5, 847–853. [CrossRef] [PubMed] Rascol, O.; Perez-Lloret, S.; Ferreira, J.J. New treatments for levodopa-induced motor complications. Mov. Disord. 2015, 30, 1451–1460. [CrossRef] [PubMed]

Int. J. Mol. Sci. 2017, 18, 551

83.

26 of 28

Stowe, R.; Ives, N.; Clarke, C.E.; Deane, K.; van Hilten, J.; Wheatley, K.; Gray, R.; Handley, K.; Furmston, A. Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson s disease patients with motor complications. Cochrane Database Syst. Rev. 2010, 7, CD007166. 84. Lertxundi, U.; Isla, A.; Solinis, M.A.; Domingo-Echaburu, S.; Hernandez, R.; Peral-Aguirregoitia, J.; Medrano, J. Anticholinergic burden in Parkinson’s disease inpatients. Eur. J. Clin. Pharmacol. 2015, 71, 1271–1277. [CrossRef] [PubMed] 85. Owolabi, L.F.; Samaila, A.A.; Sunmonu, T. Gastrointestinal complications in newly diagnosed Parkinson’s disease: A case-control study. Trop. Gastroenterol. 2014, 35, 227–231. [PubMed] 86. Knudsen, K.; Krogh, K.; Østergaard, K.; Borghammer, P. Constipation in Parkinson’s disease: Subjective symptoms, objective markers, and new perspectives. Mov. Disord. 2017, 32, 94–105. [CrossRef] [PubMed] 87. Tran, T.; Brophy, J.M.; Suissa, S.; Renoux, C. Risks of Cardiac Valve Regurgitation and Heart Failure Associated with Ergot- and Non-Ergot-Derived Dopamine Agonist Use in Patients with Parkinson’s Disease: A Systematic Review of Observational Studies. CNS Drugs 2015, 29, 985–998. [CrossRef] [PubMed] 88. Suzuki, M.; Nakamura, T.; Hirayama, M.; Ueda, M.; Katsuno, M.; Sobue, G. Cardiac parasympathetic dysfunction in the early phase of Parkinson’s disease. J. Neurol. 2016, 264, 333–340. [CrossRef] [PubMed] 89. Barone, P.; Santangelo, G.; Amboni, M.; Pellecchia, M.T.; Vitale, C. Pisa syndrome in Parkinson’s disease and Parkinsonism: Clinical features, pathophysiology, and treatment. Lancet Neurol. 2016, 15, 1063–1074. [CrossRef] 90. Altmann, V.; Schumacher-Schuh, A.F.; Rieck, M.; Callegari-Jacques, S.M.; Rieder, C.R.; Hutz, M.H. Influence of genetic, biological and pharmacological factors on levodopa dose in Parkinson’s disease. Pharmacogenomics 2016, 17, 481–488. [CrossRef] [PubMed] 91. Jiménez-Jiménez, F.J.; Alonso-Navarro, H.; García-Martín, E.; Agúndez, J.A. Advances in understanding genomic markers and pharmacogenetics of Parkinson’s disease. Expert Opin. Drug Metab. Toxicol. 2016, 12, 433–448. [CrossRef] [PubMed] 92. Kurzawski, M.; Białecka, M.; Dro´zdzik, M. Pharmacogenetic considerations in the treatment of Parkinson’s disease. Neurodegener. Dis. Manag. 2015, 5, 27–35. [CrossRef] [PubMed] 93. Schumacher-Schuh, A.F.; Rieder, C.R.; Hutz, M.H. Parkinson’s disease pharmacogenomics: New findings and perspectives. Pharmacogenomics 2014, 15, 1253–1271. [CrossRef] [PubMed] 94. Rieck, M.; Schumacher-Schuh, A.F.; Callegari-Jacques, S.M.; Altmann, V.; Schneider Medeiros, M.; Hutz, M.H. Is there a role for ADORA2A polymorphisms in levodopa-induced dyskinesia in Parkinson’s disease patients? Pharmacogenomics 2015, 16, 573–582. [CrossRef] [PubMed] 95. Schumacher-Schuh, A.F.; Altmann, V.; Rieck, M.; Tovo-Rodrigues, L.; Monte, T.L.; Callegari-Jacques, S.M.; Medeiros, M.S.; Rieder, C.R.; Hutz, M.H. Association of common genetic variants of HOMER1 gene with levodopa adverse effects in Parkinson’s disease patients. Pharmacogenom. J. 2014, 14, 289–294. [CrossRef] [PubMed] 96. Rieck, M.; Schumacher-Schuh, A.F.; Altmann, V.; Francisconi, C.L.; Fagundes, P.T.; Monte, T.L.; Callegari-Jacques, S.M.; Rieder, C.R.; Hutz, M.H. DRD2 haplotype is associated with dyskinesia induced by levodopa therapy in Parkinson’s disease patients. Pharmacogenomics 2012, 13, 1701–1710. [CrossRef] [PubMed] 97. Moreau, C.; Meguig, S.; Corvol, J.C.; Labreuche, J.; Vasseur, F.; Duhamel, A.; Delval, A.; Bardyn, T.; Devedjian, J.C.; Rouaix, N.; et al. Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson’s disease. Brain 2015, 138, 1271–1283. [CrossRef] [PubMed] 98. Ahmed, S.S.; Husain, R.S.; Kumar, S.; Ramakrishnan, V. Association between MDR1 gene polymorphisms and Parkinson’s disease in Asian and Caucasian populations: A meta-analysis. J. Neurol. Sci. 2016, 368, 255–262. [CrossRef] [PubMed] 99. Lohr, K.-M.; Masoud, S.T.; Salahpour, A.; Miller, G.W. Membrane transporters as mediators of synaptic dopamine dynamics: Implications for disease. Eur. J. Neurosci. 2017, 45, 20–33. [CrossRef] [PubMed] 100. Kim, H.J.; Jeon, B.; Chung, S.J. Professional ethics in complementary and alternative medicines in management of Parkinson’s disease. J. Park. Dis. 2016, 6, 675–683. [CrossRef] [PubMed] 101. Carrera, I.; Fernández-Novoa, L.; Sampedro, C.; Cacabelos, R. Neuroprotective effect of atremorine in an experimental model of Parkinson’s disease. Curr. Pharm. Des. 2017. [CrossRef] [PubMed] 102. Cacabelos, R. Bioactive Extract Obtained from Vicia Faba and Its Use in the Treatment and/or Prevention of Neurodegenerative Diseases. European Patent EP16382138, 29 March 2016.

Int. J. Mol. Sci. 2017, 18, 551

27 of 28

103. Goodarzi, Z.; Mele, B.; Guo, A.; Hanson, H.; Jette, N.; Patten, S.; Pringsheim, T.; Holroyd-Leduc, J. Guidelines for dementia or Parkinson’s disease with depression or anxiety: A systemic review. BMC Neurol. 2016, 16, 244. [CrossRef] [PubMed] 104. Cavalcanti, J.R.; Pontes, A.L.; Fiuza, F.P.; Silva, K.D.; Guzen, F.P.; Lucena, E.E.; Nascimento-Júnior, E.S.; Cavalcante, J.C.; Costa, M.S.; Engelberth, R.C.; et al. Nuclear organization of the substantia nigra, ventral tegmental area and retrorubral field of the common marmoset (Callithrix jacchus): A cytoarchitectonic and TH-immunohistochemistry study. J. Chem. Neuroanat. 2016, 77, 100–109. [CrossRef] [PubMed] 105. Sulzer, D.; Cragg, S.J.; Rice, M.E. Striatal dopamine neurotransmission: Regulation of release and uptake. Basal Ganglia 2016, 6, 123–148. [CrossRef] [PubMed] 106. Chandler, D.J.; Waterhouse, B.D.; Gao, W.J. New perspectives on catecholaminergic regulation of executive circuits: Evidence for independent modulation of prefrontal functions by midbrain dopaminergic and noradrenergic neurons. Front. Neural Circuits 2014, 8, 53. [CrossRef] [PubMed] 107. Xing, B.; Li, Y.C.; Gao, W.J. Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex. Brain Res. 2016, 1641, 217–233. [CrossRef] [PubMed] 108. Wakamatsu, K.; Tabuchi, K.; Ojika, M.; Zucca, F.A.; Zecca, L.; Ito, S. Norepinephrine and its metabolites are involved in the synthesis of neuromelanin derived from the locus coeruleus. J. Neurochem. 2015, 135, 768–776. [CrossRef] [PubMed] 109. Buddhala, C.; Loftin, S.K.; Kuley, B.M.; Cairns, N.J.; Campbell, M.C.; Perlmutter, J.S.; Joel, S. Dopaminergic, serotonergic, and noradrenergic deficits in Parkinson disease. Ann. Clin. Transl. Neurol. 2015, 2, 949–959. [CrossRef] [PubMed] 110. Jellinger, K.A. Post mortem studies in Parkinson’s disease—Is it possible to detect brain areas for specific symptoms? J. Neural Transm. Suppl. 1999, 56, 1–29. [PubMed] 111. Grouleff, J.; Ladefoged, L.K.; Koldsø, H.; Schiøtt, B. Monoamine transporters: Insights from molecular dynamics simulations. Front. Pharmacol. 2015, 6, 235. [CrossRef] [PubMed] 112. Lohr, K.M.; Bernstein, A.I.; Stout, K.A.; Dunn, A.R.; Lazo, C.R.; Alter, S.P.; Wang, M.; Li, Y.; Fan, X.; Hess, E.J.; et al. Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo. Proc. Natl. Acad. Sci. USA 2014, 111, 9977–9982. [CrossRef] [PubMed] 113. Nagatsu, T.; Nagatsu, I. Tyrosine hydroxylase (TH), its cofactor tetrahydrobiopterin (BH4), other catecholamine-related enzymes, and their human genes in relation to the drug and gene therapies of Parkinson’s disease (PD): Historical overview and future prospects. J. Neural Transm. 2016, 123, 1255–1278. [CrossRef] [PubMed] 114. Conti, M.M.; Meadows, S.M.; Melikhov-Sosin, M.; Lindenbach, D.; Hallmark, J.; Werner, D.F. Monoamine transporter contributions to l-DOPA effects in hemi-parkinsonian rats. Neuropharmacology 2016, 110, 125–134. [CrossRef] [PubMed] 115. Mittal, R.; Debs, L.H.; Patel, A.P.; Nguyen, D.; Patel, K.; O’Connor, G.; Grati, M.; Mittal, J.; Yan, D.; Eshraghi, A.A.; et al. Neurotransmitters: The Critical Modulators Regulating Gut-Brain Axis. J. Cell. Physiol. 2016. [CrossRef] [PubMed] 116. Cenci, M.A. Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications. Front. Neurol. 2014, 5, 242. [CrossRef] [PubMed] 117. Jain, S.; Goldstein, D.S. Cardiovascular dysautonomia in Parkinson disease: From pathophysiology to pathogenesis. Neurobiol. Dis. 2012, 46, 572–580. [CrossRef] [PubMed] 118. Olanow, C.W. Levodopa: Effect on cell death and the natural history of Parkinson’s disease. Mov. Disord. 2015, 30, 37–44. [CrossRef] [PubMed] 119. Nagatsu, T.; Sawada, M. Biochemistry of postmortem brains in Parkinson’s disease: Historical overview and future prospects. J. Neural Transm. Suppl. 2007, 72, 113–120. 120. Vermeiren, Y.; de Deyn, P.P. Targeting the norepinephrinergic system in Parkinson’s disease and related disorders: The locus coeruleus story. Neurochem. Int. 2016, 102, 22–32. [CrossRef] [PubMed] 121. Feinstein, D.L.; Kalinin, S.; Braun, D. Causes, consequences, and cures for neuroinflammation mediated via the locus coeruleus: Noradrenergic signaling system. J. Neurochem. 2016, 139, 154–178. [CrossRef] [PubMed] 122. Braun, D.; Madrigal, J.L.; Feinstein, D.L. Noradrenergic regulation of glial activation: Molecular mechanisms and therapeutic implications. Curr. Neuropharmacol. 2014, 12, 342–352. [CrossRef] [PubMed]

Int. J. Mol. Sci. 2017, 18, 551

28 of 28

123. Espay, A.J.; LeWitt, P.A.; Kaufmann, H. Norepinephrine deficiency in Parkinson’s disease: The case for noradrenergic enhancement. Mov. Disord. 2014, 29, 1710–1719. [CrossRef] [PubMed] 124. Rommelfanger, K.S.; Weinshenker, D. Norepinephrine: The redheaded stepchild of Parkinson’s disease. Biochem. Pharmacol. 2007, 74, 177–190. [CrossRef] 125. Mejias-Aponte, C.A. Specificity and impact of adrenergic projections to the midbrain dopamine system. Brain Res. 2016, 1641, 258–273. [CrossRef] [PubMed] 126. Aziz, N.A.; Pijl, H.; Frölich, M.; Roelfsema, F.; Roos, R.A. Diurnal secretion profiles of growth hormone, thyrotrophin and prolactin in Parkinson’s disease. J. Neuroendocrinol. 2011, 23, 519–524. [CrossRef] [PubMed] 127. Willis, G.L. Parkinson’s disease as a neuroendocrine disorder of circadian function: Dopamine-melatonin imbalance and the visual system in the genesis and progression of the degenerative process. Rev. Neurosci. 2008, 19, 245–316. [CrossRef] [PubMed] 128. Schaefer, S.; Vogt, T.; Nowak, T.; Kann, P.H. German KIMS board. Pituitary function and the somatotrophic system in patients with idiopathic Parkinson’s disease under chronic dopaminergic therapy. J. Neuroendocrinol. 2008, 20, 104–109. [CrossRef] [PubMed] 129. Gruszka, A.; Ren, S.G.; Dong, J.; Culler, M.D.; Melmed, S. Regulation of growth hormone and prolactin gene expression and secretion by chimeric somatostatin-dopamine molecules. Endocrinology 2007, 148, 6107–6114. [CrossRef] [PubMed] 130. Wells, S.; Murphy, D. Transgenic studies on the regulation of the anterior pituitary gland function by the hypothalamus. Front. Neuroendocrinol. 2003, 24, 11–26. [CrossRef] 131. Jin, J.; Hara, S.; Sawai, K.; Fülöp, F.; Nagy, G.M.; Hashizume, T. Effects of hypothalamic dopamine (DA) on salsolinol (SAL)-induced prolactin (PRL) secretion in male goats. Anim. Sci. J. 2014, 85, 461–467. [CrossRef] [PubMed] ˙ 132. Nitkowska, M.; Tomasiuk, R.; Czyzyk, M.; Friedman, A. Prolactin and sex hormones levels in males with Parkinson’s disease. Acta Neurol. Scand. 2015, 131, 411–416. [CrossRef] [PubMed] 133. Kimber, J.; Watson, L.; Mathias, C.J. Neuroendocrine responses to levodopa in multiple system atrophy (MSA). Mov. Disord. 1999, 14, 981–987. [CrossRef] 134. Kimber, J.R.; Watson, L.; Mathias, C.J. Distinction of idiopathic Parkinson’s disease from multiple-system atrophy by stimulation of growth-hormone release with clonidine. Lancet 1997, 349, 1877–1881. [CrossRef] 135. Winkler, A.S.; Landau, S.; Chaudhuri, K.R. Serum prolactin levels in Parkinson’s disease and multiple system atrophy. Clin. Auton. Res. 2002, 12, 393–398. [CrossRef] [PubMed] 136. Ogawa, A.; Kanazawa, M.; Takayanagi, M.; Kitani, Y.; Shintaku, H.; Kohno, Y. A case of 6-pyruvoyl-tetrahydropterin synthase deficiency demonstrates a more significant correlation of L-Dopa dosage with serum prolactin levels than CSF homovanillic acid levels. Brain Dev. 2008, 30, 82–85. [CrossRef] [PubMed] 137. Müller, T.; Welnic, J.; Woitalla, D.; Muhlack, S. Endurance exercise modulates levodopa induced growth hormone release in patients with Parkinson’s disease. Neurosci. Lett. 2007, 422, 119–122. [CrossRef] [PubMed] 138. Kasuya, E.; Yayou, K.; Sutoh, M. L-DOPA attenuates prolactin secretion in response to isolation stress in Holstein steers. Anim. Sci. J. 2013, 84, 562–568. [CrossRef] [PubMed] 139. Székács, D.; Bodnár, I.; Mravec, B.; Kvetnansky, R.; Vizi, E.S.; Nagy, G.M.; Fekete, M.I. The peripheral noradrenergic terminal as possible site of action of salsolinol as prolactoliberin. Neurochem. Int. 2007, 50, 427–434. [CrossRef] [PubMed] 140. Levandis, G.; Balestra, B.; Siani, F.; Rizzo, V.; Ghezzi, C.; Ambrosi, G. Response of colonic motility to dopaminergic stimulation is subverted in rats with nigrostriatal lesion: Relevance to gastrointestinal dysfunctions in Parkinson’s disease. Neurogastroenterol. Motil. 2015, 27, 1783–1795. [CrossRef] [PubMed] 141. Cacabelos, R. Biochemical changes and cardiovascular function in Parkinson’s disease. Clin. Med. Biochem. 2016, 2, 2. [CrossRef] 142. Zhang, Z.; Du, X.; Xu, H.; Xie, J.; Jiang, H. Lesion of medullary catecholaminergic neurons is associated with cardiovascular dysfunction in rotenone-induced Parkinson’s disease rats. Eur. J. Neurosci. 2015, 42, 2346–2355. [CrossRef] [PubMed] © 2017 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).