Mol Neurobiol DOI 10.1007/s12035-014-8689-6

Preconditioning as a Potential Strategy for the Prevention of Parkinson’s Disease Mojtaba Golpich & Behrouz Rahmani & Norlinah Mohamed Ibrahim & Leila Dargahi & Zahurin Mohamed & Azman Ali Raymond & Abolhassan Ahmadiani

Received: 2 February 2014 / Accepted: 23 March 2014 # Springer Science+Business Media New York 2014

Abstract Parkinson’s disease (PD) is a chronic neurodegenerative movement disorder characterized by the progressive and massive loss of dopaminergic neurons by neuronal apoptosis in the substantia nigra pars compacta and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. A numerous of cellular processes including oxidative stress, mitochondrial dysfunction, and accumulation of α-synuclein aggregates are considered to contribute to the pathogenesis of Parkinson’s disease. A further understanding of the cellular and molecular mechanisms involved in the pathophysiology of PD is crucial for developing effective diagnostic, preventative, and therapeutic strategies to cure this devastating disorder. Preconditioning (PC) is assumed as a natural adaptive process whereby a subthreshold stimulus can promote protection against a subsequent lethal stimulus in the brain as well as in other tissues that affords robust brain tolerance facing neurodegenerative insults.

Multiple lines of evidence have demonstrated that preconditioning as a possible neuroprotective technique may reduce the neural deficits associated with neurodegenerative diseases such as PD. Throughout the last few decades, a lot of efforts have been made to discover the molecular determinants involved in preconditioning-induced protective responses; although, the accurate mechanisms underlying this “tolerance” phenomenon are not fully understood in PD. In this review, we will summarize pathophysiology and current therapeutic approaches in PD and discuss about preconditioning in PD as a potential neuroprotective strategy. Also the role of gene reprogramming and mitochondrial biogenesis involved in the preconditioning-mediated neuroprotective events will be highlighted. Preconditioning may represent a promising therapeutic weapon to combat neurodegeneration. Keywords Parkinson’s disease . Preconditioning . Oxidative stress . Mitochondrial dysfunction

Mojtaba Golpich and Behrouz Rahmani as co-first authors, contributed equally to this work. M. Golpich : N. Mohamed Ibrahim : A. A. Raymond Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Cheras Kuala Lumpur, Malaysia B. Rahmani : A. Ahmadiani Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran L. Dargahi NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Z. Mohamed : A. Ahmadiani (*) Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia e-mail: [email protected] A. Ahmadiani e-mail: [email protected]

Introduction Parkinson’s disease (PD) is one of is the most common neurological movement disorder linked to unclear etiology having possible effects of genetic-environmental factors [1]. PD is mainly characterized through progressive degeneration in the melanized dopaminergic neurons of the substantia nigra (SN) and also in linked brain stem nuclei, a reduction of dopamine (DA) level in the mesolimbic and nigrostriatal pathways, neuromelanin deposition, and the existence of Lewy bodies. However, the cellular mechanisms that result in cell death in the nigrostriatal system in PD are unclear [2, 3], but it is generally accepted that the causes of PD are mainly oxidative stress, mitochondrial dysfunction, aberrant protein folding, and abnormal protein aggregation [4, 5].

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In another dimension, it is illustrated that a variety of sublethal insults (e.g., transient hypoxia) could induce a natural adaptive cytoprotective process in the brain, heart, and other organs that would result in increasing tissue tolerance to a subsequent and potentially lethal ischemia. This underpinning competence of living cells is dubbed as “preconditioning/ ischemic tolerance” which allows them to survive exposure to potentially recurrent stressors [6]. Some associations have been made previously between PD and preconditioning as a novel strategy for the prevention of this neurodegenerative process. The main objective of this review article is to investigate different aspects of PD with an emphasis on pertinent evidence for preconditioning as a strategy for its prevention.

Parkinson’s Disease: Clinical Manifestation and Pathophysiology PD leads to both non-motor and motor signs. The diagnostic motor symptoms include bradykinesia/akinesia, rigidity (both axial and limbs), resting tremor, and postural instability. PD affects all ages but it is more common in the elderly, affecting approximately 1 % of patients at 60 years of age. The clinical manifestations are only apparent when almost 70–80 % of striatal dopamine has already been lost. Non-motor problems such as sensory (pain and visual problems), autonomic (drooling, dysphagia, constipation, and sexual dysfunction), cognitive-behavioral/psychiatric disorders (depression, apathy, anxiety, psychosis, dementia), and sleep-related problems are more and more identified and lead to poorer quality of life [7–9]. Also, it has been observed that most of the non-motor problems become increasingly prominent with declining motor function [10, 11]. Different mechanisms have been implicated in DA neurodegeneration. Many of these mechanisms include genetic mutations while others are linked to environmental exposures [12]. Epidemiological investigations suggest an association with pesticides and other environmental toxins and biochemical researches implicate a systemic failure in mitochondrial complex [13]. Approximately, 90–95 % of PD cases are sporadic and known as idiopathic, while 5–10 % of cases are categorized as familial PD [1]. Idiopathic PD is often a complex interaction between the innate vulnerability of the nigrostriatal dopaminergic system, contact with environmental toxins, including inflammatory triggers and a possible genetic predisposition. The initial reason for idiopathic Parkinson’s disease (iPD) is dopaminergic neurons degeneration inside the substantia nigra (SN) pars compacta [14]. Moreover, apart from DA neuron, other neuronal degenerations have been also reported in PD, for instance, cholinergic neuronal degeneration in cerebral cortices, neuronal degeneration of serotonergic in the dorsal

raphe nucleus (DRN), and adrenergic neuronal loss in the locus coeruleus [15, 16]. Further validation of this model had been shown simply by serotonin and dopamine decreases in all regions, but only those in the striatum, frontal cortex, amygdala, hippocampus, nucleus accumbens, and hypothalamus reached meaningful contents in comparison to the neurochemical changes seen in PD cases [17]. Therefore, the mechanisms underlying neurodegeneration in PD remains unclear. In sporadic PD according to neuropathological diagnosis, lesions occur at the beginning in anterior olfactory nucleus as well as vagus nervousness and dorsal motor nucleus of the glossopharyngeal. After that, cortical regions gradually get affected along with less vulnerable nuclear grays. This progressive process of the disease in the stem of brain follows an ascending course with little interindividual differences [18]. The interaction between environmental and genetic factors activates a cascade of molecular events leading to mitochondrial dysfunction, oxidative stress, and impairment of protein metabolism [2, 19]. Apart from the above mechanisms, it is suggested that chronic neuroinflammation also performs a crucial role in the pathophysiology of PD [20]. Mitochondrial Dysfunction Since the brain is the organ system that is dependent on mitochondrial energy supply, it is specifically sensitive to mitochondrial dysfunction [21]. Mitochondria are highly dynamic organelles which can quickly detect and respond to altered cellular environments [22]. Conversely, a sufficient amount of energy from the mitochondria is essential for neuronal survival and neuronal excitability [23]. The significant reduction of adenosine triphophosphate (ATP) and phosphocreatine (PCr) in the putamen and of ATP in the midbrain as high energy metabolites are indicative of mitochondrial dysfunction in the mesostriatal dopaminergic neurons in early and advanced PD [21]. Reduction of the ATP production is not just the outcome of mitochondrial dysfunction. In addition, there are other potentially deleterious events such as enhanced formation of free radicals, induction of permeability transition, impaired intracellular calcium homeostasis, and oxidative stress, which in predispose affected cells to necrosis or apoptosis depending on the rate of consumption and depletion of ATP [24, 25]. Prohibition of mitochondrial respiratory chain may result in incomplete consumption of O2 and decreased and increased production of ATP and free radical, respectively. Free radicals directly act as inhibitors of the mitochondrial respiratory chain which can cause a detrimental cycle that leads to oxidative cell damage [23]. Nowadays, preventing and blocking this damaged cycle is the purpose of the most PD therapeutic surveys [26]. It is noticeably more sensitive to both oxidative and nitrosative

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stress than other respiratory chain complexes, being a target for both reactive nitrogen species and also reactive oxygen species (ROS) [27, 28]. Mitochondria metabolism is responsible for a majority of ROS production in cells implicated in numerous pathological alterations of the central nervous system (CNS) including neurodegeneration [27, 29]. Complex I (NADH, ubiquinone oxidoreductase) represents the largest complex of respiratory chain which is a major source of ROS, particularly in mitochondria of brain [27, 28, 24]. Complex I has been assumed being one of the main points of both endogenous and environmental oxidative stressors in causing mitochondrial dysfunction observed in the nigral neurons of PD cases [30]. Accumulating documents recommends that mitochondrial dysfunction, especially, defects in mitochondrial complex I of the respiratory chain has been considered a potential unifying factor in the pathogenesis of the neurodegenerative disorders including Alzheimer disease (AD) and PD [31, 32, 25]. In PD, impaired mitobiogenesis was detected in the frontal cortex with bioenergetic consequences at Complex I, but the underlying mechanisms are likely multifactorial. Complex I assembly factors and several upstream transcription factors are involved in mitobiogenesis. If mitobiogenesis of the frontal cortex can be stimulated in PD, appearance and progression of disabling cognitive and behavioral deficits in this disease might be slowed [33]. In this regard, several other postmortem studies have shown a meaningful decline in the mitochondrial complex I activity as well as coenzyme Q10, ubiquinone, and also complex IV in the substantia nigra of PD brains [34, 35]. Oxidative Stress Mitochondrial function deficit has two important outcomes: the generation of free radicals and depletion of ATP which cause oxidative stress and impairment of all ATP-dependent cellular processes, respectively [19]. Increasing oxidative stress is a central characteristic observed in the physiopathology of sepsis. Lipopolysaccharide (LPS) and several cytokines enhance oxidative stress via ROS producing substances/conditions that promote an oxidative-mediated cellular injury [36]. Furthermore, excessive production of ROS causes an imbalance in the redox system of cells and react with nucleic acids and proteins to change their functions or trigger peroxidation of lipid concluding cell death. Due to high rate of oxygen consumption by the brain and consequently, the high levels of free radicals generation, brain tissues are specifically susceptible to oxidative injury [37, 38]. It has been shown that the higher ROS yields resulting in a vicious cycle [39]. Defective mitochondrial complex I that is causing production of free radicals performs a significant role in generation of oxidative injury in dopamine metabolism [40]. Several postmortem studies of PD brains have demonstrated that the oxidative stress comes after mitochondrial dysfunction consequence and DA oxidative metabolism have a

prominent role in pathogenesis of PD [39, 41, 31]. In addition, oxidative and nitrosative stress in PD are intimately linked to mitochondrial injury [42]. It would appear that both oxidative and nitrosative stress are essential in neuronal degeneration and closely associated with other parts of neurodegenerative processes, like inflammation and cell death [37]. The main biochemical characteristics of PD, being serious depletion in dopamine (DA) amount, enhanced lipid peroxidation (LPO) and decreased glutathione (GSH) in dopaminergic neurons can result in mitochondrial dysfunction, oxidative stress, and apoptosis [39]. The depletion of GSH in the SN which accompanied with a concomitant enhancement in ROS levels is considered as a first marker of oxidative stress in PD. To summarize, mitochondrial dysfunction and oxidative stress play the fundamental role in degeneration and dopaminergic neuronal loss in the substantia nigra (SN) of PD cases [42].

Aberrant Protein Folding/Abnormal Protein Aggregation Generally, the neuronal dysfunction and loss resulted by the aggregated forms of proteins which are immunity activators and cellular stress inducers in neurodegenerative diseases [43]. It is observed that in various transgenic animal and viral models, overproduction of α-synuclein leads to formation of inclusion and neurodegeneration, similar with a number of motor behavioral deficits. PD is identified by deposition of misfolded/aggregated α-synuclein proteins in multiple areas of the brain. Neuronal cells preferentially release damaged and aggregated forms of α-synuclein under protein misfolding stress conditions. Pathological forms of α-synuclein spread between neurons via this release and result in neuroinflammation [44]. Moreover, one of the most important mechanisms of intracellular protein degradation is the proteosomal degradation. Proteosomal deficiency affects degradation of the misfolded protein such as the accumulation of α-synuclein in PD. α-Synuclein aggregation is considered as a key event in the development of Lewy body pathology in PD [45]. In PD, Lewy bodies play a key role as the focal pathological hallmark and their presence is crucial for the postmortem diagnosis. In fact, Lewy body formation containing misfolded and aggregated forms of α-synuclein is a pathobiologic signature for PD [46]. Nevertheless, these are not exclusive to PD and could be observed in some other diseases, for instance, diffuse Lewy body disease and dementia with Lewy bodies [18], which are grouped together synucleinopathies. In addition, production of oxidative and nitrosative stresses by mitochondrial dysfunction are considered as main causes of protein accumulation in various pathogenic processes [26]. Due to extreme production of nitric oxide (NO), recent surveys have recommended that nitrosative stress may intercede excitotoxicity partly by eliciting protein misfolding and

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aggregation and mitochondrial fragmentation even in the absence of genetic predisposition [47]. Because of problems regarding the monitoring aggregates in their native states, understanding the mechanisms underlying aggregation in vivo in biological systems is less. Likewise, this is attributable to factors that cause protein misfolding and aggregation in vitro. A further understanding of the molecular mechanism of protein misfolding and aggregation will help us to simplify reasonable techniques to avoid them [43]. Apoptosis Enhanced apoptosis and cell death is the eventual result of mitochondrial dysfunction and oxidative harm. Undoubtedly, a large number of the proteins involved in oxidative damage and mitochondrial dysfunction have additionally been proposed to contribute to apoptosis [48, 49]. It is well realized that contribution of free radicals in the cytosolic variations leading to delayed types of programmed cell death, i.e., apoptosis (type I) or autophagy (type II). Those free radicals are produced by an enhancement in the level of excitotoxins, such as glutamate [50]. Programmed cell death can be induced by two widely characterized pathways including the intrinsic and extrinsic pathways. While, release of some factors from mitochondria which result in caspase-9 activation contribute in regulation of the intrinsic pathway, the extrinsic pathway is normally started by Fas and tumor necrosis factor receptors (TNF-Rs) as cell surface “death receptors” that leading to activation of caspase8 through the adaptor protein Fas-associated death domain (FADD). Proteolytic caspases which their activation causes an extremely regulated process of cell death are considered as the core of these pathways [51]. The mitochondrial transmembrane potential disruption is an important event which results in the release of cytochrome c and activation of caspase-3 by various mechanisms [52, 53]. Cytochrome c assumed as an essential part in mitochondria-dependent apoptotic pathway (intrinsic pathway) in neurons [54]. It is exhibited that the interaction of cytochrome c with apoptotic protease activating factor (Apaf-1) leads the recruitment of procaspase-9, accompanying the activation of caspase-3, and eventually participate in apoptotic cell death. Besides, one of the early events occurs in apoptosis is the release of apoptosis-inducing factor (AIF) as an apoptotic factor by the mitochondrion. Chromosomal DNA cleavage can be incited by the cellular redistribution of AIF. Indeed, translocation of AIF from mitochondria to the nucleus results in chromatin condensation and largescale DNA fragmentation [52, 53]. Surveys in experimental models and in PD cases are evocative of multiple death pathways including intrinsic and extrinsic apoptosis and also autophagy [55]. In this way, the substantia nigra displayed both of apoptotic and autophagic

cell death [50]. Multiple lines of evidence has pointed the key role of the intrinsic pathway of PD-associated neurodegeneration, whereas the extrinsic pathway signals play an essential role to mediate inflammation, which are also known as neurotoxicity mediators in PD [51]. Apoptotic death of DA neurons in PD can be started by oxidative stress, impairment in complex I of electron-transport chain and neuroinflammation [54, 56]. Besides, release of cytochrome c from mitochondria is thought to be a key step which starts apoptotic neuron death in several neurodegenerative diseases including that in PD. Interestingly, preliminary studies indicated that macroautophagy is a degradative process, which can be neuroprotective [57].

Parkinson’s Disease: Current Therapeutic Perspectives Parkinson’s disease (PD) is the second most frequent progressive, chronic, neurodegenerative disorder after Alzheimer’s disease (AD) by having an estimated prevalence involving 0.5–1 % in people aged 65–69 years, climbing to 1–3 % with people aged ≥80 years [58]. It has been evaluated that PD has a prevalence of 31 to 347 for every 100,000 populations worldwide. This sickness has a prevalence rate in the USA of 187 per 100,000 with a yearly frequency of 20 per 100,000 [59]. However, the disease seems to include cell death in several brain regions [18], protecting dopamine (DA) neurons alone will considerably improve a lot of the motor symptoms and some non-motor signs and symptoms [60]. Along these lines, common treatments prepare successful control of symptoms, especially in the initial stages of the disease, but the majority of the patients develop motor troubles with long-period treatment and characteristics unresponsive to dopaminergic therapies such as postural instability, dementia, and failing [61]. Current difficulties in the management regarding Parkinson’s disease significantly depend on the fact that we managing a predominantly symptomatic approach, as neuroprotective studies have not produced consistently positive results because of restrictions in study design and trouble in recognizing symptomatic profit from neuroprotective benefits. Moreover, this review gathers the limitations (Table 1) regarding currently available treatments and the latest investigations for management of PD such as medications of motor symptoms, neurotrophic factors, accessible surgical techniques, e.g., deep brain stimulation (DBS), cell therapy by transplantation of neuronal stem cell (NSCs), and gene therapy. Medications of Motor Symptoms Current pharmacological interventions are symptomatic and largely aimed at rising dopamine levels by increased

Mol Neurobiol Table 1 Therapeutic approaches in PD Approach/es

Limiting Factor(s)

Reference(s)

Neurotrophic factor therapy, e.g., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) Medications for motor symptoms, e.g., L-DOPA

Problems of (the) long-term delivery of these proteins into the CNS

[62]

Long-term complications of levodopa therapy such as loss of benefit, sever dyskinesias, motor fluctuations, on–off phenomena, postural instability, and dementia a. Adverse side effects of surgery: - Brain hemorrhage - Infarction - Seizures - Death b. Side effects of surgical DBS: - Worsening dyskinesia - Paraesthesias - Speech and gait disturbances a. Difficulties of the differentiation of NSCs into specific dopaminergic neurons Generation of sufficient number of DA neurons for transplantation a. Significant restriction for development due to the existence of blood–brain barrier (BBB) b. Unwanted side effects regarding lack of evaluated cell specific promoters that are relevant for PD

[63, 61, 64]

Surgery, e.g., deep brain stimulation (DBS)

Cell therapy, e.g., transplantation of neuronal stem cell (NSC)

Gene therapy, e.g., overexpression of cerebral dopamine neurotrophic factor in the striatum via recombinant adeno-associated virus type 2 (AAV2. CDNF)

production and/or inhibition of metabolism of this important neurotransmitter [72]. Levodopa remains the highest level for the treatment of motor symptoms [73] but DA agonists (e.g., pramipexole, apomorphine, ropinirole), monoamine oxidase B (MAO-B) inhibitor (e.g., selegiline and rasagiline), catechol-O-methyl transferase (COMT) inhibitors (e.g., tolcapone and entacapone), and different drugs such as anticholinergics and amantadine are also used as current treatments [74–76]. The therapeutic profit of L-3,4-dihydroxyphenylalanine (L-DOPA) is ordinarily due to the restoration of dopamine (DA) extracellular contents inside the striatum of PD patients. Release of L-DOPA-derived DA is determined by the prevalent serotonergic 5-hydroxytryptamine (5-HT) innervations inside the brain. Taking L-DOPA chronically results in defect of 5-HT neuronal function and eventually overall decrease of efficacy of L-DOPA [77]. Furthermore, a few surveys have demonstrated that the treatment with L-DOPA results in the death of surviving dopaminergic neurons in the CNS [73]. To exemplify, some long-term complications of levodopa treatment are loss of profit, severe dyskinesia, motor fluctuations, on–off phenomena, postural instability, and dementia [63, 61, 64]. It does not prevent the inevitable development of the disease; however, dopamine replacement treatment has enhanced quality of life in PD and enhanced survival rates. None of the available medications have been demonstrated to have a disease-modifying effect or to moderate the progression of PD. The lack of a neuroprotective agent is the serious unmet therapeutic need in PD [78].

[65, 66]

[67–69]

[70, 71]

Neurotrophic Factors The recognition of small molecules that can provide neuroprotection is the most sensible way toward therapeutic intervention for neurodegenerative diseases [12]. It has been recommended that treatment with neurotrophic factors (NTFs) may mediate dopaminergic neuronal survival, prevent surviving dopaminergic neuronal death and provoke proliferation of their axonal nerve terminals with reinnervations of the deafferented striatum, although prolonged delivery of these proteins into the CNS is problematic [62]. Neurotrophic factors are proteins that promote the growth, differentiation, and survival of neurons. They are consequently recognized as magic therapeutic agents for the treatment of neurodegenerative disorders distinguished by elective neuronal degeneration. Numerous researches have noted that neurogenesis is expanded by intracerebral injection of trophic factors in damaged and normal adult brains [79]. On the other hand, in particular situations, immune responses which probably interceded by the secretion of trophic factors from inflammatory and/or glial cells in brain may have a neuroprotective effect. The first neurotrophin which detected for its stimulatory effect on growth, differentiation, and survival of neurons in central and peripheral nervous system (CNS and PNS) was the nerve growth factor (NGF). This factor may contribute in the immune system modulation, protection of axons and myelin against inflammatory damage, and also decreasing the enhanced excitotoxicity during acute inflammatory activation. Thus, according to immunomodulatory effects and neuroprotective activity, NGF can indicate a

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novel therapeutic method for the remedy of various brainrelated disorders [80]. Furthermore, apomorphine-induced rotational behavior in 6-hydroxydopamine (6-OHDA) rat model of PD mostly decreased by intrastriatal infusion of liver growth factor (ISLGF) treatment. It is recommended that LGF is mediated by the activation of microglia/macrophages in striatum to stimulate the dopamine terminals sprouting [79]. It has been demonstrated that 2 weeks of administration of resveratrol can prominently reduce the turns of rats, rotational test, in the rat model of 6-OHDA-injured Parkinson’s disease. Resveratrol treatment essentially reduced 6-OHDA-increased levels of TNF-α mRNA and COX-2 and COX-2 protein in the SN of the rats. These discoveries greatly recommend that resveratrol may have neuroprotective effects in 6-OHDA-induced PD rat models that can be connected to the reduction of inflammatory response, which in turn provides some mechanistic basis for its potential use in the clinical treatment of PD [81]. Limited animal model research has showed that acetaminophen may also protect neurons from degeneration. Acetaminophen has been shown to protect primary rat embryonic DA neurons from glutamate toxicity, and provided partial neuroprotection in rats treated with 1-methyl-4-phenyl pyridinium (MPP+), a neurotoxin that triggers neurodegeneration of DA [82]. These findings propose that acetaminophen could be a prophylactic as well as adjuvant therapy for neurodegenerative diseases such as PD [12]. Surgery and Deep Brain Stimulation Improved understanding of the pathophysiologic mechanisms underlying and the clinical feature of PD, as well as refinement of methods and techniques in neurosurgery, neuroradiology, and neurophysiology, have extended the recent interest in the surgical therapy (lesioning and deep brain stimulation of the globus pallidus, thalamus, and subthalamus) and its role in the treatment of PD patients [83]. Surgery is generally regarded for people with intolerable unfavorable side effects from medication and those patients who have considerable cognitive reserve [68, 84–86]. Initial surgical treatment included lesioning of the globus pallidus and thalamus, but recently, deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) or subthalamic nucleus (STN) [75] is the desired surgical treatment. The pedunculopontine nucleus (PPN) has been investigated as a potential target for DBS and is specifically useful in patients who suffer from freezing of gait (FOG) [87]. The ventral intermediate nucleus (ViM) of thalamus is the primary area targeted for the relief of PD tremor in both lesioning and DBS procedures. It has been declared that in more than 85 % of patients targeting this nucleus was extremely effective in alleviating parkinsonian tremor.

Thalamotomy typically does not enhance akinesia or bradykinesia and might exacerbate speech and gait disorders in some patients, and moreover, bilateral thalamotomy results in a high rate of speech and cognitive issues which restricts the use of this procedure [88–90]. However, thalamotomy has been mostly superseded by DBS of the thalami. Similar to thalamotomy, pallidotomy has been replaced by DBS of the GPi and subthalamic nuclei (STN) which is relatively a more useful approach with less undesirable effects compared pallidotomy or thalamotomy. Fewer prevalence of speech and cognitive functions have been declared in STN lesioning with the advantage of being able to minimize the medication dosage [88]. Currently, DBS is increasingly accepted by the mainstay of surgical treatment for PD. It is an evidence-based lifechanging treatment of patients with difficult motor complications relevant to chronic levodopa therapy such as dyskinesia and fluctuations and severe intractable tremor [91]. However, despite being effective in decreasing motor complications and motor symptoms, DBS does not improve axial symptoms such as gait difficulties, postural instability, and non-motor symptoms. In fact, in some situation, it may cause worsening, paraesthesias, gait disturbances, and speech [66]. Cell Therapy Recent cellular and molecular treatments are being applied in animals, and these include fetal cells from pigs, transfected cells, or embryonic stem cells. Neural transplantation might be determined as implantation of non-neuronal or living neuronal tissue into a host nervous system [92]. In neurodegenerative diseases such as PD, neural stem cells (NSCs) are extensively certified as a cell source for replacement strategies. However, the usage of NSCs is restricted due to the differentiation of NSCs into specific dopaminergic neurons has confirmed difficult [67]. Implicitly, adequate number of DA neurons need to be produced for transplantation into the striatum [68, 69]. Moreover, other difficulties associated to the use of fetal tissue involve variability of functional result with some patients showing significant amelioration and others modest, if any clinical profit. Last but not least issue is incidence of troublesome dyskinesias in a notable ratio of patients after transplantation. Therefore, in PD, neural transplantation is still at an experimental stage [93]. Stem cell (SC)-based therapies may effectively support activation of neurogenesis (maturation, migration, and integration of newly generated neurons) through the production of diffusible trophic factors in a functional network [94, 95]. Ren and his colleagues newly studied the function of autologous mesenchymal stem cells (MSCs) expressing glial cell-derived neurotrophic factor (GDNF) for protection against stable systemic Parkinsonian state induced by MPTP in cynomolgus monkeys. They represented that the motor

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functions were spared in the contralateral limbs of monkeys after unilateral implantation of GDNF-MSCs into the striatum and substantia nigra, but not in those receiving MSCs alone. Besides, the findings displayed that in the striatum of the grafted hemisphere, dopamine levels were higher and dopamine uptake was promoted. With respect to the above data, it is indicated that autologous MSCs might be a safe vehicle to deliver GDNF for promoting nigro-striatum functions [96]. Regarding some other effects of cellular therapies, it has been illustrated that in a PD mouse model, grafted neural stem/precursor cells in lesioned striatum functionally integrate in the striatum, as demonstrated by the statistically considerable decline of contralateral rotations after apomorphine treatment [97]. In addition, extracted data indicate that graft of adult mesenchymal stem cells partially restores the vesicular striatal pool of dopamine and dopaminergic markers and decrease behavioral effects induced by 6-hydroxydopamine lesion [98]. Additionally, it has been observed that to improve bladder dysfunction in rats after unilateral injection of 6-OHDA into the medial forebrain bundle (MFB), transplantation of allogeneic rat bone marrow mesenchymal stromal cells (rBMSCs) enhances urodynamic pressures at 42 days after treatment, more noticeably than microencapsulation (ErBMSC). This was linked with a higher number of tyrosine hydroxylase-positive neurons in the treated substantia nigra pars compacta of rBMSC animals, recommending that functional enhancement need a juxtacrine effect [99]. In overall, currently, cell therapies have quickly developed with the new development in molecular biological technology including gene transfer [100]. Gene Therapy As mentioned before, pharmacological and surgical treatments prepare only symptomatic profits in PD. As none of the newly available therapies have convincingly demonstrated disease-modifying effects either in slowing or reversing the disease; thus; patients experience progressively worsening in symptom control, as the condition develops, with the development of disabling non-motor and motor complications. These problems have resulted in wide research into the possible use of gene therapy as a possible treatment choice for PD [101]. Somatic manipulation of the nervous system without the participation of the germinal line recognized as an effective strategy. The production of transitory, unique, and local knockout, knockdown, overexpression, or ectopic expression of a gene by usage of viral vectors as a developing therapy results in the possibility of analyzing both in vitro and in vivo molecular basis of neural function. In this way, to transport transgenic sequences, engineered viral particles are transferred into distinct brain regions to

express the transgenic products by transducer cells. Currently, studies on vectors used to transfer genes into the brain have concentrated on gene therapy of experimental models of neurodegenerative disorders such as AD or PD [102, 103]. Gene therapy for PD has several limitations for improvement such as lack of evaluated cell-specific promoters and the presence of blood–brain barrier (BBB) [26]. As long as the promoter in the vector performs a major role in most these features, choosing of this parameter is critical [71]. Compared to other famous trophic factors, cerebral dopamine neurotrophic factor (CDNF) was detected to be stronger and more selective for dopaminergic neurons protection. A recent research on 6-OHDA model of PD rat displayed the functional restorative and neuroprotective impacts of CDNF overexpression in the striatum through recombinant adeno-associated virus type 2 (AAV2. CDNF). The results of this study have demonstrated that striatal transfer of AAV2. CDNF led to the improvement of 6-OHDA-induced behavior disorders and a considerable recovery of tyrosine hydroxylase immunoreactive (TH-ir) fiber density in the striatum and THir neurons in the substantia nigra pars compacta (SNpc). Furthermore, functional recovery of dopaminergic neurons was confirmed by PET analyses. Elicited findings suggest that for subsequent clinical applications in treatment of PD, striatal administration of AAV2. CDNF might be considered [104]. Besides, in another finding, GTP cyclohydrolase 1 (GCH1) and a single adeno-associated viral (AAV) vector coexpressing tyrosine hydroxylase (TH) was utilized to consider the relation between vector dose and the value and rate of improvement in hemi-parkinsonian rats. It has been supported that intrastriatal injections of a TH-GCH1 dose of 1E10 genomic copies (gc) generated a perfect improvement in drugnaïve behavior tests without causing neuronal loss. Interestingly, while a TH-GCH1 dose of >1E11 gc led to cell loss in globus pallidus, lower vector dose produced negligible to no functional recovery [105], implying that the behavioral function improvement and neuronal protection is dependent on “therapeutic” vector dose. Moreover, it has been found overexpression of the lysosomal receptor via the nigral injection of recombinant adenoassociated virus vectors induce the chaperone-mediated autophagy. This resulted in improvement of chaperone-mediated autophagy dysfunction and lowering of α-synuclein levels. This approach can provide a novel treatment in PD and related synucleinpathies [106]. Commonly, viral promoters display a high expression of the transgene, which are generally not particular to one cell type and therefore might result in undesirable side effects. The cell characteristics of the vector may be significantly increased the rough applying and endogenous cell specific promoter such as the glial fibrilly acidic protein (GFAP) promoter to target glia and synapsin or neuron-specific enolase promoter to target neurons. However, these promoters could be utilized

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for gene therapy regarding PD; they are not those which appropriate to this disease. A microarray research for the transcriotome of PD patient has illustrated that several genes have a high expression in PD striatum. The promoters of these genes could potentially be utilized to make vectors that are cell specific and applicable for PD [71].

management of pressure regions of inactive patients, and facilitating end-of-life decisions for the patient as well as friends and relatives.

Preconditioning: as a Novel Neuroprotective Strategy in PD

Complementary and Supportive Therapy Epidemiological research display positive effects of continuous physical activity and balanced diet on cardiovascular fitness. In some chronic neurodegenerative disorders such as PD and Alzheimer’s disease, physical activity has become a favored supportive symptomatic therapy. Nutrition also has been reported to apply positive effects on brain function [107]. A plant-based diet can provide various profits in PD. Extracted data recommend that plant food diet (PFD) might be effective in the management of PD patients by developing their motor performances [108]. In addition, novel studies demonstrate that ketogenic diet (KD), ketone bodies (KB), and their components (acetoacetate, acetone, and D-beta-hydroxybutyrate) have neuroprotective effects on chronic and acute neurological disorders. It has found that dopaminergic neurons of substantia nigra (SN) were protected by KD against (6-OHDA) neurotoxicity in PD rat model [109]. Ameliorated motor function and increased longevity have been illustrated by physical practice therapy in people who suffer from PD [68]. In animal research, functional improvement is increased by exercise after striatal lesions [110, 111]. Environmental enrichment that contains physical practice has been demonstrated to have a protective impact on neuronal cell death in the substantia nigra pars compacta (SNpc) of 6-OHDA and 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice [112]. Moreover, it is certified that dopaminergic neurons are protected by chronic running practice against inflammation-induced insults and develops neuronal survival. Likewise, activation of the brain-derived neurotrophic factor (BDNF) signaling pathway induces neuroprotective effects of practice; the modulation of inflammation status does not play a significant role in this event. Although the detail mechanism is still unknown, BDNF signaling cascade acts as a key factor in protection against inflammation-induced dopaminergic neuron loss [113–115]. When all other treatment strategies have become inefficient, a palliative care is mostly needed in the ultimate stages of the disease. The purpose of palliative care is to improve the quality of life for the patient and people around him or her. A number of important problems of palliative care are the following: care in the community while appropriate care can be given there, decreasing or withdrawing drug intake to minimize drug side effects, avoiding pressure lesions by

Preconditioning is a natural adaptive process which is considered as an approach to making cytoprotection in brain, heart, and other organs [6]. In the following sections, this review focuses on investigations concerning fundamental reprogramming events related in preconditioning that confer neuroprotection in CNS. Afterward, the neuroprotective effects of preconditioning will be maintained in the research models of PD. Preconditioning in CNS Preconditioning is a status in which a minor noxious stimulus protects from subsequent and more severe insults [116]. In this respect, brain preconditioning refers to a broad range of therapies which induce a neuronal tolerance state where neuronal tissue get more resistant to a following lethal damage [117]. In stroke models, preconditioned brains show obvious lack of harmful inflammatory mediators commonly observed in response to stroke damage and therefore, it is believed that the preconditioning can certainly trigger signaling cascades that activate effector mechanisms in charge of neuroprotection. These mechanisms may have a crucial role in attenuation of cell injury pathways, such as oxidative and nitrosative stress, excitotoxicity, ionic unbalance, metabolic brokenness, aggravation, and methods identified with necrotic and apoptotic cell death. The cell signaling cascades provoking upregulation of survival pathways or downregulation of necrotic and apoptotic pathways are not fully understood; however, some researches have provided us with some ideas [118]. Enhancement of endogenous protection or chemical activation processes are other approaches of preconditioning [119]. Available literature demonstrated that some chemical reagents have been applied to start protection, regularly by participating in the action of important proteins involved in cell injury. Others contribute signal transmitters in the complex mechanism that is the foundation of ischemic preconditioning. The general feature of chemical preconditioning also eventuates from the fact that excitation of tolerance in one organ may distribute through the paracrine mechanism or PNS to other organs, regarded as remote preconditioning [119]. The basic principle in preconditioning against ischemic damage is that the dose of the preconditioning stimulus should be sufficiently high to have an impact, but at a subthreshold level that will not cause injury [120]. Different and notable stressors can act as triggers of preconditioning, and cross-

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tolerance can be generated applying various stimuli for preconditioning and detrimental challenge [121]. This extensive variety of stimuli that have been applied in preconditioning models include low dose of lipopolysaccharide (LPS) as bacterial endotoxin, mild ischemia, hypoxia, hypothermia and hyperthermia, trauma, seizures, cortical spreading depression, 3-nitropropionic acid, and anesthetic inhalants. Upon introduction to the above, protection from the same or an alternative succeeding stronger insult is generated. LPS is maybe the most interesting neuroprotective stimulus because it needs no interruption of the CNS [116, 122]. A sublethal preconditioning has been suggested as a neuroprotective strategy against various CNS neurodegenerative diseases. The maintained condition called “tolerance” is an endogenous neuroprotective mechanism that can show in two widely different ways [123, 121]. Following the inducing stimulus, it can take effect within hours, referred to as rapid or early tolerance, or days, referred to as delayed or classical tolerance [124]. Rapid, early tolerance occurs within hours, independent of new gene transcription via alterations in neurotransmitters, channels, and ubiquitin–proteasome degradation of death-signaling and structural proteins, leading to short but vigorous neuroprotection. Conversely, classical, delayed tolerance develops over 1–3 days, dependent on new gene transcription and de novo protein synthesis, and elicits a neuroprotective effect that continues for several days [121]. Finally, an important difference between these two ways is that neuroprotection in the first way is transient, while the neuroprotection in the second one is robust and long lasting [125]. Preconditioning: Gene Reprogramming The concept that preconditioning results in a basic reprogramming event that presents neuroprotection is a novel and essential idea in the field of ischemic tolerance [126]. The mechanism that protects the organism against further harm is endogenously orchestrated by reprogramming which causes a finely regulated change in the balance of pro-inflammatory and anti-inflammatory cytokines [127]. It is illustrated that multitudinous preconditioning stimuli agents such as lowdose lipopolysaccharide (LPS) preconditioning lead to mild activation of TLR4, an event that happens before ischemia and at last brings about reprogramming of Toll-like receptors (TLRs) which dramatically enhances result by reprogramming the signaling response to damage. The genomic response to ischemia is adjusted by LPS preconditioning through reprogramming stroke-induced TLR signaling. This type of reprogramming happens via higher activation of the Interferon regulatory factor 3 (IRF3) pathway [128]. In the LPS-preconditioned mice, the enhancement of interferon (IFN) and type I interferon-associated genes in response to stroke reflects the secondary response

to LPS in classic endotoxin tolerance and also supports a probable reprogramming of the TLR response to stroke, arising in a Toll-IL-1 receptor (TIR)-domain-containing adapterinducing interferon-β (TRIF)-mediated event [129]. Hence, genomic reprogramming of TLR signaling suggests a highbenefit, low-risk opportunity to battle brain damage in the cerebral ischemia event [130, 127]. Genomic expression patterns observed after preconditioning with low-dose LPS provide supportive documents of such reprogramming and show that protection may result through increased production of anti-inflammatory mediators such as s-TNFR1 and interleukin10 (IL-10) which leads to induction of neuroprotective pathways that improve cell survival and additionally by considerable suppression of harmful proinflammatory pathways such as those interceded by tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 [131]. In ischemic tolerance, Gene suppression subsequently seems to be a conserved characteristic of reprogramming. The role of reprogramming in gene suppression is obscure yet, however, it may enhance transcriptional silencing or other post-transcriptional mechanisms after induction of the preconditioning stimuli [121]. Preconditioning: Mitochondria Biogenesis Recently, it has been demonstrated that division (fission), fusion, transport along axons and dendrites, biogenesis, and degradation as the dynamic features of mitochondria perform a crucial function in neurodegeneration [132]. During the life cycle of mitochondria, mitochondrial biogenesis assumes a critical part to keep mitochondrial homeostasis and finally meet the physiological demands of eukaryotic cells [133]. It is proposed that sequential loss of mitochondrial DNA (mtDNA) amount in long-term focal cerebral ischemia points to the failure of mitochondrial renewal mechanisms. Moreover, strong research evidence recommends a probable reduction of ROS production by the biogenesis of a higher pool of functional mitochondria [134]. On the other hand, enhanced biogenesis is compatible with the mtDNA copy number and enhanced mitochondrial gene expression. The gene expression profile involved in mitochondrial biogenesis includes peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF-1) and transcription factor B1, and mitochondrial (TFB1M) [135]. PGC-1α is a transcriptional co-activator and acts as the main regulator of mitochondrial biogenesis, and its expression is adjusted by neuronal nitric oxide production in brain hypoxia-induced, as a model of acute transient hypoxia in brain subcortex, expands in mtDNA. It is discovered that overexpression of PGC-1α in neurons plays a protective role in a neurotoxin mouse model in the study of PD [135–137]. Several lines of evidence also represent that the deficit in PD is

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at or above the level of PGC-1α expression, which in turn regulates function of complex I mitochondrial electron transfer [33]. TFAM synthesis is a final effector process that is required for the reproduction of mitochondrial DNA and induced by activity of NRF-1 as an intermediate transcription factor [138]. TFAM is an essential factor-encoded nuclear transcription that translocates into mitochondria and activates mtDNA transcription and replication by binding to the promoter region within the D-Loop region of mtDNA. In some diseases such as obesity, TFAM may be targeted as a good therapeutic objective [139, 140]. The last data indicate to an interesting association between glycogen synthase kinase 3 beta (GSK3β) and mitochondrial biology. PGC-1α stabilization and enhanced PGC-1α levels in primary neurons have been linked to GSK-3β inhibition. Furthermore, inactivation of GSK-3β has been discovered to expand cell content of NRF-1, a PGC1α transcriptional partner which is involved in the genes expression demanded for mitochondrial respiratory chain function. Nevertheless, a comprehensive study of the probable role of GSK-3β inhibition in mitochondrial biogenesis is absent until now [134]. Interestingly, a significant number of the preconditioning stimuli that provoke tolerance may also trigger mitochondrial biogenesis or other key mitochondrial components [22]. For instance, biomarkers of mitochondrial biogenesis were triggered subsequent cerebral hypoxic preconditioning in ischemia and neonatal hypoxia/ischemia in areas which survived the damage [141, 137, 142]. It is indicated that sublethal lipopolysaccharide (LPS) temporary enhanced the expression of key components of the mitochondrial transcriptional machinery, involving NRF-1 and TFAM, mitochondrial protein levels, mtDNA copy number, and markers of functional mitochondria such as maximal respiration capacity, citrate synthase activity, and improved cellular ATP content. Critically, knockdown of TFAM abolished both the induction of mitochondrial biogenesis and concomitantly the neuroprotective preconditioning effects of LPS. It has been remarked on that these events are coordinated by several signaling pathways. Nevertheless, inhibition of AMP-activated protein kinase (AMPK) suppresses NRF-1 and TFAM expression by LPS; activation of AMPK was basic for both induction of NRF-1 and TFAM. However, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling was fundamental for the nuclear translocation of NRF-1 and following induction of TFAM, Akt was not essential for the upstream initiation of biogenesis cascades. Likewise, Akt has additionally been involved in upregulation of NRF-1 transcription by activation of nuclear factor erythroid-derived 2-like 2 (Nfe2l2) [22]. In the near future, induction or improvement of mitochondrial biogenesis may confirm a modern neuroprotective approach. Besides, multiple investigations offer that disruption of mitochondrial function is considered as a critical cause in

the pathophysiology of numerous neurological disorders and adaptive mitochondrial biogenesis has been studied in the nervous system [138]. Indeed, the mitochondrial biogenesis pathway has come as a potential therapeutic target for PD [135]. Preconditioning Mediated by LPS LPS, a component of Gram-negative bacterial cell wall, is an efficient pro-inflammatory compound, which provokes microglial activation and causes neurodegeneration, and has thereby become a beneficial approach to study the probable relationship between neurodegeneration and neuroinflammation [143]. It has been demonstrated that LPS triggers systemic inflammation, which causes nuclear factor kappa-light-chainenhancer of activated B cells (NF-kB) activation in the CNS with following production of chemokines and cytokines such as TNF-α expression [144]. Since TNF-α is usually recognized for its detrimental impacts in various neurological disorders, abolition of TNF-α production, which has been identified as a typical characteristics of LPS tolerance for a number of years, must be responsible for the neuroprotection induced by LPS preconditioning. Taken together, all these data declare a double role connected with TNF-α in LPS preconditioning phenomenon. While extravagant production of TNF-α perform a destructive role in the CNS inflammation, moderate level of this cytokine may have the capability to suppress the TNF-α production in inflammatory response, which might in turn contribute to the neuroprotective effects of LPS preconditioning. Moreover to inhibition of TNF-α overproduction, preconditioning prevents LPS-induced microglia activation [143]. Probably, because of the fact that microglial activation is not generally seen in most recent preconditioning models, the mode of action and the accurate roles of microglia in LPS preconditioning are greatly unclear, even to date [122, 131]. Interestingly, superoxide dismutase (SOD) might contribute the mechanism of neuroprotection as an effective factor in LPS-induced brain ischemic tolerance [143]. LPS is a famous particular ligand for Toll-like receptor 4 (TLR-4), one of the Toll-like receptors (TLRs) that indentify foreign pathogens [120]. TLRs, which are normally regarded as the innate immune receptors, signal through the adaptor proteins MyD88 (myeloid differentiation primary response gene 88) and TRIF (Toll-IL-1 receptor (TIR)-domain-containing adapter-inducing interferon-β) [128]. TLR signaling pathways that activate NF-kB can provoke pro-inflammatory mediators that considered as a harmful effect. On the other hand, the neuroprotective effect of TLR signaling is related to the pathways which result in IRFs (interferon regulatory factors) activation and anti-inflammatory responses. Therefore, there is a great balance between pathways resulting in degeneration or protection [128].

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To summarize, it is indicated that TLR induced neuroprotection happens by reprogramming the genomic response to the damage-associated molecular pattern molecules (DAMPs), which are generated in response to ischemic injury. As mentioned before, the activation of TLR4 signaling preferably results in IRF-mediated gene expression in this reprogrammed state. This reprogrammed response is categorized in two main groups: the first one includes suppressed pro-inflammatory signaling and advanced anti-inflammatory/ type I IFN signaling; however, the second one involves advanced anti-inflammatory/type I IFN signaling in the absence of suppressed pro-inflammatory signaling [128]. Therefore, suppression of the pro-inflammatory MyD88–TNF pathway is made by upregulating pathway inhibitors, namely, Src homology (2)-containing inositol phosphatase-1 (Ship1), Toll interacting protein (Tollip), IL-1 receptor-associated kinase M (IRAK-M), and tripartite-motif protein (Trim30α), among others, which results in reduced inflammatory cytokine responses during secondary exposure to TLR4 ligands compared to first exposure alone [129]. All together, these data greatly support a protective role for TRIF-mediated IRF3 activation in the neuroprotective phenotype induced by LPS preconditioning (Figs. 1 and 2 illustrate the schematic diagrams of TLR4 signaling and gene reprogramming following low-dose LPS preconditioning) [128]. Numerous genes were regulated in a consecutive way with particular patterns of expression at different time points after LPS recommending that CNS vulnerability may depend on the time interval between LPS and the future hit [144]. Furthermore, it is observed that intraperitoneal injection of the lipopolysaccharide induces a rapid innate immune response. Likewise, this systemic inflammatory response can lead to lethal septic shock and be destructive; on the other hand, administration of low doses of LPS elicits a protective state of tolerance to next exposure to LPS at doses that would typically result in severe damage [122, 145]. Ordinarily, neuroprotection provoked by LPS depends on time and dose. The protection is elicited 24 h after administration of LPS and continues to 7 days but is vanished by 14 days. The level of the LPS dose which triggers protection depends on the animal stroke model and the route of administration and ranges from 0.02 to 1 mg/kg [119]. Because of its simplicity of application, unveiling the molecular pathways in LPS neuroprotective signaling has tremendous potential for therapeutic applications [122]. Some studies have uncovered that LPS pretreatment could trigger cross tolerance, whereby the protection against neuronal damage in spinal cord injury or ischemia [143]. The neurobehavioral sequelae of traumatic brain injury can be attenuated by LPS preconditioning stimulus [146, 147]. Interestingly, Kumral M. et al. demonstrated that LPS preconditioning protects the immature brain against following endotoxininduced white matter damage [148]. In the ischemic

hippocampal CA1, some research illustrated that LPS preconditioning may provide neuroprotection [149]. Ischemic preconditioning and LPS contribute to infarct size reduction [150]. It was found that low-dose LPS preconditioning in neonatal rats significantly decreases hypoxic ischemiainduced neuroinflammation and provides long-term neuro and vasculoprotection against pathologic and behavioral abnormalities [151]. LPS-induced preconditioning is a strong neuroprotective phenomenon in the ischemic developing brain that is age dependent [120]. Although LPS preconditioning has no effect on seizures in rats in the pilocarpine model of epilepsy, quantitative and qualitative analyses of histological sections of epileptic rat brain indicated that it might have neuroprotective effects in the CA1, CA3, and dentate gyrus (DG) hippocampal sectors [119]. Likewise, the studies of Mirrione and colleagues uncovered that preconditioning with LPS 24 h before induction of seizure might have a protective effect which is abrogated by unilateral hippocampal microglia/macrophage ablation [152]. LPS-induced striatal inflammation plays as a failure of the mitochondrial respiratory chain in both the striatum and substantia nigra, which was pursued by progressive degeneration of the dopamine nigrostriatal pathway, accumulation of α-synuclein and ubiquitin in the remaining nigral dopaminergic neurons, and behavioral disorder [153]. In contrast, dopaminergic neurons are protected by lowdose LPS preconditioning against inflammatory harm in rat midbrain slice culture. Better understanding the mechanism of LPS preconditioning offers a sparkle of hope in treatment of Parkinson’s disease in future [143].

Additional Preconditioning Stimuli Agents in Relevance with Parkinson’s Disease 6-Hydroxydopamine (6-OHDA) as a neurotoxin used for the development of in vivo models of PD. Exposure to 6-OHDA results in dopaminergic cell death which is believed to be caused by a possible direct effect of 6-OHDA on the mitochondrial respiratory chain and reactive oxygen species (ROS) derived from 6-OHDA auto-oxidation. On the other hand, the process has not been fully cleared [154, 155]. Investigation concerning impact of sublethal 6-OHDA preconditioning on the response to following oxidative stress in dopaminergic cells disclosed that exposure to sublethal dose of 6-OHDA (5–10 μM) protected against the toxic effects of a subsequent exposure to a higher dose (50 μM). Furthermore, it is proposed that production of 6-OHDA- and paraquatinduced reactive oxygen species (ROS) was decreased by previous sublethal H2O2 exposure in PC12 cells [156].

Mol Neurobiol Fig. 1 Induction of TLR4 signaling cascades by low dose of LPS leads to NF-κB activation with dramatically upregulation of pro-inflammatory genes expressions and a mild activation of IRF3

In addition, it was found that exposure of a dopaminergic cell line to sublethal oxidative stress can protect against further oxidative stress because of translational and post-translational modifications as well as confer of cross-tolerance against a various insult proteasome inhibition [60]. Several lines of evidence illustrated that hyperoxia preconditioning provides neuronal protection against central nervous system ischemic harms. Common pathways consist of mitochondrial dysfunction, apoptosis, and caspase activation are involved in acute neurodegeneration (e.g., after cerebral ischemia) and chronic neurodegeneration (e.g., neuronal death

in PD). Long-term hyperoxia preconditioning attenuates the behavioral symptoms of 6-OHDA-induced Parkinsonism [157]. In addition, it is maintained that low concentrations of thrombin as thrombin preconditioning could provide protection against 6-hydroxydopamine infusions in vivo [158]. To review some other under debated preconditioning stimuli agents, some in vitro studies have showed that xanthine/ xanthine oxidase, FeSO4, non-lethal serum deprivation, H2O2, or heat shock defend against cell death induced by rotenone, 1-methyl-4-phenyl-pyridinium (MPP+), and dopamine (DA) exposure [60].

Mol Neurobiol Fig. 2 Low-dose LPS preconditioning prior to high dose of LPS injection alters TLR4 signaling cascades and leads to robust activation of IRF3 and suppressed NF-κB activity and pro-inflammatory genes expression by several inhibitors including Ship1, Tollip, IRAKM, and Trim30α

Conclusion By definition, a strategy to slow or pause of neuronal loss progression is dubbed neuroprotection. Neuroprotection may lead to rescue, regeneration, or recovery of the nervous system, its cells, function, and structure [159]. As maintained before, preconditioning as a natural adaptive process confers neuroprotection in CNS [126]. Likewise, it has been shown that preconditioning provides neuronal protection in relevance with in vivo PD models [157, 158, 156]. By taking in to account of all above-mentioned issues, it is presumable that

preconditioning would hand in a new prospect in the field of prevention of neurodegenerative diseases such as PD. In review of research methods and models, it is noticeable that preconditioning has been applied before production of neuronal degeneration intended to set up the animal models of PD. On the other hand, in these in vivo models, preconditioning has been applied as a pretreatment method. In another view, at the time of clinical diagnosis of PD as an occasional neurodegenerative disease, patients usually have already lost 60 % or more of the neurons in the SNpc [160]. By comparing these aspects, the first thing which pops into mind based on

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today investigations is that to turn the liability of preconditioning to an asset in clinical fields of PD; we need functional screening procedures to detect patients at risk and subsequently preconditioning may use for prevention. In another dimension, it is still unclear that whether preconditioning could prevent the further progression of PD in patients after diagnosis or not. Generally, more studies are required to come to a better picture of the discussed issue.

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