Progress in Neuro-Psychopharmacology & Biological Psychiatry 56 (2015) 122–128

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The role of neurotrophins in bipolar disorder Gustavo Scola a,b, Ana Cristina Andreazza b,c,⁎ a b c

Department of Psychiatry, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada Department of Pharmacology and Department of Psychiatry, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada

a r t i c l e

i n f o

Article history: Received 26 June 2014 Received in revised form 25 August 2014 Accepted 26 August 2014 Available online 2 September 2014 Keywords: Bipolar disorder Glial cell line-derived neurotrophic factor Insulin-like growth factor-1 Neurotrophins Vascular endothelial growth factor

a b s t r a c t Bipolar disorder (BD) is a chronic psychiatric illness of which the pathophysiology remains partially unknown. Abnormalities of neurotrophins and other trophic factors orchestrate important alterations which could be implicated in the etiology of BD. Therefore, the main objective of this review is to examine the recent findings and critically evaluate the potential role of neurotrophins that may allow us to substantially improve the development of novel treatments. The most recently published findings highlight that brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF-1) and vascular endothelial growth factor (VEGF) present distinct patterns in the different stages of BD, suggesting their potential in the identification of the BD subgroups and may ultimately advance treatment strategies. © 2014 Elsevier Inc. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . Neurotrophins: general description . . . . . . . . . . . . Neurotrophins, trophic factors and bipolar disorder . . . . . Neurotrophins . . . . . . . . . . . . . . . . . . . . . . 4.1. Nerve growth factor (NGF) . . . . . . . . . . . . . 4.2. Brain-derived neurotrophic factor (BDNF) . . . . . . 4.3. Neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) 5. Other factors . . . . . . . . . . . . . . . . . . . . . . 5.1. Glial cell line-derived neurotrophic factor (GDNF) . . 5.2. Insulin-like growth factor-1 (IGF-1) . . . . . . . . . 5.3. Vascular endothelial growth factor (VEGF) . . . . . . 6. Concluding remarks . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: BD, bipolar disorder; BDNF, brain derived neurotrophic factor; CNS, central nervous system; ERK, extracellular signal-regulated kinase; GDNF, glial cell line-derived neurotrophic factor; GFRalpha-1, GDNF family receptor alpha 1; GSK3, glycogen synthase kinase-3; IGF-1, insulin-like growth factor; MAPK, mitogen-activated protein kinase; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; NGF, growth factor; NT3, NT-4/5, neurotrophins-3-4/5; NTs, neurotrophins; p75NTR, p75 neurotrophin receptor; PI-3 K, phosphatidylinositol 3-kinase; SNP, single nucleotide polymorphism; TNF, tumor necrosis factor; TrK, TrK tyrosine kinase receptors; VEGF, vascular endothelial growth factor. ⁎ Corresponding author at: University of Toronto, Medical Science Building, Room 4204, 1 King's College Circle, Toronto, ON, M5S 1A8. Tel./fax: +1 416 978 6042. E-mail addresses: [email protected] (G. Scola), [email protected] (A.C. Andreazza).

http://dx.doi.org/10.1016/j.pnpbp.2014.08.013 0278-5846/© 2014 Elsevier Inc. All rights reserved.

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1. Introduction Bipolar disorder (BD) is a complex illness that presents many molecular and morphological alterations suggestive of impairment in cellular plasticity and resilience (Frey et al., 2013). As consistently reported in post-mortem studies, these modifications are generally associated with the disruption of distinct subregions and functions of the brain, one of which is the deregulation of neurotrophins (NTs) (Mufson et al., 1999). These factors that regulate cell dynamics are expressed in

G. Scola, A.C. Andreazza / Progress in Neuro-Psychopharmacology & Biological Psychiatry 56 (2015) 122–128

the brain in a region-specific manner and in the peripheral tissues as well. In addition to this, NTs are also capable of signaling neurons, glial cells and other cellular systems to enable survival, differentiation and growth (Huang and Reichardt, 2001; Kaplan and Miller, 2000; Mufson et al., 1999). Interestingly, these factors are primarily regulated during development and continue to be expressed in different structures of the adult brain. For example, NTs demonstrate the ability to stimulate hippocampal neurogenesis in the mature brain (Huang and Reichardt, 2001; Kaplan and Miller, 2000; Mufson et al., 1999). Several studies have been conducted using different samples such as plasma, serum and post-mortem brain tissues. The differences between these biofluids or tissues could provide independent information regarding the different levels of trophic factors and may assist in the understanding of the pathophysiology of the disorder. Taking these variations in consideration, we aimed to compile a review with the major findings regarding the alterations in the profile of NTs in BD and critically analyze the findings. The relationship between the effects of these factors and the cellular responses in BD may allow us to substantially improve the development of novel treatments. 2. Neurotrophins: general description Among the processes and messengers involved in the regulation of cellular dynamics, such as cellular proliferation, differentiation, and growth, a group of specific proteins called NTs has received massive attention due to their crucial involvement in the maintenance of brain function (Huang and Reichardt, 2001; Kaplan and Miller, 2000; Mufson et al., 1999). Various NTs are expressed in the brain and possess specific abilities to mediate functional and structural changes in central and peripheral connections, such as synaptic function (regulating neurotransmitters and ion channels) and plasticity. Moreover, these factors play important roles outside the central nervous system (CNS), for example, in the maintenance of immune cells and cardiac development (Sariola, 2001). The nerve growth factor family of neurotrophins including brainderived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophins-3-4/5 (NT-3, NT-4/5) promote changes in cellular responses after binding to two specific types of cell surface receptors, the TrK tyrosine kinase receptors and the p75 neurotrophin receptor (p75NTR), a distant member of the tumor necrosis factor (TNF) receptor family (Chao, 1994). The effects of other trophic factors, such as glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) will also be explored in this review. Moreover, these trophic factors bind to different receptors from the nerve growth factor family of NTs but exert their regulation of cellular effects in a similar manner. Their mechanisms of action are also described in this review. The TrK receptor family, TrKa, TrKb and TrKc has a high-affinity for mature neurotrophins and mediates the trophic effects of the NGF family. More specifically, NGF activates TrKa, BDNF and NT-4/5 recognize TrKb, and finally, NT-3 binds to TrKa, TrKb, and Trkc with a higher affinity for TrKc (Huang and Reichardt, 2001; Kaplan and Miller, 2000). In addition, GDNF has also been shown to activate TrK receptors (Huang and Reichardt, 2001). Through these receptors, different NTs activate specific signaling pathways that induce the suppression of apoptotic proteins such as cdc-42/ras/rho G protein families, phosphatidylinositol 3-kinase (PI-3K) and activate anti-apoptotic proteins such as the mitogen-activated protein kinase (MAPK) pathway. Overall, these pathways are vital for cell survival, development, growth and synaptic plasticity. For more information regarding TrK regulation, refer to Huang and Reichardt (2001). Moreover, each NT can also bind to the neurotrophin p75NTR receptor which possesses a low-affinity for mature NTs. Following the interaction between NT and p75NTR, the TrK receptor family exhibits reduced responsiveness to NTs. The role of p75NTR is still unclear; however, it is believed that the activation of this receptor could lead to

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disruption of axonal growth and programmed cell death in neurons (Huang and Reichardt, 2001; Kaplan and Miller, 2000). p75NTR is believed to mediate several signaling mechanisms through the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), which potentiates TrK activity (Kaplan and Miller, 2000) and the activation of Jun Kinase, p53 and Bax induces apoptosis (Huang and Reichardt, 2001; Kaplan and Miller, 2000). 3. Neurotrophins, trophic factors and bipolar disorder Numerous studies have shown the importance of the effects of NTs in stress response and the progression of mood disorders. BDNF is one of the most studied and abundant NTs in the brain, which is significantly reduced in the serum of patients with BD (Frey et al., 2013). In addition to BDNF, other neurotrophic factors such as NGF, NT-3 and NT-4/5 may orchestrate a global response in the pathophysiology of BD when present in imbalanced levels. Members of other families of proteins that regulate survival and development in the central nervous system (CNS), such as GDNF, IGF-1 and VEGF were found to be deregulated and may also play an important role in BD. With this description in mind, we aimed to provide an overview of current findings regarding the effects of NTs and other trophic factors in BD. The first section focuses on the effects of the NGF family, while the second describes the properties of GDNF, IGF-1 and VEGF. The molecular mechanisms of each trophic factor and experimental findings regarding the effects of medication were also included in this review. In addition, all data was summarized in Table 1. 4. Neurotrophins 4.1. Nerve growth factor (NGF) In the brain, NGF promotes protection of sympathetic and cholinergic neurons in the hippocampus and neocortex against programmed cell death and neurodegeneration (Freeman et al., 2004; Nguyen et al., 2010). Importantly, NGF is not only formed in the brain but can be produced in different peripheral cell types such as fibroblasts, suggesting that NGF does not reflect brain-tissue concentrations. Additionally, this NT displays important effects on stimulating axonal growth, learning and memory (Goldberg and Chengappa, 2009). Similarly to BDNF, NGF binds to the p75NTR and to the high affinity nerve growth factor receptor (TrKa). Once NGF is bound to TrKa, the second messengers of the PI-3K/Akt-glycogen synthase kinase-3 (GSK3) pathway are activated (Jones et al., 2003). In general, this pathway is responsible for signal transduction processes, cell survival, proliferation, differentiation, and intracellular trafficking and, has been markedly associated with the pathophysiology of BD (Jones et al., 2003; Kim et al., 2013). However, the role of this NT remains unclear in the pathophysiology of BD as there are few studies that specifically evaluate its effects in BD, some with conflicting results. Barbosa et al. reported that NGF was decreased in the serum of patients with BD in the manic stage when compared to euthymic patients and healthy controls (Barbosa et al., 2011a). More recently, a study stated no significant differences in serum NGF levels between manic patients with bipolar I disorder and healthy controls in a baseline analysis (Kim et al., 2013). Rybakowski et al. (2013) also investigated the levels of NGF in depressed BD patients resistant and not resistant to treatment with antidepressants after a single infusion of ketamine and found no significant differences between the groups (Rybakowski et al., 2013). Despite the fact that NGF was the first NT to be identified, there is very little evidence about its potential role in the pathophysiology of BD. 4.2. Brain-derived neurotrophic factor (BDNF) As mentioned earlier, BDNF plays an important role in the regulation of neuronal development as well as in learning and memory (Poo,

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2001). BDNF is synthesized as a precursor protein, known as preproBDNF. Following the cleavage of the preproBDNF peptide into proBDNF via various intracellular proteases, proBDNF is then converted into mature BDNF by extracellular proteases. Interestingly, each form of BDNF induces opposite effects via TrKb and p75NTR. Mature BDNF binds to the high-affinity neurotrophin TrKb receptor, which regulates cells through activation of proteins, such as PI-3K and NFκB, responsible for cell survival and synaptic plasticity. Importantly, there are a few reports showing that the BDNF/Trkb pathway could be associated with the pathophysiology of BD (Hashimoto et al., 2004; Shaltiel et al., 2007; Wang et al., 2013). Recently, Wang et al. (2013) published that the NTRK2 polymorphism negatively influences the response of lithium treatment in a Chinese cohort (Wang et al., 2013). On the other hand, proBDNF favorably binds to the low-affinity neurotrophin p75 receptor and activates the apoptotic pathway through mediation of c-Jun N-terminal kinases (JNKs), p53 and Bax (Kaplan and Miller, 2000). As far as we know, the regulation between proBDNF and mature BDNF is mediated by synaptic competition (Je et al., 2012). BDNF proform is secreted in the brain, and conversion of proBDNF to mature BDNF is realized extracellular by the tissue plasminogen activator and plasmin protease system (Barker, 2009; Je et al., 2012). Mature BDNF is essential because its plays an important role in regulating cell networking (Holm et al., 2009). In normal physiological conditions, proBDNF is mostly converted to mature BDNF (Barker, 2009; Je et al., 2012); however in BD this phenomenon is still unclear. Moreover, BDNF levels are sex (menstrual cycle dependent) and mass index related. In addition, BDNF is also found in peripheral tissues including skeletal muscle (Matthews et al., 2009), the liver (Cassiman et al., 2001), blood, plasma (Fujimura et al., 2002) and the cardiovascular system (Donovan et al., 2000). BDNF levels in the blood are predominately stored in platelets (Karege et al., 2005), but there is a lack of information regarding the source of peripheral BDNF and its regulation through stress, endocrine factors or environmental stimuli (Chen and Chang, 2009). Thus far, we know that blood-BDNF levels could be derived from the above-listed peripheral tissues and the brain (Chen and Chang, 2009). Importantly, it is also necessary to highlight that BDNF concentrations in the blood reflect brain-tissue BDNF levels (Klein et al., 2011) and this NT has complete passage across the brain–blood barrier (Pan et al., 1998). Munkholm et al. (2014) have shown that BDNF levels in plasma were higher in subjects with BD in euthymic, depressive, manic and hypomanic states when compared to healthy controls. The study also states that patients with longer duration of illness presented higher levels of BDNF and this finding could be influenced by the medication administrated (Munkholm et al., 2014). Rosa et al. reported that patients with BD in a subsyndromal stage present similar plasma BDNF levels as healthy controls (Rosa et al., 2014). In contrast, patients with manic, hypomanic or depressive stages of BD (Cunha et al., 2006; Lin, 2009) present decreased serum BDNF levels, with euthymic patients exhibiting BDNF levels similar to healthy controls (Fernandes et al., 2011). Furthermore, a study using transformed lymphoblasts from patients with BD (Tseng et al., 2008) also reported decreased BDNF levels when compared to healthy controls. Interestingly, another recent study reported that the hippocampus of subjects with BD presents decreased BDNF mRNA levels (Ray et al., 2014). Additionally, it was found that patients with BD presented alterations in 5methylcytosine levels at the BDNF promoter region (D'addario et al., 2012), supporting previous studies. Another study showed that only patients with BD in the later stages of the illness (10–20 years) presented decreased levels of BDNF in comparison to patients in earlier stages (0– 3 years;) (Kauer-Sant'anna et al., 2009). Recently, Södersten et al. (2014) studied two different cohorts (Sahlgrenska and Karolinska sets) and reported the ratio between mature and proBDNF and mature BDNF levels were higher in patients with BD than in healthy controls. However, serum proBDNF levels were found to be lower in patients compared to controls, which suggests that the alteration in the conversion of pro to mature BDNF may be associated to the pathophysiology of

BD (Södersten et al., 2014). Moreover, this decrease in the levels of global BDNF may be less effective in supporting differentiation, growth and survival of neurons, disturbing normal cell regulation and impairing long-term memory, both of which are found to be altered in BD. Interestingly, peripheral BDNF (serum) is believed to be inversely associated with age and duration of illness (Yatham et al., 2009). Another important aspect to be discussed regarding BDNF in BD is the presence of a single nucleotide polymorphism (SNP) in the chromosomal region 11p13. In the BDNF gene there is a substitution of a valine(G) to methionine(A) in the 5′ proregion on nucleotide 196 within codon 66, commonly known as BDNF Val66Met. This SNP leads to a reduction in proBDNF intracellular trafficking in cortical neurons, causing selective impairment in CNS function (Neves-Pereira et al., 2002; Sklar et al., 2002). Furthermore, this SNP seems to be related to a range of psychiatric disorders including anxiety disorders (Lang et al., 2005), schizophrenia (Chen et al., 2014; Ho et al., 2006), unipolar depression (Hwang et al., 2006), late life depression (Taylor et al., 2007) and altered brain morphology (Montag et al., 2009). Moreover, studies have shown that BDNF levels normalized after treatments with mood-stabilizers, antidepressants and antipsychotics (Sen et al., 2008). The interactions between the mechanisms of action of these drugs leading to the increase in BDNF levels are partially understood and have yet to be fully determined. 4.3. Neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) NT-3 and NT-4, also known as NT-5, are derived from a common ancestral gene and belong to the NGF family. Differently from NGF, NT-3 and NT-4/5 can cross the blood–brain barrier and remain stable in the blood (Pan et al., 1998). Interestingly, there is another protein, NT-6, which is not found in mammals (Götz et al., 1994). These NTs are similar in sequence and structure and support the survival and differentiation of neurons in the CNS as well as stimulate the growth and differentiation of new neurons and synapses. Curiously, NT-3 was the third NT characterized after NGF and BDNF. Moreover, both NT-3 and NT-4 retain the ability to induce neuronal formation from neural stem cells through activation of TrKc and TrKb, as described above. Some studies have linked the effects, or lack thereof, of NT-3 and NT-4 to the pathophysiology of BD. Waltz et al. investigated the serum levels of NT-3 in patients with BD (under medication) during manic, depressed, and euthymic states. While NT-3 levels were increased in manic and depressed patients, euthymic patients and healthy controls were found to have normal levels (Walz et al., 2007). A few years later, the same group investigated the possible effects of medication on NT-3 levels in patients with BD (Fernandes et al., 2010). The results were compared to patients on medication during manic and depressive episodes. The authors reported that serum levels of NT-3 in drug-free patients (increased) did not differ from patients on medication both in manic and depressive episodes when compared to healthy controls (Fernandes et al., 2010). Kapczinski's group have also found that serum levels of NT-4/5 are elevated in patients with BD compared to healthy controls. These levels were increased in patients with mania, depression and euthymia (Walz et al., 2009). On the other hand, Rybakowski et al. (2013) also investigated the levels of NT-3 and NT4/5 in patients with BD responding to mood-stabilizing medication and not responding to mood-stabilizing medication and found no significant differences in the levels of these factors between groups (Rybakowski et al., 2013). The interactions between the effects of NT-3 and NT4/5 leading to the alterations in the brains of patients with BD are not completely understood and require future research. 5. Other factors 5.1. Glial cell line-derived neurotrophic factor (GDNF) GDNF is related to the transforming growth factor-β family and is expressed throughout the brain (Airaksinen and Saarma, 2002).

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Table 1 Recent findings in the literature related to the plasma/serum levels of neurotrophins and other trophic factors in patients with bipolar disorders and healthy controls. Trophic factors

NGF

BDNF

Findings in BD

↓ in the manic stage when compared to euthymic patients and healthy controls No significant differences between manic patients with BDI and healthy controls No significant differences between patients resistant and not resistant to treatment with antidepressants after single ketamine infusion Patients in a subsyndromal stage present similar levels as healthy controls ↓ in the manic, hypomanic and depressive stages

Euthymic patients exhibit similar levels to healthy controls (meta-regression analysis) ↓ in transformed lymphoblasts when compared to healthy controls ↓ only in the later stages of the illness in comparison to patients in earlier stages ↑ ratio between mature and proBDNF levels in patients than in healthy controls

NT3

Characteristics of subjects

Cohorts

Reference

12/18 8/11 15/21 38/64 56/67 4/21

Brazilians

Barbosa et al., 2011a,b

Koreans

Kim et al., 2013

Polish

Rybakowski et al., 2013

Subsyndromal stage Healthy controls Manic stage Depressive stage Euthymia Healthy controls n.a.

22/28 22/28

British

Rosa et al., 2014

12/20 6/15 12/20 12/6 n.a.

Brazilians

Cunha et al., 2006

n.a.

Fernandes et al., 2011

Bipolar disorder Healthy controls Bipolar disorder Healthy controls Bipolar disorder Healthy controls

6/6 7/6 9/21 11/19 15/33⁎– 130/ 133⁎⁎ 19/24⁎– 48/64⁎⁎ 15/33⁎– 130/ 133⁎⁎ 19/24⁎– 48/64⁎⁎

Canadians

Tseng et al., 2008

Brazilians Canadians Sahlgrenska⁎ Karolinska⁎⁎

Kauer-Sant'Anna et al., 2009 Södersten et al., 2014

Sahlgrenska⁎ Karolinska⁎⁎

Södersten et al., 2014

Diagnosis

Number male/female

Manic stage Euthymia Healthy controls Bipolar disorder Healthy controls Depressive stage

↓ proBDNF levels in patients compared to controls

Bipolar disorder Healthy controls

↑ levels in plasma in euthymic, depressive, manic and hypomanic states when compared to healthy controls

Euthymia Manic stage Depressive stage Mixed stage Healthy controls Manic stage Euthymia Depressive stage Healthy controls Manic stage Depressive stage Healthy controls Manic stage Depressive stage Healthy controls Depressive stage

75 24 63 6 80 14/17 15/15 10/9 35/45 4/6 1/9 5/15 4/6 1/9 5/15 4/21

New Zealand Denmark

Munkholm et al., 2014

Brazilians

Walz et al., 2007

Brazilians

Fernandes et al., 2010

Brazilians

Fernandes et al., 2010

Polish

Rybakowski et al., 2013

Manic stage Euthymia Depressive stage Healthy controls Depressive stage

19/35 28/11 15/46 6/24 4/21

Brazilians

Walz et al., 2009

Polish

Rybakowski et al., 2013

Partial or full remitted state BDI/BDII Healthy controls Manic Stage Euthymia Depressive stage Healthy controls Remissive state Depressive stage Healthy controls Manic stage Depressive stage Healthy control Depressive stage

4/13 9/8 17/39

Japanese Brazilians

Takebayashi et al., 2006

8.4/6.5 6/9 4/10 4.3/9.6 5/24 2/11 15/13 10/12 8/10 22/28 4/21

Brazilians

Rosa et al., 2006

Japanese

Otsuki et al., 2008

Chinese

Zhang et al., 2010

Polish

Rybakowski et al., 2013

Manic stage Euthymia

12/18 8/11

Brazilians

Barbosa et al., 2011a,b

↑ in manic and depressive stages, but not in the euthymic patients when compared to healthy controls

↑ in drug-free patients

↑ in patients on medication both in manic and depressive episodes when compared to healthy controls

NT4/5

Patients resistant and not resistant to treatment with antidepressants do not have significant differences in the levels of this NT after single ketamine infusion ↑ in manic, depressive and euthymic stages

GDNF

Patients resistant and not resistant to treatment with antidepressants do not have significant differences in the levels of this NT after single ketamine infusion ↓ in BDI and BDII when compared to healthy controls

↑ in immune cells in manic and depressive stages, but not in euthymic patients when compared to healthy controls

No alteration in the expression levels of GDNF mRNA was found in patients with depressive and remissive BD when compared to healthy controls ↑ after mood-stabilizers treatment

Patients resistant and not resistant to treatment with antidepressants do not have significant differences in the levels of GDNF after single ketamine infusion ↑ in euthymic patients in comparison to manic and healthy controls

(continued on next page)

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Table 1 (continued) Trophic factors

IGF-1

Findings in BD

↓ mRNA levels of IGF-binding protein-2 in the post-mortem prefrontal cortex of patients

↓ in patients with BD compared to patients with schizophrenia

VEGF

Up-regulated in lymphoblastoid cells from lithium-responsive patients ↑ in manic stage in comparison to healthy controls ↑ mRNA expression levels in depressive stage when compared to healthy controls ↓ mRNA levels after lithium treatment in remissive patients when compared to healthy controls

Characteristics of subjects Diagnosis

Number male/female

Healthy controls Bipolar disorder Healthy controls

15/21 9/6 8/6

Bipolar disorder Healthy controls Responders Non responders Manic stage Healthy controls Depressive stage Remissive state Healthy controls Remissive state Healthy controls

15/8 30/13 8/8 6/10 13/22 27/33 2/10 7/25 15/13 4/5 4/5

However, GDNF does not cross the blood–brain barrier and it is also synthesized, secreted and activated by a variety of peripheral tissues (Airaksinen and Saarma, 2002; Boado and Pardridge, 2009). It is still unclear if the peripheral levels of this NT could be associated with the CNS levels. This factor exerts its biological effects through the Ret receptor tyrosine kinase (Durbec et al., 1996) and a multicomponent receptor complex known as GDNF family receptor alpha 1 (GFRalpha-1)(Lin et al., 1993). Moreover, this NT was the first factor of the GDNF family to be discovered and has proven to be more potent at promoting survival of dopaminergic neurons than other NTs (Lin et al., 1993). GDNF also exerts neuroprotective effects and is responsible for the development and maintenance of central/peripheral neurons (Airaksinen and Saarma, 2002) and there are some reports indicating its use as a neurotherapeutic agent (Boado and Pardridge, 2009). In addition, this trophic factor has also been associated with the modulation of synaptic plasticity (Airaksinen and Saarma, 2002; Lin et al., 1993; Rosa et al., 2006) and several studies have been conducted to examine its effects on BD. One of the first reports suggesting that altered levels of GDNF may be related to the pathophysiology of BD involved analyzing the blood from Japanese patients (Takebayashi et al., 2006). This study reported that total GDNF levels were found to be lower in patients with BD I and BD II when compared to healthy controls. In the same year, Rosa et al. (2006) published that GDNF content in immune cells were found to be increased in patients in a manic stage and increased in patients in a depressive stage, but not in euthymic patients when compared to healthy controls in a Brazilian cohort (Rosa et al., 2006). In 2008, Otsuki et al. reported no alterations in the expression levels of GDNF mRNA in patients with depressive and remissive BD when compared to healthy controls (Otsuki et al., 2008). Zhang et al. (2010) evaluated a Chinese Han cohort of patients with manic and depressive stages of BD for serum GDNF levels and found that they were significantly lower in both stages when compared to healthy controls. However, after 8 weeks of treatment with mood-stabilizers there was an increase in the serum levels of GDNF (Zhang et al., 2010). Interestingly, another study using a Brazilian cohort reported that GDNF plasma levels were higher in euthymic patients in comparison to manic and healthy controls when analyzed through euthymia vs. mania, euthymia vs. healthy controls and mania vs. healthy controls (Barbosa et al., 2011b). Furthermore, Rybakowski et al. (2013) also investigated the levels of GDNF in patients with BD responding to mood-stabilizing medication and patients not responding to medication and found no significant differences between the two groups (Rybakowski et al., 2013). These findings regarding the effects of GDNF in BD reveal that different stages of the disorder and drug treatment can alter the expression of this trophic factor. GDNF may be considered as a non-specific peripheral

Cohorts

Reference

Post-mortem tissues from the Stanley Foundation Neuropathology Consortium Spanish

Bezchlibnyk et al., 2007

Italians

Squassina et al., 2013

Korean set

Lee and Kim, 2012

Japanese

Shibata et al., 2013

Japanese

Kikuchi et al., 2011

Palomino et al., 2013

marker that can respond to drug treatment (Zhang et al., 2010) considering the strong evidence of its involvement in BD. 5.2. Insulin-like growth factor-1 (IGF-1) This factor is a polypeptide trophic factor that regulates survival and differentiation of neuronal and peripheral cells (Zheng et al., 2002). IGF1 is primarily produced in the liver and can be transported to the brain easily when bound to binding proteins, such as IGFBP 1–6 in the plasma and cerebrospinal fluid (Riikonen, 2006). Generally, IGF-1 is responsible for modulating human brain development and promoting neuroprotection following damage to neurogenesis, myelination and synaptogenesis (Palomino et al., 2013). This trophic factor binds to the cell surface Type 1 IGF receptor, widely expressed in the CNS specifically during the development of the brain or in response to injury (Pereira et al., 2011). After binding to its receptor, IGF-1 activates the PI-3K/Akt kinase pathway that phosphorylates the winged-helix family of transcription factors regulating the cellular cycle in rat hippocampal neurons (Zheng et al., 2002). Since these transcription factors are highly conserved in mammals (ie. present in humans and rats), we can apply these findings related to the IGF-1 signaling cascade to humans. Moreover, this factor has an important role in the promotion of dorsal root ganglion neuronal development and peripheral axonal regeneration and growth (neuritogenesis) (Jones et al., 2003; Kimpinski et al., 1997). Importantly, the effects of IGF-1 are more pronounced in the adult brain than in the developing brain (Bondy and Lee, 1993). Genetic studies have shown that IGF-1 may have a strong role in the development of BD (Pereira et al., 2011), since its gene is located on chromosomal region 12q23.2, a region linked to BD pathophysiology (Curtis et al., 2003). Bezchlibnyk et al. reported that the mRNA levels of IGFbinding protein-2, which is a protein that binds with high affinity to either IGF-1 or IGF-2 to transport these factors to other tissues or organs, were found to be decreased in the prefrontal cortex of patients with BD (Bezchlibnyk et al., 2007). A recent study reported that peripheral levels of IGF-1 were lower in patients with BD compared to patients with schizophrenia (Palomino et al., 2013). Interestingly, IGF-1 was found to be up-regulated in lymphoblastoid cells from lithium-responsive patients with BD (Squassina et al., 2013), suggesting that a potential mechanism of action of lithium may be involved in the regulation of IGF-1 secretion. Studies have suggested a possible molecular link between stress, depression, and hippocampal neurogenesis via the IGF-1 signaling cascade (Curtis et al., 2003; Kempermann and Kronenberg, 2003; Palomino et al., 2013; Pereira et al., 2011). Thus, the evidence provided in this section suggests the importance of this NT in the pathophysiology of BD. In addition, the possibility that lithium may regulate IGF-1 levels (Palomino et al., 2013) should be explored in greater detail.

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5.3. Vascular endothelial growth factor (VEGF) VEGF is produced in many cell types and is not limited to the vascular system alone. It also plays an important role in neuronal plasticity as it has been implicated in neuronal protection, survival, regeneration and cellular differentiation (Fournier et al., 2012; Nowacka and Obuchowicz, 2012; Ruiz De Almodovar et al., 2009). However, VEGF does not cross the blood–brain barrier, suggesting that VEGF might stimulate the CNS through effects on the brain vasculature (Ruiz De Almodovar et al., 2009). This hypoxia-induced angiogenic protein produces its biological effects by binding to three different VEGF receptors: VEGFR1, VEGFR2 and VEGFR3 (Nowacka and Obuchowicz, 2012). The interaction between the protein and its receptors has been shown to activate the extracellular signal-regulated kinase (ERK) pathways, Erk1/2 and Akt signaling pathways in the adult rat hippocampus and cultured hippocampal neuronal progenitor cells (Fournier et al., 2012). Importantly, some studies have shown that higher levels of this factor are associated with major depressive disorder (Iga et al., 2007; Takebayashi et al., 2010) while lower levels of VEGF may be associated with suicidal ideation (Isung et al., 2012). Increased plasma VEGF levels were also found in patients with BD in a manic stage in comparison to healthy controls (Lee and Kim, 2012). Shibata et al. (2013) reported that mRNA expression levels were increased in patients with BD in a depressive stage when compared to healthy controls (Shibata et al., 2013). Interestingly, one study showed that lithium treatment was able to decrease VEGF mRNA levels in remissive patients with BD when compared to healthy controls (Kikuchi et al., 2011). The findings discussed in this section demonstrate that VEGF levels may vary accordingly with the state of the disease in BD. Moreover, this factor may be associated with the pathophysiology of BD; however, further clinical studies are required to support this hypothesis.

6. Concluding remarks We reviewed the recent findings in the literature related to the involvement of the nerve growth factor family of neurotrophins and other trophic factors in the pathophysiology of BD. It is important to highlight that the studies regarding the topic described in this review provided limited data with low number of subjects from different ethnicities suggesting the need of more robust studies to confirm the effects of these NTs in BD. Importantly, the evidence provided in the review suggest that more attention should be given to the role of neurotrophins in BD and also, a better understanding of the role of each trophic factor could revolutionize the drug treatment for BD. So far, we found that most published findings on BDNF have demonstrated a correlation between low levels of this NT and BD. The results regarding BDNF have been consistently replicated in multiple studies involving blood and tissue samples, particularly in the depressive stage. Importantly, treatment with mood-stabilizers, specifically lithium, has been shown to normalize BDNF levels (Sen et al., 2008) in BD, suggesting that BDNF has the potential to be used as a biomarker to aid in diagnosis and to monitor the progression of the illness (Frey et al., 2013). Moreover, BDNF may be a promising target for treatment for BD and other psychiatric disorders. For this, more studies investigating the effects of pro and mature BDNF on BD should be conducted. Examination of GDNF in BD reveals that different stages of the disorder alter the expression of this factor. Treatment with mood-stabilizers increased the levels of this trophic factor (Zhang et al., 2010), suggesting that GDNF may be an intervention target for the treatment of BD. Similarly to BDNF and GDNF, studies regarding the expression of IGF-1 and VEGF presented a strong correlation within the pathophysiology of BD, with drug treatment having an important regulatory effect on both trophic factors levels (Kikuchi et al., 2011; Squassina et al., 2013). Therefore, more studies are needed to elucidate the role of these factors in BD and to verify their potential as a biomarker.

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In summary, alterations in trophic factor levels in the brain and periphery in BD have important pathophysiological implications, including morphological alterations in the brain. Abnormalities of prefrontal white matter in patients with BD were recently reported by our group (Versace et al., 2013) and these alterations may be, in part, related to dysregulation in the physiological expression of these trophic factors. Changes in the levels of these trophic factors contribute to non-synergistic effects causing disruptions in their abilities to stabilize and maturate the existing synapses, regulate the neuronal cells and improve axonal arborisation, which could lead to the morphological modifications found in patients with BD. Moreover, future studies highlighting the differences of neurotrophin levels between BD and Major Depressive Disorder are indeed encouraged by the field. From a clinical perspective, it is hoped that current research aimed at understanding the roles of NTs and other trophic factors in BD will lead to the development of novel therapeutics, which could improve the quality of life of patients with the disorder. Conflicts of interest Authors declare no conflicts of interest and all authors have approved the final article. Acknowledgments The authors thank the CAMH Foundation (1000109) and the Canadian Institutes of Health Research (MOP 133439) as sources of funding in support of this report and Victoria Laliberté for her help in editing this manuscript. References Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 2002;3:383–94. Barbosa IG, Huguet RB, Neves FS, et al. Impaired nerve growth factor homeostasis in patients with bipolar disorder. World J Biol Psychiatry 2011a;12:228–32. Barbosa IG, Huguet RB, Sousa LP, et al. Circulating levels of GDNF in bipolar disorder. Neurosci Lett 2011b;502:103–6. Barker PA. Whither proBDNF? Nat Neurosci 2009;12:105–6. Bezchlibnyk YB, Xu L, Wang JF, et al. Decreased expression of insulin-like growth factor binding protein 2 in the prefrontal cortex of subjects with bipolar disorder and its regulation by lithium treatment. Brain Res 2007;1147:213–7. Boado RJ, Pardridge WM. Comparison of blood–brain barrier transport of glial-derived neurotrophic factor (GDNF) and an IgG-GDNF fusion protein in the rhesus monkey. Drug Metab Dispos 2009;37:2299–304. Bondy C, Lee WH. Correlation between insulin-like growth factor (IGF)-binding protein 5 and IGF-I gene expression during brain development. J Neurosci 1993;13:5092–104. Cassiman D, Denef C, Desmet VJ, et al. Human and rat hepatic stellate cells express neurotrophins and neurotrophin receptors. Hepatology 2001;33:148–58. Chao MV. The p75 neurotrophin receptor. J Neurobiol 1994;25:1373–85. Chen KC, Chang LS. Arachidonic acid-induced apoptosis of human neuroblastoma SK-NSH cells is mediated through mitochondrial alteration elicited by ROS and Ca(2+)evoked activation of p38alpha MAPK and JNK1. Toxicology 2009;262:199–206. Chen SL, Lee SY, Chang YH, et al. The BDNF Val66Met polymorphism and plasma brainderived neurotrophic factor levels in Han Chinese patients with bipolar disorder and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2014;51C:99–104. Cunha AB, Frey BN, Andreazza AC, et al. Serum brain-derived neurotrophic factor is decreased in bipolar disorder during depressive and manic episodes. Neurosci Lett 2006;398:215–9. Curtis D, Kalsi G, Brynjolfsson J, et al. Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23-q24, and suggests the presence of additional loci on 1p and 1q. Psychiatr Genet 2003;13:77–84. D'Addario C, Dell'Osso B, Palazzo MC, et al. Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII. Neuropsychopharmacology 2012;37:1647–55. Donovan MJ, Lin MI, Wiegn P, et al. Brain derived neurotrophic factor is an endothelial cell survival factor required for intramyocardial vessel stabilization. Development 2000; 127:4531–40. Durbec P, Marcos-Gutierrez CV, Kilkenny C, et al. GDNF signalling through the Ret receptor tyrosine kinase. Nature 1996;381:789–93. Fernandes BS, Gama CS, Walz JC, et al. Increased neurotrophin-3 in drug-free subjects with bipolar disorder during manic and depressive episodes. J Psychiatr Res 2010;44:561–5. Fernandes BS, Gama CS, Ceresér KM, et al. Brain-derived neurotrophic factor as a statemarker of mood episodes in bipolar disorders: a systematic review and metaregression analysis. J Psychiatr Res 2011;45:995–1004.

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