Kazuko Sakata

Review Article

Austin J Pharmacol Ther. 2014;2(1): 1006.

Brain-Derived Neurotrophic Factor for Depression Therapeutics.

Kazuko Sakata *

Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, USA

*Corresponding author: : Kazuko Sakata, Department of Pharmacology/Psychiatry, College of Medicine,University of Tennessee Health Science Center, 874 Union Ave, Room 430, Memphis, TN 38163

Received: January 01, 2014; Accepted: January 22, 2014; Published: January 27, 2014;

Abstract

Increasing evidence over the last two decades has indicated that the pathophysiology of major depressive disorder (MDD) and the action of antidepressants both involve brain-derived neurotrophic factor (BDNF), a major neuronal growth factor in the brain. MDD is a complex disorder that results from genetic and environmental influences, singly or in combination. This article reviews the current knowledge of BDNF and depression therapeutics, focusing especially on the gene regulation of BDNF and other BDNF–related mechanisms for recent depression therapeutics, including glutamatergic antidepressants and brain stimulation. It is still unclear why some people are more susceptible to MDD and why many show individual differences in their treatment responses.This article also briefly reviews more recent findings on the epigenetic and genetic status of the BDNF gene in brain and blood, which may explain MDD susceptibility and predict response to depression treatment.

Introduction

Major depressive disorder (MDD) is the leading cause of disability in developed countries (˜350 million people are affected worldwide), with devastating symptoms including depressed mood, loss of interest or pleasure, executive dysfunctions, psychomotor retardation, suicide ideation, and eating and sleep disturbances [1]. However, the current treatment outcome is suboptimal—only one–third of patients show remission after a first–line treatment and only about a half of patients show complete remission following multiple treatments that take several months to years [2]. A more efficacious treatment and preventions are needed to combat MDD and to increase quality of life and reduce the disease burden. It is therefore imperative to understand the mechanisms of this disorder and its recovery.

BDNF and depression

A large body of evidence over the past decade has suggested that the pathophysiology of MDD and its recovery involve gene regulation of brain–derived neurotrophic factor (BDNF) [3–6]. BDNF is a major neuronal growth factor in the brain, which regulates neurogenesis, neuronal maturation and survival, and synaptic plasticity. Low levels of BDNF have been observed in the brain of suicide subjects and depressed patients [7–10], particularly in the regions (i.e., hippocampus, prefrontal cortex, and amygdala) that show atrophy in depressed patients and stressed animals [11–13]. Reduced BDNF levels have been also observed in blood of depressed patients, and these low levels can be reversed following depression treatment [14]. Causal relations between stress and BDNF have been clarified by using rodents; physical stress (acute and chronic immobilization) and corticosterone (a hormone induced by stress) have been shown to decrease BDNF levels in the hippocampus [15]. Negative environmental effects like psychological stress (re–exposure to cue associated with foot shocks [16] and chronic social defeat [17]) and chronic alcohol intake [18] also decrease BDNF levels in the hippocampus. On the other hand, different types of depressiontherapeutics (e.g., antidepressants and brain stimulations, see 3 and 4 below) increase BDNF levels and can reverse the stress–induced BDNF reduction [19]. Direct antidepressant effects of BDNF have been also reported; infusion of BDNF into the hippocampus produced sustained antidepressant–like effects in rodents [20–23]. These findings give hope that increasing the levels of BDNF in the related brain regions and targeting the involved pathways may become a new strategy for the prevention and treatment of MDD.

Gene regulation of BDNF

The expression of BDNF is tightly regulated by at least 9 promoters in both humans [24,25] and rodents [26,27]. Each promoter regulates BDNF expression differently in a region/cell–specific manner and has distinct function responding to stress, neuronal activity, and MDD treatments (see [6] for review). Stress reduces the activity of BDNF promoters IV and VI through epigenetic regulation processes that involve increases in histone H3 lysine 27 (H3K27) trimethylation [17,28] (see [29] for detailed epigenetic mechanisms of the BDNF gene). Recent studies have shown that the post–mortem brain of suicidal human subjects also display increased methylation at BDNF promoter/exon IV; this reduces transcription of the Bdnf gene [30]. Further, early–life maltreatment of infants has been reported to increase methylation of the promoter IV–controlled Bdnf DNA (exons IV and IX) and leads to persistent reduction in BDNF expression in the prefrontal cortex in adulthood [31]. Our group recently showed that a lack of promoter IV–driven BDNF [32] leads to depressionlike behavior in mice [33]. Promoter IV is the best–known activitydependent promoter among the known promoters; it responds to neuronal activity to increase BDNF levels [34–36], particularly in the cortex and hippocampus [37,38]. These findings suggest an intriguinghypothesis for critical roles of activity–dependent expression of BDNF in sustaining neuronal activity by a positive feedback mechanism [6]; namely, increased neuronal activity induces activity–dependent BDNF expression, which then induces neuronal activity to maintain active brain functions. Any disruption in the activity–dependentBDNF expression would therefore lead to a decrease in neuronal activity and function, which could in turn lead to depression [Figure 1].

It should be noted that BDNF increases activity/functions of both excitatory and inhibitory neurons. In particular, activity–driven BDNF expression is critical for increasing maturation and functions of the GABAergic inhibitory neurons [32,39–42]. Thus, the activated excitatory neurons likely receive tight inhibition by thenearby GABAergic neurons via the activity–driven BDNF expression. This enhancement of neuronal excitation and inhibition may increase synchronous neuronal activity in a neuronal circuit to control timingdependent signal processing [32]. The enhanced timing–dependentexcitation and inhibition may be critical for flexible learning (e.g., extinction of bad memories and fear) and recovery from MDD [43]. The neural functions of BDNF in the neuronal network including all kinds of neurons remain to be elucidated in the future.

Figure 1: Activity-dependent BDNF hypothesis of depression. Increased neuronal activity, induced by an enriched environment (e.g., physical exercise, mental stimulation with learning exercise and sensory input, and social interactions) and/or medication up-regulates BDNF expression in the hippocampus and cortex. This, in turn, increases neuronal activity and this positive feedback loop can maintain an active mind state. In contrast, any disruption in BDNF expression, caused by epigenetic regulation processes, stress, and/or reduced neuronal activity, would lead to decreases in neuronal activity and activity-driven BDNF expression. This vicious cycle of decreasedneuronal activity and reduced BDNF expression may cause depression. Modified and used with permission from [6].



Figure 1:  Activity-dependent BDNF hypothesis of depression. Increased neuronal activity, induced by an enriched environment (e.g., physical exercise, mental stimulation with learning exercise and sensory input, and social interactions) and/or medication up-regulates BDNF expression in the hippocampus and cortex. This, in turn, increases neuronal activity and this positive feedback loop can maintain an active mind state. In contrast, any disruption in BDNF expression, caused by epigenetic regulation processes,  stress, and/or reduced neuronal activity, would lead to decreases in neuronal activity and activity-driven BDNF expression. This vicious cycle of decreased neuronal activity and reduced BDNF expression may cause depression.Modified and used with permission from [6].

In contrast to stress⁄negative factors, healthy factors such as longterm (4–8 weeks) physical exercise [44–46], learning training [47,48], and being reared in an enriched environment [49,50], all induceexpression of BDNF in the hippocampus and cortex, controlled via its multiple promoters (see [6] for review). For example, physical exercise (4 weeks of running) induces relatively strong BDNF expression through promoters I, II, and III (but not through promoters IV and VI) [50–52], while novel objects (e.g. toys) induces moderate BDNF expression through promoter I, II, III, IV and VI in the hippocampus [52]. Stimuli that induce long–term potentiation (LTP), a form of synaptic plasticity, also induce BDNF mRNA expression in the hippocampus—the brain region important for memory formation, suggesting a role of BDNF in learning [53,54]. The currentlyprescribed monoaminergic antidepressants [e.g., selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), tetracyclic antidepressants, and monoamine oxidase inhibitors treatments (MAOI)] increase monoamine levels in the brain, but direct application of monoamines (serotonin, norepinephrine, dopamine) to hippocampal neurons has failed to induce BDNF expression in an acute phase (3 hrs) [55]. However, chronic (<3 weeks) administration of different classes of monoaminergic antidepressants has been shown to increase Bdnf gene expression through different promoters in the hippocampus and cortex. For example, fluoxetine (SSRI) works on promoter II [56]; phenelzine (MAOI) works on promoters I and VI [56]; duloxetine (a serotonin–norepinephrine reuptake inhibitor, SNRI) works on promoters III and IXa [57]; and imipramine (TCA) works on promoters IV and VI [17]. However, the amount of increase is not robust compared to that seen with neuronal depolarization (see [6] for review).

The recent development of mutant mice that lack promoter IVdriven BDNF but retain intact other promoters and the BDNF coding region (KIV, [32]) has begun to answer some of the questions about the role of endogenous gene regulation of BDNF in antidepressant effects. In our investigations, we have not been able reproduce previous results showing that chronic (3 weeks) treatments with different kinds of antidepressants increased hippocampal BDNF levels in both normal and mutant mice [58]. The previously reported increases in BDNF levels in response to chronic monoaminergic antidepressant treatment may in fact have been a secondary effect due to increased behavioral activity over the time (>3 weeks) induced by the increased monoamine levels. The behavioral activity, and thus the behavioral activity–driven BDNF induction, may be compromised in a certain laboratory setting. In the depression mouse model that lacks promoter IV–driven BDNF, an enriched environment treatment showed a better effect in increasing BDNF levels through multiple promoters and neurogenesis and in reversing depression–like behavior than did treatments with different types of monoaminergic antidepressants [43,50]. These findings indicate that neuronal activity, rather than the monoamine modulation itself, may be a strong inducer of BDNF levels. It should be noted that the chronic treatment with the monoaminergic antidepressants and enriched environment produced antidepressanion–like behavioral effects tested in the tail suspension test in KIV mice [43,50]. This fact indicates that promoter IVdriven BDNF is not required for the preclinical antidepressant–like effects.

Bidirectional roles of BDNF depending on the brain regions: BDNF mRNA levels are abundant in the cortex and hippocampus but are much less in the ventral brain regions except some thalamic nucleus [59], where activity of promoters I, II and VI have been observed [38]. However, the ventral brain regions show moderate BDNF protein expression by anterograde transport of BDNF [60]. The BDNF regulation by stress and its effect in the ventral brain regions are opposite to that in the cortex and hippocampus: Stress increases BDNF protein levels in the nucleus accumbens and BDNF in this region causes depression–like behavior [61, 62]. It remains unclear which promoter is responsible for this stress–induced BDNF increase and how these changes affect the neural network functions in the connected brain regions.

New–lines of depression therapeutics

Antidepressants acting on glutamate receptors

Neuronal activity–driven BDNF induction via glutamate, the major excitatory neurotransmitter, and depolarization has been well studied over the last two decades [55,63,64]. Recently, glutamatergic drugs (including agonists and antagonists) have been shown to have acute antidepressant effects (see reviews [65,66]). Glutamate receptors are classified as ionotropic (i) and metabotropic (m) glutamate receptors (GluRs). The iGluRs include N–methyl–D–aspartate (NMDA) and a–amino–3–hydroxy–5–methyl–4–isoxazolepropionic acid (AMPA) receptors, while mGluRs, which are coupled with ion channels orG–proteins, include the group containing mGluR1 through mGluR8. Interestingly, almost all of these glutamatergic drugs that show antidepressant (–like) effects also increase BDNF levels and act on its signaling pathways [Table 1].

Table 1: Glutamatergic drugs, antidepressant effects, and BDNF.



  
    Target 
    Drug 
    Major mechanism of action 
    Antidepressant effects 
      in human 
    Antidepressant effects 
      in rodents 
    BDNF levels 
      in human 
    BDNF levels 
      in rodents 
    Reference 
  
  
    NMDAR 
    Ketamine
    Non-competitive    antagonist
    Yes
    Yes
    ↑ 
    ↑ 
    [67-72]
  
  
    NMDAR 
    MK-0657
    Selective NR2B antagonist
    Yes
     
    ↑ 
     
     
      [73]
  
  
    NMDAR 
    Acamprosate
    NMDA and mGluR5 antagonist
    Inconclusive
    Yes
    ↑ 
     
    [73-75]  
  
  
    NMDAR 
    Memantine
    Non-competitive    low-affinity antagonist
    No
     
     
    ↑ 
     
      [76-78]
  
  
    AMPAR 
    Ampakines
    Positive allosteric    modulator
    Yes
    Yes
     
    ↑ 
    [79-85]
  
  
    mGluR2/3 
    LY379268
    Agonist
    Clinical trials    undergoing
    Yes ↑ (enhancement with antidepressants)
     
    ↑ (with antidepressants)
    [86-90]
  
  
    mGluR2/3 
    LY341495
    Antagonist
    Clinical trials    undergoing
    Yes
     
    ↑ (enhancement with DOI)
    [91-92]
  
  
    mGluR5 
    MPEP
    Selective antagonist
     
    Yes
     
    ↑ (hippocampus) ↓ (cortex)
    [93-96]
  
  
    Other 
    Riluzole
    Reduces extra-synaptic    glutamate by inhibiting presynaptic release and enhancing glial uptake
    Yes (preliminary)
     
     
    ↑ 
    [97-99]



Table 1:  Glutamatergic drugs, antidepressant effects, and BDNF.

Ketamine, a NMDR receptor antagonist, produces an acute antidepressant effects that lasts for a week in patients with depression when provided at a low dose [67–69]. Ketamine is thought to block NMDA receptors on GABAergic neurons, thereby inhibiting GABA neurons (reducing GABAergic inhibition) and increasing the excitability of glutamatergic neurons [70]. Ketamine rapidly increases BDNF–protein levels without BDNF gene upregulation in the rodent brain, while protein synthesis is necessary for ketamine’s antidepressant–like effects [71]. This protein up–regulation, whilebypassing BDNF gene upregulation, may account for the fast action of ketamine. In a clinical study, ketamine has been also reported to increase plasma BDNF levels in depression patients at 4 hr postinfusion [72]. Interestingly, responders show a greater induction of BDNF than do non–responders [72].

MK–0657, a selective NR2B antagonist, also exerts a relatively acute antidepressant effect in treatment–resistant depression patients within 5 days, while increased plasma BDNF levels are observed after9 days of treatment [73].

Acamprosate, an NMDA and mGluR5 antagonist, has shown antidepressant effects in a preclinical study and promotes increasesin BDNF levels in the serum of human subjects [74]. However, the results of a clinical pilot study are still inconclusive regarding its efficacy as an antidepressant medication [75].

Memantine, another NMDA receptor antagonist, induces BDNF expression in rat brain [76,77]; however, a recent clinical study does not support its antidepressant efficacy [78].

Ampakines, which are drugs that potentiate AMPA receptors, also increase BDNF expression in the hippocampus and prefrontal cortex in rodents [79–83]. Ampakines show antidepressant effects in both rodents (LY392098 [84]) and in depressed patients (Org 26576, [85]).

The mGlu2⁄3 receptor ligands (both agonists and antagonists) involve BDNF and are being tested as adjunctive therapy in patients with major depression [90]. These compounds appear to shorten the latency of antidepressant medication. An mGluR2⁄3 agonist, LY379268, when administered to rodents, produces antidepressantlike behavioral effects when combined with 3 days of fluoxetine and chlorimipramine, although it produces only small antidepressant–like effects on its own [86]. LY379268 acutely increases the amount of Gadd45–β (growth arrest and DNA–damage–inducible beta) that binds to BDNF promoter IX [87]. Gadd45– β increases DNA demethylation. LY379268 also increases BDNF mRNA levels in the cerebral cortex and hippocampus with a peak at 3 h from treatment [88]. Chronic treatment (10 weeks) of LY379268 also increases cortical BDNF levels [89]. An mGluR2⁄3 antagonist, LY341495, also exerts antidepressantlike effects in 30 min and after 24 hr in rodents [91]. Interestingly, the sustained antidepressant–like effect (after 24 hr), but not theacute effect (in 30 min), depends on the activation of BDNF and its receptor TrkB signaling [91]. LY341495 has been also reported to enhance BDNF mRNA induction when combined with 5–dimethoxy– 4–iodoamphetamine (DOI), a serotonin receptor 2 agonist, but it does not induce BDNF levels on its own [92].

A selective mGluR5 antagonist, 2–methyl–6–(phenylethynyl) pyridine (MPEP), produces antidepressant–like effects in rodents ([93,94], see review [95]). Chronic MPEP treatment increases hippocampal but reduces cortical BDNF mRNA levels [96]. Repeated MPEP administration for 12 days reduces mRNA levels of the NMDA receptor NR1 subunit in the forebrain [100]; thus, a finalantidepressant effect of mGlu5 antagonism is proposed to be similar to that evoked by NMDA receptor antagonists [101], such as ketamine[67,68].

Riluzole, another type of glutamatergic modulator, reduces extrasynaptic glutamate by inhibiting presynaptic release and enhancing astroglial uptake. This compound has also shown antidepressant efficacy in clinical pilot studies: Open–label trials in treatmentresistant depression patients have yielded promising results [97,98]. Repeated, but not single, injections of riluzole have been reported to result in prolonged elevation of hippocampal BDNF [99]. The BDNF induction seems paradoxical since riluzole inhibits voltagedependent sodium channels and reduces extra–synaptic glutamate levels, whereas BDNF is induced by neuronal activity and glutamate. One explanation could be that the mechanisms other than neuronal activity⁄glutamate mediate the BDNF induction since riluzole has complex mechanisms of action (e.g., it dose and dependently affects various calcium⁄potassium channels and GABAA receptors [102]). Astudy has shown that the BDNF increase by riluzole requires activation of the p38 mitogen–activated protein kinase via N–type Ca2+ channels and adenosine A1 receptors [103]. It remains unknown whether thereduced neuronal activity and glutamate levels are actually involved in the BDNF induction by riluzole.

An agonist for the BDNF receptor, TrkB

Recently, 7,8–dihydroxyflavone (7,8–DHF) was identified as the first selective TrkB agonist [104]. Chronic oral administration of this compound has been reported to produce antidepressant–like effects in rodents [105], suggesting its future use in the treatment of various disorders, including MDD. A systemic administration of 7,8–DHF in rodents has been shown to enhance extinction of conditioned fear, and particularly strikingly in mice that had previously been stressed [106]. Fear extinction is a BDNF–dependent process, arising particularly within the pathways of hippocampus [107], prefrontal cortex [43,108], and amygdala [109]. Deficits in extinction of conditioned fear have been suggested to underlie aspects of stress disorders including posttraumatic stress disorder (PTSD) [110]. This TrkB agonist shows potential for the treatment of stress disorders including PTSD and MDD. However, some caution should be taken when considering TrkB activation. Previous studies have shown that the antidepressant effects of BDNF are bidirectional and dependent on dorsal or ventral brain regions: a BDNF increase in the dorsal brain regions (e.g., hippocampus and prefrontal cortex) produces antidepressant–like effects [20–23], while an increase in the ventral brain regions (e.g., nucleus accumbens and ventral tegmental area)causes depression [61,62]. Thus, 7,8–DHF may need to be directly targeted into specific brain regions (e.g., hippocampus and prefrontal cortex). The TrkB activation should also be within an endogenous range of TrkB activation in order to avoid desensitization of theendogenous BDNF system due to the exogenous force. Future studies need to investigate the safety (e.g., carcinogenic potential) and efficacy of this TrkB agonist for psychiatric disorders including MDD.

Brain stimulation

Electroconvulsive shock (ECS) therapy is most often used for patients with severe major depression who have not responded to other antidepressant treatments. Both acute (2 h) and chronic (10day) ECS has been shown to increase BDNF mRNA approximately 2– to 3–fold in the hippocampus [19]. Deep brain stimulation is also used for treatment resistant depression, and it also increases BDNF levels in the rat brain [111] and in human serum [112]. Vagal nerve stimulation (VNS) has been approved for treatment resistant depression by the Food and Drug Administration since 2005. VNS given for just three hours increases BDNF mRNA levels in rat hippocampus and cerebral cortex [113], while chronic VNS increases BDNF mRNA levels in the hippocampus [114].

Antidepressant effect acting on TrkB without gene induction of BDNF

Recent findings suggest that treatments for depression may acutely act on the BDNF pathway, but without BDNF gene induction, which takes hours. For example, the rapid antidepressant response seen following ketamine administration is mediated by BDNFprotein induction in the absence of BDNF gene up–regulation [71]. Antidepressant treatments (fluoxetine and imipramine) rapidly increase phosphorylation of the BDNF receptor, TrkB, in the PFC and hippocampus within 30–60 min of drug administration; these processes occur without BDNF induction [115,116]. Increased intracellular cAMP and membrane depolarization are known to rapidly increase the incorporation of TrkB into the neuronal plasmamembrane [117]. Moreover, both acute and chronic VNS also elevate phosphorylation of TrkB at tyrosines 515, 705, and 816 in the hippocampus, while traditional antidepressants (fluoxetine or desipramine) elevate phosphorylation of TrkB at tyrosines 705 and 816, but not at tyrosine 515 [118]. These TrkB phosphorylations induced by antidepressants and VNS activate phospholipase–Cγ signaling and lead to the phosphorylations of CREB [116,119] and Akt⁄ERK [118]. These phosphorylations can then induce transcription of genes involved in neurogenesis and neuronal growth, including induction of other growth factors as well as BDNF itself [120], thereby producing positive neurotrophic effects.

BDNF mRNA trafficking and local protein synthesis

The acute effects of antidepressants and VNS in increasing BDNF protein levels and TrkB phosphorylation may involve local protein synthesis and release of BDNF. The Bdnf gene has two polyadenylation sites that lead to either a short or long 3’ untranslated region (UTR). The long 3’–UTR, which is mainly localized in dendrites [121] and stabilized by neuronal activity [122], is involved in rapid activitydependent translation of the BDNF protein [123]. A single–nucleotide polymorphism (SNP) in the BDNF gene can create a difference in the local protein synthesis and release of BDNF. One of the best known of these SNPs is an amino acid substitution of valine (Val) to methionine (Met) at codon 66 (Val66Met) in the proBDNF protein. This BNDF Val66Met SNP influences the function of BDNF by reducing trafficking and activity–dependent secretion of BNDF protein in the brain [124–127]. These changes in BDNF mRNA trafficking and local protein synthesis may affect the activity–dependent remodeling of spine⁄dendrite structure and synaptic plasticity, and thus affect the response to depression treatments (see [4,11, 13,128–130] for review).

Individual differences in treatment responses due to epigenetic and genetic status

Recent studies have shown that different epigenetic and genetic statuses of the BDNF gene may account for variations in MDD treatment responses. Decreased methylation of H3K27 at BDNF promoter⁄exon IV (which increases expression of BDNF exon IV) in the postmortem prefrontal cortex has been observed in depressed subjects with a history of antidepressant treatment [131]. Only responders to chronic antidepressant treatment (8 weeks of citalopram), but not non–responders, showed decreased methylation of H3K27 at promoter⁄exon IV and increased BDNF exon IV mRNA levels in blood cells [132]. These findings suggest that the histone methylation at promoter⁄exon IV may be a biomarker of treatment response.

Another study by Perroud et al. recently reported that the presence of DNA methylation in CpG islands in promoter IV⁄exon IV in the blood cells can also predict the treatment response in borderline personality disorder [133]. They showed that 4 weeks of intensive dialectical behavior therapy decreased the BDNF methylation status (which increases BDNF transcription) in responders, but increased it in nonresponders [133]. They also found a relationship between child maltreatment and higher methylation of BDNF DNA, but found no orrelation between the BDNF DNA methylation levels and serum BDNF protein levels [133]. On the other hand, other studies have shown that a failure of BDNF to increase in serum [134] or plasma [135] during the first week of antidepressant treatment predicts the final non–response and non–remission with high sensitivity, uggesting that early changes in peripheral BDNF may constitute or reflect a necessary prerequisite for final treatment response.

Tadic et al. reported that major MDD patients showing hypomethylation of the BDNF promoter region (at CpG site –87 of exon IV) are unlikely to benefit from antidepressant pharmacotherapy, and that they show a decrease in plasma BDNF levels during the first week of treatment [136]. These studies suggest that measuring BDNF RNA levels and its methylation status in the blood cells may serve as a biomarker of depression recovery and response to antidepressants.

In addition to the epigenetic regulation of the BDNF promoters, studies have indicated that the differences in treatment effects for MDD can also depend on the polymorphisms of the BDNF gene. The well–studied Val66Met SNP (Met allele) causes reductions in dendritic trafficking and activity–dependent secretion of BDNF[125–127]. A recent study showed that the BDNF Met allele in mice caused a blockage of synaptogenic and antidepressant actions of ketamine, suggesting that the therapeutic response to this drug might be attenuated or blocked in depressed patients who carry the loss of function Met allele [137]. However, a meta–analysis did not reveal any BDNF Val66Met polymorphism associated with treatment response in patients with MDD [138]. Another study reported the opposite esult, where BDNF Met carriers showed a higher remission rate for geriatric depression than was seen for BDNF (Val⁄Val) homozygotes [139].

Studies on the MDD risk of the Val66Met SNP in human subjects have produced inconsistent results, which may reflect factors such as the size and ethnicity of the studied populations [140–142] (see review [6]). In addition to the Val66Met SNP, recent studies have revealed new SNPs in the Bdnf gene: Six SNPs and two haplotypes (one including Val66Met, another near exon VIIIh) are associated with MDD andeight SNPs are associated with response to antidepressant treatment [143]. The intronic variants 5’–upstream of the BDNF coding region located near exons VIIh and V show the most significant effects in MDD and antidepressant response, respectively [143]. Further, another SNP (rs12273363) in the upstream of the Bdnf gene has been associated with MDD susceptibility in patients with a history of childhood adversity [144], and that this SNP was recently found to reduce promoter IV activity [145]. In addition, novel SNPs in the DNF promoters I, –281A and G–712A, have been reported to protect gainst anxiety or are associated with substance abuse [146,147]. Promoter I is another activity–dependent promoter [37,148] and a recent study has also reported changes in its DNA methylation profiles in the blood cells of MDD patients [149]. Future studies remain to elucidate the effect of these SNPs on the Bdnf gene regulation in the brain and on MDD treatment responses

A combination of several independent risk alleles within the TrkB gene has also been associated with suicide attempts among patients with MDD [150]. These findings suggest that the individual differences in the BDNF–TrkB pathway due to epigenetic⁄genetic status may contribute to the risk of MDD and to the differences in treatment response.

Conclusions

Stress reduces BDNF levels via epigenetic regulations. On the other hand, most of the currently used therapeutics for MDD (e.g., reducing stress, antidepressant treatments, introducing exercise and enriched environments, and brain stimulation) increase BDNF levels. Drugs that can target the mechanisms that induce BDNF and activate BDNF–TrkB signaling (e.g., increasing BDNF promoter activity, transcription stability, trafficking, activity–driven release, TrkB agonists, drugs that increase TrkB phosphorylation and activate PI3⁄Akt⁄ERK, etc.) may therefore become potent antidepressant treatments. Further understanding of the BDNF mechanisms will provide information regarding the potential targets for novel drugs and other interventions for combating MDD. In particular, the mechanisms that explain how individual differences in epigenetic condition and SNPs in the Bdnf gene affect the BDNF mechanisms (transcription, translation, trafficking, secretion, receptor activation, etc.) may help to develop individualized treatment of MDD. We still do not understand why some people are more susceptible to MDD hile others better tolerate the same stress, and why so many patients fail to respond to current treatments. Specific epigenetic and genetic factors may act complementarily, and further clarification of this stress⁄treatment x genetic⁄epigenetic interaction may provide the required insight for prediction of MDD risks and MDD treatment responses, thereby leading to effective individualized prevention and treatment of MDD. Knowledge obtained from preclinical and clinicalstudies will be critical for further advancement of our understanding of the role of BDNF in MDD treatment. In addition, elucidating BDNF mechanisms in blood and monitoring blood BDNF levels may become useful for developing indicators⁄predictors of depression recovery.

References

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Citation: Sakata K. Brain-Derived Neurotrophic Factor for Depression Therapeutics. Austin J Pharmacol Ther. 2014;2(1): 1006. ISSN: 2373-6208.

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