Major Neurotrophic Factors Research Articles

Dimethyl Fumarate Preconditioning can Reinforce the Therapeutic Potential of Bone Marrow Mesenchymal Stem Cells through Trophic Factor Profile Enhancement.

Numerous studies have confirmed the therapeutic efficacy of bone marrow-derived mesenchymal stem cells (BM-MSCs) in addressing neurologic disorders. To date, several preconditioning strategies have been designed to improve the therapeutic potential of these stem cells. This study was designed to evaluate the preconditioning effect of dimethyl fumarate (DMF) on the expression of main trophic factors in human BM-MSCs. Initially, the identity of stem cells was confirmed through the evaluation of surface markers and their capacity for osteogenic and adipogenic differentiation using flow cytometry and differentiation assay, respectively. Subsequently, stem cells were subjected to different concentrations of DMF for 72 hours and their viability was defined by MTT assay. Following 72-hour preconditioning period with 10 µM DMF, gene expression was assessed by quantitative RT-PCR. Our findings demonstrated that the isolated stem cells expressed cardinal MSC surface markers and exhibited osteogenic and adipogenic differentiation potential. MTT results confirmed that 10 µM DMF was an optimal dose for maintaining cell viability. Preconditioning of stem cells with DMF significantly upregulated the expression of BDNF, NGF, and NT-3. Despite a slight increase in transcript level of GDNF and VEGF after DMF preconditioning, this difference was not statistically significant. Our findings suggest that DMF preconditioning can enhance the expression of major neurotrophic factors in human BM-MSCs. Given the curative potential of both BM-MSCs and DMF in various neurological disease models and preconditioning outcomes, their combined use may synergistically enhance their neuroprotective properties.

Serum BDNF and suicidal ideation in drug-na\xefve and drug-treated MDD patients: a case\u2013control study

BackgroundDisturbances in structural and synaptic plasticity have been linked to depression and suicidal ideation. One of the major neurotrophic factors, the brain-derived neurotrophic factor (BDNF), is involved in the maintenance and survival of neurons and synaptic plasticity. This case–control study assesses the serum BDNF and suicidal ideation among drug-naïve and drug-treated MDD patients attending university hospitals and comparing them to healthy control. A simple random sample of 57 MDD patients and 57 age- and sex-comparable controls were enrolled. The researchers conducted a semi-structured interview to collect the demographic characteristics and disease history. Structured Clinical Interview for DSM-5 (SCID-5), Hamilton Depression Rating Scale (HDRS), and Beck Scale for Suicidal Ideation (BSS) were applied to the participants. Blood samples were collected to measure plasma BDNF level.ResultsThe MDD group had lower BDNF than the control group. Within the MDD group, drug-naïve patients had significantly lower BDNF than drug-treated patients. Female patients had lower BDNF than male patients. Positive family history of MDD was associated with low BDNF. Severe and moderate cases had lower BDNF than mild cases. High BSS (≥24) was associated with low BDNF. A statistically significant positive correlation was found between BDNF and age, disease duration, duration of the current episode, and the number of previous episodes.On the other hand, a statistically significant negative correlation was found between BDNF and age of MDD onset, HDRS, and BSS. A regression model was highly statistically significant in the prediction of HDRS. BDNF and disease duration were negatively correlated with HDRS. On the other hand, depression treatment status was not significantly associated with the HDRS prediction model.ConclusionOur findings extend the neurotrophic concept of depression by identifying the decreased BDNF levels as a peripheral biomarker of MDD. Our assessment of depression and suicidal ideation (SI) and their relationship to decreased BDNF levels shed light on the etiopathology of MDD and its related suicidality. They should be more studied to understand better the mechanisms by which they develop. To further explore the effect of BDNF in suicide, larger study sizes and a range of psychiatric diagnoses associated with suicide attempts are required.

The impact of BDNF variant on bipolar susceptibility, suicidal behavior, and response to lithium carbonate in bipolar patients

Synaptic plasticity is intimately involved in the pathophysiology and treatment of bipolar disorder and disruptions in neuroplasticity can play an important role in the process of suicide behavior in bipolar patients. One of the major neurotrophic factors with essential role in the maintenance and survival of neurons and synaptic plasticity is Brain-Derived Neurotrophic Factor (BDNF) which is encoded by BDNF gene. The impact of BDNF variant on predisposition to bipolar disorder, suicidal behavior and response of patients to lithium carbonate was investigated in this study on 201 bipolar patients compared with 201 healthy controls. The tetra primers -Amplification Refractory Mutation System-PCR method was used for genotyping. Results were confirmed by Sanger sequencing method. The obtained results showed significant association of different genotypes of rs6265 with bipolar susceptibility, suicide tendency, suicide ideation as well with various responses of patients to the treatment.Overall, it appears that BDNF variant may serve as an important biological risk factor in bipolar pathogenesis, suicidality, and various responses to lithium carbonate in bipolar patients in Iranian population.

Dimethyl fumarate up-regulates expression of major neurotrophic factors in the epidermal neural crest stem cells.

There is an agreement that combining treatments can lead to substantial improvement, therefore the present study assessed the effects of different concentrations of dimethyl fumarate (DMF) on viability of epidermal neural crest stem cells (EPI-NCSCs). In addition, this investigation was designed to evaluate the effects of DMF on relative expression of major trophic factors mainly the ones with neurotrophic effects, expressed in EPI-NCSCs in order to enhance their therapeutic potential. To determine the appropriate concentration of DMF for EPI-NCSCs treatment, the MTT assay was employed and based on the obtained data, EPI-NCSCs treated with 10μM DMF for 6, 24, 72 or 168 h. In each time point, quantitative RT-PCR technique was used to evaluate NGF, NT-3, BDNF, GDNF and VEGF transcripts. The acquired data showed that 10μM DMF significantly increased the mRNA expression of NGF, NT-3 and BDNF, 72 h following treatment; however, DMF inhibitory effect on GDNF mRNA expression was observed in various time points. No significant changes were detected for VEGF transcript. Our findings reveled that expression of major neurotrophic factors were up-regulated by dimethyl fumarate treatment. Therefore, combining EPI-NCSCs with DMF treatment might be a valuable strategy to improve their therapeutic functions in vivo.

Regulatory Effects of Neuroinflammatory Responses Through Brain-Derived Neurotrophic Factor Signaling in Microglial Cells.

Inhibition of microglial over-activation is an important strategy to counter balance neurodegenerative progression. We previously demonstrated that the adenosine monophosphate-activated protein kinase (AMPK) may be a therapeutic target in mediating anti-neuroinflammatory responses in microglia. Brain-derived neurotrophic factor (BDNF) is one of the major neurotrophic factors produced by astrocytes to maintain the development and survival of neurons in the brain, and have recently been shown to modulate homeostasis of neuroinflammation. Therefore, the present study focused on BDNF-mediated neuroinflammatory responses and may provide an endogenous regulation of neuroinflammation. Among the tested neuroinflammation, epigallocatechin gallate (EGCG) and minocycline exerted BDNF upregulation to inhibit COX-2 and proinflammatory mediator expressions. Furthermore, both EGCG and minocycline upregulated BDNF expression in microglia through AMPK signaling. In addition, minocycline and EGCG also increased expressions of erythropoietin (EPO) and sonic hedgehog (Shh). In the endogenous modulation of neuroinflammation, astrocyte-conditioned medium (AgCM) also decreased the expression of COX-2 and upregulated BDNF expression in microglia. The anti-inflammatory effects of BDNF were mediated through EPO/Shh in microglia. Our results indicated that the BDNF-EPO-Shh novel-signaling pathway underlies the regulation of inflammatory responses and may be regarded as a potential therapeutic target in neurodegenerative diseases. This study also reveals a better understanding of an endogenous crosstalk between astrocytes and microglia to regulate anti-inflammatory actions, which could provide a novel strategy for the treatment of neuroinflammation and neurodegenerative diseases.

Priming with FGF2 stimulates human dental pulp cells to promote axonal regeneration and locomotor function recovery after spinal cord injury

Human dental pulp cells (DPCs), adherent cells derived from dental pulp tissues, are potential tools for cell transplantation therapy. However, little work has been done to optimize such transplantation. In this study, DPCs were treated with fibroblast growth factor-2 (FGF2) for 5–6 consecutive serial passages and were transplanted into the injury site immediately after complete transection of the rat spinal cord. FGF2 priming facilitated the DPCs to promote axonal regeneration and to improve locomotor function in the rat with spinal cord injury (SCI). Additional analyses revealed that FGF2 priming protected cultured DPCs from hydrogen-peroxide–induced cell death and increased the number of DPCs in the SCI rat spinal cord even 7 weeks after transplantation. The production of major neurotrophic factors was equivalent in FGF2-treated and untreated DPCs. These observations suggest that FGF2 priming might protect DPCs from the post-trauma microenvironment in which DPCs infiltrate and resident immune cells generate cytotoxic reactive oxygen species. Surviving DPCs could increase the availability of neurotrophic factors in the lesion site, thereby promoting axonal regeneration and locomotor function recovery.

Glucose Can Epigenetically Alter the Gene Expression of Neurotrophic Factors in the Murine Brain Cells.

Glucose is believed to improve the memory in both human and mice, but the detailed insights were mostly elusive. In this study, we focused on two major neurotrophic factors, brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 1 (FGF1), which are believed to be associated with the memory enhancement and assessed their expressional regulation among the murine neuronal and glial cells. Our findings showed that the glucose administration increased phosphorylated Akt, phosphorylated CREB, exon 1- and exon 4-specific BDNF transcripts, and FGF1 transcripts that are associated with the epigenetic changes expected to open the chromatin and a reduction in histone deacetylase 2 (HDAC2) in neurons and astrocytes of the murine hippocampus. The glucose administration enhanced the long-term potentiation and the number of dendritic spines in the CA1 and CA3 subfields of hippocampus. The intrahippocampal injection of short hairpin RNA against TrkB canceled the glucose-mediated memory enhancement. Like the glucose, we also report that the HDAC inhibitor can enhance the memory through the BDNF-TrkB pathway but it targeted different brain cell populations to enhance the BDNF and FGF1 transcripts. In addition, the soluble FGF1 treatments significantly increased the BDNF expression in astrocytes and neurons, suggesting that the glucose-mediated induction of the neurotrophic factors could contribute to the memory. Our study provides the valuable insights, explaining the distinctive neuronal and glial cell regulation of the neurotrophic factors by glucose and HDAC inhibitor, which could likely explain how our brain cells can control the release of neurotrophic factors.

Melatonin antagonizes interleukin-18-mediated inhibition on neural stem cell proliferation and differentiation.

Neural stem cells (NSCs) are self‐renewing, pluripotent and undifferentiated cells which have the potential to differentiate into neurons, oligodendrocytes and astrocytes. NSC therapy for tissue regeneration, thus, gains popularity. However, the low survivals rate of the transplanted cell impedes its utilities. In this study, we tested whether melatonin, a potent antioxidant, could promote the NSC proliferation and neuronal differentiation, especially, in the presence of the pro‐inflammatory cytokine interleukin‐18 (IL‐18). Our results showed that melatonin per se indeed exhibited beneficial effects on NSCs and IL‐18 inhibited NSC proliferation, neurosphere formation and their differentiation into neurons. All inhibitory effects of IL‐18 on NSCs were significantly reduced by melatonin treatment. Moreover, melatonin application increased the production of both brain‐derived and glial cell‐derived neurotrophic factors (BDNF, GDNF) in IL‐18‐stimulated NSCs. It was observed that inhibition of BDNF or GDNF hindered the protective effects of melatonin on NSCs. A potentially protective mechanism of melatonin on the inhibition of NSC's differentiation caused IL‐18 may attribute to the up‐regulation of these two major neurotrophic factors, BNDF and GNDF. The findings indicate that melatonin may play an important role promoting the survival of NSCs in neuroinflammatory diseases.

운동과 뇌신경가소성: 고강도 인터벌 운동의 효과성 고찰

운동은 중추와 말초의 각종 성장인자(BDNF, IGF-1, VEGF)들의 상호작용에 의해 뇌신경가소성을 증진시키고 인지기능을 향상시킨다. 지금까지 저·중강도 지속성 유산소 운동의 효과를 검증하는 선행연구가 주로 이루어졌기 때문에 고강도 운동에 따른 뇌신경성장인자의 발현 및 인지기능 개선 효과에 대한 연구는 미흡한 실정이다. 하지만 최근의 과학적 증거들은 고강도 인터벌 운동이 시간 효율성, 안전성, 심폐지구력 개선 및 체중 감소에 효과적임을 암시하고 있으며, 미스포츠의학회(ACSM)에서 권장하는 일반인을 위한 운동지침에서도 무리가 되지 않는 수준에서 고강도 인터벌 운동 수행을 강조하고 있다. 특히 최근에 발표된 선행 연구에서 고강도 인터벌 운동은 말초조직과 뇌에서의 BDNF, IGF-1, VEGF의 발현을 증가시키고 그로 인한 인지기능 발달에 기여한다는 것을 보고하였으며, 관련된 유력한 생리학적 기전으로 고강도 인터벌 운동으로 인한 뇌의 저산소화와 뇌신경대사의 부가적인 에너지원이 될 수 있는 젖산 이용성 증가가 대두되고 있다. 따라서 향후 저산소화 및 젖산 이용성 증가에 따른 뇌신경성장인자 발현 개선에 어떤 분자생물학적 기전이 관여하는지를 탐구할 필요가 있으며, 또한 동일한 운동량을 가진 저·중강도 지속성 유산소 운동과의 비교 연구를 통해 뇌신경성장인자의 발현 및 인지기능 개선에 있어 고강도 인터벌 운동의 우수성을 입증하는 연구가 요구된다. Exercise increases the expression and interaction of major neurotrophic factors such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF) at both central and peripheral tissues, which contributes to improved brain and neural plasticity and cognitive function. Previous findings have been to understand the effect of light or moderate intensity aerobic exercise on neurotrophic factors and cognitive function, not that of high intensity aerobic exercise. However, recent findings suggest that high intensity interval training is a safe, less time-consuming, efficient way to improve cardiorespiratory fitness and weight control, thus American College of Sport Medicine (ACSM)’s guidelines for exercise prescription for various adult populations also recommend the application of high intensity interval training to promote their overall health. High intensity interval training also enhances the expression of BDNF, IGF-1, and VEGF at the brain and peripheral tissues, which improves cognitive function. Increased frequency of intermittent hypoxia and increased usage of lactate as a supplementary metabolic resource at the brain and neural components are considered a putative physiological mechanism by which high intensity interval training improves neurotrophic factors and cognitive function. Therefore, future studies are required to understand how increased hypoxia and lactate usage leads to the improvement of neurotrophic factors and what the related biological mechanisms are. In addition, by comparing with the iso-caloric moderate continuous exercise, the superiority of high intensity interval training on the expression of neurotrophic factors and cognitive function should be demonstrated by associated future studies.

Lithium: from mood stabilizer to putative cognitive enhancer

The monovalent cation lithium, whose introduction in psychiatry dates back at the end of the 1940s, remains the first-line agent in the management of patients with bipolar disorder (BD). It is effective in the treatment of moderate-to-severe acute mania, prophylactic for recurrent manic and depressive episodes, and reduces the risk of suicide. It can also boost antidepressants effects in the treatment of major depressive disorder (Albert et al., 2014). More recently, a growing body of evidence seems to suggest that the benefits of lithium extend beyond mood stabilization. In vitro, lithium has been shown to provide neuroprotection against excitotoxicity induced by glutamate and N-methyl-D-aspartate (NMDA) receptor activation, calcium, thapsigargin, β-amyloid, aging, serum/growth factor deprivation, low potassium concentration, C2-ceramide, aluminum, ouabain, and specific HIV regulatory proteins. Lithium's neuroprotective effects have further been demonstrated in a series of in vivo animal models of ischemic/hemorrhagic stroke, traumatic brain/spinal cord injury (TBI/SCI), Huntington's disease (HD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), fragile X syndrome (FXS), Parkinson's disease (PD), retinal degeneration, multiple sclerosis (MS), alcohol-induced degeneration, Down syndrome, spinocerebellar ataxia-1, HIV-associated neurotoxicity, and irradiation (Chiu et al., 2013). In spite of this, very little is understood about its mechanism of action. Recent research findings indicate that lithium's neuroprotective effects may stem, at least in part, from its ability to inhibit the glycogen synthase kinase-3β (GSK-3β) by directly binding to its enzyme's magnesium-sensitive site and indirectly by enhancing phosphorylation of this kinase at specific serine residues. Indeed lithium's direct inhibition of GSK-3β leads to activation of several transcription factors, including cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), heat-shock factor-1 (HSF-1), and β-catenin, with subsequent induction of major neurotrophic, angiogenic, anti-inflammatory, and anti-apoptotic factors such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), heat shock protein 70 (HSP70), and B-cell lymphoma/leukemia-2 protein (Bcl-2), respectively. Suppressed GSK-3β further reduces the activity of the pro-apoptotic proteins p53 and Bax and their negative regulatory action on Bcl-2. Noteworthy, BDNF and NGF have been reported to function as both downstream molecules resulting from the inhibition of GSK-3β and upstream signals able to inhibit this molecular pathway via specific survival signaling cascades such as the phosphatidylinositol-3-kinase (PI3K)/Akt and the MAP kinase (MEK)/ERK pathways. Lithium also indirectly inhibits GSK-3β via PI3K-dependent activation of protein kinase C (PKC), cAMP-dependent activation of protein kinase A (PKA), and the Wnt/β-catenin pathway (via Frizzled receptors). On the other hand, by decreasing inositol 1,4,5-trisphosphate (IP3) levels, lithium has been shown to induce autophagy, a sort of ‘quality control’ process believed to be particularly important in neurodegenerative disorders such as HD, AD, ALS, and PD characterized by the accumulation of misfolded disease-causing proteins. In these same neurodegenerative disorders as well as in stroke, TBI/SCI, retinal degeneration, MS, and HIV, lithium inhibits glutamate-induced excitotoxicity mediated by NMDA receptors, specifically attenuating the NR2B subunit constitutive tyrosine phosphorylation, and subsequent calcium influx, thus suppressing excitotoxicity-induced p38 and c-Jun N-terminal kinase (JNK), and subsequent transcription factor activator protein-1 (AP-1) activation to block neuronal apoptosis. Inhibition of oxidative stress, implicated in numerous central nervous system (CNS) disorders such as BD, stroke, TBI/SCI, HD, AD, and ALS may further underlie lithium beneficial effects towards these pathologies (Chiu et al., 2013, Figure 1).

NGF but not BDNF overexpression protects hippocampal LTP from beta-amyloid-induced impairment

Two major neurotrophic factors, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are involved in a number of physiological processes associated with neuronal growth, survival and plasticity. There are an increasing number of papers demonstrating their ability to serve as neuroprotective molecules under various pathological conditions. At the same time, it remains unclear whether both NGF and BDNF have similar roles under pathological conditions and their effects on the electrophysiological properties of neurons after acute pathogen exposure. In the present paper we investigated the neuroprotective role of these two neurotrophins in a well-characterized model of beta-amyloid peptide (Aβ)-dependent impairment of long-term potentiation (LTP). Using lentiviral gene delivery we performed long-term elevation of neurotrophin expression in the dentate gyrus (DG) of rats. One week after virus injection acute brain slices were incubated with beta-amyloid (25–35) for 1h and afterward in vitro LTP induction was performed in medial perforant path–DG synapses. We demonstrate that chronic elevation of NGF but not BDNF concentration protects LTP induction from beta-amyloid action. Further inhibitory analysis suggests that the effect of NGF is mediated by PI3K-signaling cascade.

Identification and characterization of neurotrophic factors in porcine small intestinal submucosa

“Small intestinal submucosa” (SIS) is a natural degradable biomaterial derived from the small intestine of vertebrates. Porcine SIS has been widely used in repairing various tissues and organs, especially in nervous tissues because intrinsic autonomic nerve plexuses are included in submucosal layer. However, little is known about active neurotrophic factors in this material. In this study, we proposed a method to prepare an extract from decellularized SIS and to identify and characterize the major neurotrophic factors in it. Decellularized SIS extract was obtained by sequential procedures: mechanical disassociation, degreasing, enzyme digestion, freeze-drying, freezer-milling, extracting, concentrating, and filtering. Contamination with cellular components in the SIS extract was evaluated by hematoxylin and eosin (H&E) staining and the content of genomic DNA. Major neurotrophic factors in SIS extract was assessed quantitatively by ELISA. The effects of SIS extracts on cells were evaluated by observation of neurite outgrowth from PC12 cells. Decellularized SIS extract was obtained successfully by the proposed method and no cellular component was found within it. Brain-derived neurotrophic factor (BDNF), erythropoietin (EPO), glial cellderived neurotrophic factor (GDNF), nerve growth factor (NGF), and platelet-derived growth factor (PDGF) were identified and characterized form SIS extract. The bioactivity of SIS extract was assessed in terms of neurite outgrowth from PC12 cells. In summary, we prepared a decellularized extract from porcine SIS and identified major neurotrophic factors present in it. SIS extract also had bioactivity with PC12 cells. From these results, we conclude that SIS may be useful to repair or improve nervous system function.

Involvement of brain-derived neurotrophic factor in late-life depression.

Brain-derived neurotrophic factor (BDNF), one of the major neurotrophic factors, plays an important role in the maintenance and survival of neurons, synaptic integrity, and synaptic plasticity. Evidence suggests that BDNF is involved in major depression, such that the level of BDNF is decreased in depressed patients and that antidepressants reverse this decrease. Stress, a major factor in depression, also modulates BDNF expression. These studies have led to the proposal of the neurotrophin hypothesis of depression. Late-life depression is associated with disturbances in structural and neural plasticity as well as impairments in cognitive behavior. Stress and aging also play a crucial role in late-life depression. Many recent studies have suggested that not only expression of BDNF is decreased in the serum/plasma of patients with late-life depression, but structural abnormalities in the brain of these patients may be associated with a polymorphism in the BDNF gene, and that there is a relationship between a BDNF polymorphism and antidepressant remission rates. This review provides a critical review of the involvement of BDNF in major depression, in general, and in late-life depression, in particular.

Reduced cerebrospinal fluid and plasma nerve growth factor in drug-naïve psychotic patients

Impaired expression and function of several major neurotrophic factors such as nerve growth factor (NGF) has been proposed to contribute to the neurodevelopmental pathology of schizophrenia. However, the evidence in the majority of studies is based on variable and inconsistent levels of plasma NGF in diverse populations of early psychosis or medicated patients with chronic schizophrenia. We report here the first study comparing NGF levels in cerebrospinal fluid (CSF) and plasma from a unique patient cohort (unmedicated, early psychotic patients with similar racial and dietary patterns) and matched healthy controls. Significantly lower levels of NGF in both CSF (p=0.038) and plasma (p=0.002) were observed in drug-naïve first-episode psychosis patients as compared to controls. The levels of NGF in the CSF correlated (p=0.05) to the plasma values in controls. The data on plasma NGF confirm the reported deficits of NGF in drug-naïve first-episode psychosis. The reduced levels first time observed here may have important implications to repeatedly reported neurobiological and clinical deficits which are discussed.

Brain-derived neurotrophic factor: role in depression and suicide.

Depression and suicidal behavior have recently been shown to be associated with disturbances in structural and synaptic plasticity. Brain-derived neurotrophic factor (BDNF), one of the major neurotrophic factors, plays an important role in the maintenance and survival of neurons and in synaptic plasticity. Several lines of evidence suggest that BDNF is involved in depression, such that the expression of BDNF is decreased in depressed patients. In addition, antidepressants up-regulate the expression of BDNF. This has led to the proposal of the "neurotrophin hypothesis of depression". Increasing evidence demonstrates that suicidal behavior is also associated with lower expression of BDNF, which may be independent from depression. Recent genetic studies also support a link of BDNF to depression/suicidal behavior. Not only BDNF, but abnormalities in its cognate receptor tropomycin receptor kinase B (TrkB) and its splice variant (TrkB.T1) have also been reported in depressed/suicidal patients. It has been suggested that epigenetic modulation of the Bdnf and Trkb genes may contribute to their altered expression and functioning. More recently, impairment in the functioning of pan75 neurotrophin receptor has been reported in suicide brain specimens. pan75 neurotrophin receptor is a low-affinity neurotrophin receptor that, when expressed in conjunction with low availability of neurotropins/Trks, induces apoptosis. Overall, these studies suggest the possibility that BDNF and its mediated signaling may participate in the pathophysiology of depression and suicidal behavior. This review focuses on the critical evidence demonstrating the involvement of BDNF in depression and suicide.

Neurotrophic factors and neuromuscular disease: I. General comments, the neurotrophin family, and neuropoietic cytokines.

Neurotrophic factors are growth factors or cytokines that are inducible polypeptides and permit intercellular communication. An explosion of information about neurotrophic factors is setting the stage for significant advances in neural disease therapy in the next century. The effects of these trophic factors are overlapping and pleiotropic, acting on many cell types and tissues to control proliferation and differentiation of developing neurons and to exert a variety of functions on mature neurons. Studies of receptors unique to several neurotrophic factor families have revealed exquisite mechanisms of signal transduction. Preclinical trials in neuromuscular disease were promising, but results from initial clinical trials have been disappointing; new and better designed clinical trials are under way. Laboratory investigators also are exploring techniques to deliver factors directly to the central nervous system by means of viral vectors or to exert neurotrophic signals on the nervous system using novel small molecules that stimulate neurotrophic factor or neuroimmunophilin receptors. Combination therapies, refined delivery techniques, and treatment timing may be the key for successful treatment with neurotrophic factors. In this two-part review, we discuss the neurobiology of neurotrophic factors, the characteristics of the major neurotrophic factors, and their therapeutic potential in neuromuscular disease.