脑源性神经营养因子及其临床研究进展

脑源性神经营养因子 (BDNF)是继神经生长因子 (NGF)后发现的第二个神经营养因子 ,在神经系统的发育、功能维持和神经元群的成形性上起重要作用。国内外正积极开发 BDNF用于神经损伤的治疗。本文就 BDNF的结构、功能、信号传导以及临床研究等作一综述     

在豌豆植物中瞬时表达大鼠神经营养因子BDNF

[目的]克隆大鼠神经营养因子BDNF基因,构建植物表达载体,在豌豆植物中表达BDNF蛋白。[方法]采用RT-PCR法克隆大鼠脑源性神经营养因子BDNF基因,构建豌豆植物表达载体p CAPE2-BDNF,利用豌豆发芽种子真空侵染法在豌豆植物中瞬时表达BDNF蛋白,以His标签抗体进行Western Blot检测目的蛋白。[结果]获得含有鼠源性神经营养因子BDNF基因的植物表达载体p CAPE2-BDNF,His标签抗体检测到目的条带。[结论]BDNF蛋白在豌豆植物中成功表达,有助于进一步对其功能活性进行分析。     

发现一种新的神经营养因子

以往人们只知道神经生长因子(NGF)可刺激神经发育和修复。在过去的几年中,至少有六种以上的神经营养因子被发现,如脑源性神经营养因子(BDNF),纤毛神经营养因子(CNTF)用胰岛素样生长因子(IGF)等。最近美国Synergen生物工程公司的研究人员发现了一种被称为胶质细胞神经营养因子(glial cell—de-     

BDNF与抑郁症的研究现状及进展

脑源性神经营养因子(brain-derived neurothrophic factor,BDNF)在中枢和外周均广泛存在,基于对其神经再生和修复功能的普遍认识,越来越多的研究开始关注BDNF在抑郁发生过程中对神经可塑性的影响以及BDNF在抗抑郁药物治疗中发挥的作用.本文综述了BDNF与抑郁症关系的基础性研究成果,以及近两年的相关研究趋势,更多的关于BDNF与其前体(precursor of brain derived neurothrophic factor,proBDNF)以及BDNF与其它神经递质在神经网络中的相互作用的研究需要被深入开展.     

小鼠海马结构氧化/抗氧化相关因子和神经营养因子表达的增龄性变化

目的通过观察小鼠年龄增长过程中海马氧化/抗氧化相关因子谷胱甘肽(GSH)含量、谷胱甘肽过氧化物酶(GSH-PX)活性、丙二醛(MDA)和脑源性神经营养因子(BDNF)、胶质细胞源性神经营养因子(GDNF)水平的变化,探讨海马内抗氧化损伤能力及神经营养因子水平的变化与海马老化的关系。方法通过β-半乳糖苷酶染色观测青年组(2-3月)、中年组(6-8月)、老年组(18-20月)雄性C57小鼠海马细胞衰老程度。比色法、硫代巴比妥酸法、酶联免疫吸附试验分别检测GSH、GSH-PX、MDA、BDNF、GDNF在各组小鼠海马内的水平。结果研究显示随着年龄增长,海马组织衰老程度逐渐增加,而抗氧化的GSH含量减少、GSH-PX活性降低;氧化损伤产物MDA含量增加;海马组织神经营养因子BDNF、GDNF水平降低。结论本研究结果提示,海马结构的老化可能与海马抗氧化能力下降、氧化损伤程度增加和BDNF、GDNF等神经营养因子水平的降低有关。     

BDNF及其受体在抗抑郁症中的作用及其机制研究

脑源性神经营养因子(brain-derived neurothrophic factor,BDNF)广泛存在于中枢和外周神经系统,具有神经再生和修复功能。近年来,研究发现BDNF在改善抑郁发生过程中神经可塑性以及抗抑郁药物治疗中发挥重要的作用。综述了BDNF及其受体在抗抑郁症中的作用及其机制研究。     

应激抑郁发生中糖皮质激素对BDNF信号通路的影响

脑源性神经营养因子(brain derived neurotrophic factor,BDNF)是一个关键性的神经营养因子,它既影响突触的形成和重构,又可以通过突触前和突触后机制改变突触传递的效能,从而对神经结构和功能可塑性发挥调节作用。BDNF主要通过结合TrkB受体激活细胞内信号系统来发挥它积极的生物学效应。研究表明,中枢神经系统BDNF表达或功能的变化与抑郁症的发生相关,而应激引起糖皮质激素(glucocorticoid,GC)的增加也是导致抑郁发生的重要原因之一。值得注意的是,GCs的增加会影响BDNF,一方面GCs降低BDNF的表达,另一方面GCs受体GR与BNDF受体TrkB相互作用。过多的GCs干扰了BDNF信号,使BDNF功能受到影响,导致抑郁患者脑内,尤其是海马结构的损害。就抑郁发生中糖皮质激素对BDNF功能影响的研究进展作一介绍。     

慢性阻塞性肺疾病大鼠海马区和血清中脑源性神经营养因子蛋白的表达变化

本文旨在探讨脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)在慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)大鼠模型海马区和血清中的表达情况,以及了解吸烟和气管内注入脂多糖的干预是否参与BDNF表达变化.采用被动...     

模拟微重力促进骨髓间充质干细胞神经营养因子的表达

目的:探究微重力对干细胞向神经元分化的影响,为临床治疗神经退行性疾病提供新的思维和方法。方法:运用流式细胞术鉴定骨髓间充质干细胞及其微重力对凋亡的影响。运用反转录PCR检测微重力干预干细胞48h及72h后神经营养因子BDNF,CNTF,NGF的表达。运用ELISA检测其分泌营养因子的浓度。结果:流式细胞仪检测细胞凋亡,两组之间并无差异。CNTF分泌在微重力干预后有明显增加(p<0.05)。BDNF浓度有轻度增加。结论:模拟微重力可以促进骨髓间充质干细胞神经营养因子的表达。     

模拟微重力促进骨髓间充质干细胞神经营养因子的表达

目的：探究微重力对干细胞向神经元分化的影响,为临床治疗神经退行性疾病提供新的思维和方法。方法：运用流式细胞术鉴定骨髓间充质干细胞及其微重力对凋亡的影响。运用反转录PCR检测微重力干预干细胞48h及72h后神经营养因子BDNF,CNTF,NGF的表达。运用ELISA检测其分泌营养因子的浓度。结果：流式细胞仪检测细胞凋亡,两组之间并无差异。CNTF分泌在微重力干预后有明显增加（p〈O．05）。BDNF浓度有轻度增加。结论：模拟微重力可以促进骨髓间充质干细胞神经营养因子的表达。     

The lighter side of BDNF

Brain-derived neurotrophic factor (BDNF) mediates energy metabolism and feeding behavior. As a neurotrophin, BDNF promotes neuronal differentiation, survival during early development, adult neurogenesis, and neural plasticity; thus, there is the potential that BDNF could modify circuits important to eating behavior and energy expenditure. The possibility that "faulty" circuits could be remodeled by BDNF is an exciting concept for new therapies for obesity and eating disorders. In the hypothalamus, BDNF and its receptor, tropomyosin-related kinase B (TrkB), are extensively expressed in areas associated with feeding and metabolism. Hypothalamic BDNF and TrkB appear to inhibit food intake and increase energy expenditure, leading to negative energy balance. In the hippocampus, the involvement of BDNF in neural plasticity and neurogenesis is important to learning and memory, but less is known about how BDNF participates in energy homeostasis. We review current research about BDNF in specific brain locations related to energy balance, environmental, and behavioral influences on BDNF expression and the possibility that BDNF may influence energy homeostasis via its role in neurogenesis and neural plasticity.     

Functional interactions between steroid hormones and neurotrophin BDNF

Brain-derived neurotrophic factor (BDNF), a critical neurotrophin, regulates many neuronal aspects including cell differentiation, cell survival, neurotransmission, and synaptic plasticity in the central nervous system (CNS). Though BDNF has two types of receptors, high affinity tropomyosin-related kinase (Trk)B and low affinity p75 receptors, BDNF positively exerts its biological effects on neurons via activation of TrkB and of resultant intracellular signaling cascades including mitogen-activated protein kinase/extracellular signal-regulated protein kinase, phospholipase Cγ, and phosphoinositide 3-kinase pathways. Notably, it is possible that alteration in the expression and/or function of BDNF in the CNS is involved in the pathophysiology of various brain diseases such as stroke, Parkinson's disease, Alzheimer's disease, and mental disorders. On the other hand, glucocorticoids, stress-induced steroid hormones, also putatively contribute to the pathophysiology of depression. Interestingly, in addition to the reduction in BDNF levels due to increased glucocorticoid exposure, current reports demonstrate possible interactions between glucocorticoids and BDNF-mediated neuronal functions. Other steroid hormones, such as estrogen, are involved in not only sexual differentiation in the brain, but also numerous neuronal events including cell survival and synaptic plasticity. Furthermore, it is well known that estrogen plays a role in the pathophysiology of Parkinson's disease, Alzheimer's disease, and mental illness, while serving to regulate BDNF expression and/or function. Here, we present a broad overview of the current knowledge concerning the association between BDNF expression/function and steroid hormones (glucocorticoids and estrogen).     

Activity-Dependent Dendritic Release of BDNF and Biological Consequences

Network construction and reorganization is modulated by the level and pattern of synaptic activity generated in the nervous system. During the past decades, neurotrophins, and in particular brain-derived neurotrophic factor (BDNF), have emerged as attractive candidates for linking synaptic activity and brain plasticity. Thus, neurotrophin expression and secretion are under the control of activity-dependent mechanisms and, besides their classical role in supporting neuronal survival neurotrophins, modulate nearly all key steps of network construction from neuronal migration to experience-dependent refinement of local connections. In this paper, we provide an overview of recent findings showing that BDNF can serve as a target-derived messenger for activity-dependent synaptic plasticity and development at the single cell level.     

BDNF-induced recruitment of TrkB receptor into neuronal lipid rafts: roles in synaptic modulation

Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic plasticity but the underlying signaling mechanisms remain unknown. Here, we show that BDNF rapidly recruits full-length TrkB (TrkB-FL) receptor into cholesterol-rich lipid rafts from nonraft regions of neuronal plasma membranes. Translocation of TrkB-FL was blocked by Trk inhibitors, suggesting a role of TrkB tyrosine kinase in the translocation. Disruption of lipid rafts by depleting cholesterol from cell surface blocked the ligand-induced translocation. Moreover, disruption of lipid rafts prevented potentiating effects of BDNF on transmitter release in cultured neurons and synaptic response to tetanus in hippocampal slices. In contrast, lipid rafts are not required for BDNF regulation of neuronal survival. Thus, ligand-induced TrkB translocation into lipid rafts may represent a signaling mechanism selective for synaptic modulation by BDNF in the central nervous system.     

Chronic Administration of Mood Stabilizers Upregulates BDNF and Bcl-2 Expression Levels in Rat Frontal Cortex

Brain-derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2) proteins are neuroprotective factors involved in neuronal signaling, survival and plasticity. Both can be regulated by cyclic AMP response element binding (CREB) protein. Decreased levels of BDNF and Bcl-2 are implicated in the pathogenesis of bipolar disorder. The present study investigated whether chronically administered mood stabilizers would increase BDNF and/or Bcl-2 levels in rat brain. Real time RT-PCR, sandwich ELISA and Western blotting were used to measure BDNF and Bcl-2 mRNA and protein levels in the frontal cortex of rats chronically administered carbamazepine (CBZ) or lamotrigine (LTG) to produce plasma concentrations therapeutically relevant to bipolar disorder. Chronic CBZ and LTG significantly increased BDNF and Bcl-2 mRNA and protein levels in the frontal cortex. A common mechanism of action of mood stabilizers in the treatment of bipolar disorder may involve neuroprotection mediated by upregulation of brain BDNF and Bcl-2 expression.     

Genetic Knockdown of Brain-Derived Neurotrophic Factor in 3xTg-AD Mice Does Not Alter Aβ or Tau Pathology

Brain-derived neurotrophic factor (BDNF) is a neurotrophin critically involved in cell survival, synaptic plasticity, and memory. BDNF has recently garnered significant attention as a potential therapeutic target for neurodegenerative diseases such as Alzheimer disease (AD), but emerging evidence suggests that BDNF may also be mechanistically involved in the pathogenesis of AD. AD patients have substantially reduced BDNF levels, which may be a result of Aβ and tau pathology. Recent evidence, however, indicates reduced BDNF levels may also serve to drive pathology in neuronal cultures, although this has not yet been established in vivo. To further investigate the mechanistic role of BDNF in AD, we generated 3xTg-AD mice with a heterozygous BDNF knockout (BDNF(+/-)) and analyzed Aβ and tau pathology. Aged 3xTg-AD/BDNF(+/-) mice have significantly reduced levels of brain BDNF, but have comparable levels of Aβ and tau pathology to 3xTg-AD/BDNF(+/+) mice. These findings indicate that chronic reduction of BDNF does not exacerbate the development of Aβ and tau pathology, and instead suggests the reduced BDNF levels found in AD patients are a consequence of these pathologies.     

A role for retinal brain-derived neurotrophic factor in ocular dominance plasticity

Visual deprivation is a classical tool to study the plasticity of visual cortical connections. After eyelid closure in young animals (monocular deprivation, MD), visual cortical neurons become dominated by the open eye, a phenomenon known as ocular dominance (OD) plasticity . It is commonly held that the molecular mediators of OD plasticity are cortically derived and that the retina is immune to the effects of MD . Recently, it has been reported that visual deprivation induces neurochemical, structural, and functional changes in the retina , but whether these retinal changes contribute to the effects of MD in the cortex is unknown. Here, we provide evidence that brain-derived neurotrophic factor (BDNF) produced in the retina influences OD plasticity. We found a reduction of BDNF expression in the deprived retina of young rats. We compensated this BDNF imbalance between the two eyes by either injecting exogenous BDNF in the deprived eye or reducing endogenous BDNF expression in the nondeprived eye. Both treatments were effective in counteracting the OD shift induced by MD. Retinal BDNF could also influence OD distribution in normal animals. These results show for the first time that OD plasticity is modulated by BDNF produced in the retina.     

Rapamycin and Interleukin-1β Impair Brain-derived Neurotrophic Factor-dependent Neuron Survival by Modulating Autophagy

The mammalian target of rapamycin (mTOR) pathway has multiple important physiological functions, including regulation of protein synthesis, cell growth, autophagy, and synaptic plasticity. Activation of mTOR is necessary for the many beneficial effects of brain-derived neurotrophic factor (BDNF), including dendritic translation and memory formation in the hippocampus. At present, however, the role of mTOR in BDNF''s support of survival is not clear. We report that mTOR activation is necessary for BDNF-dependent survival of primary rat hippocampal neurons, as either mTOR inhibition by rapamycin or genetic manipulation of the downstream molecule p70S6K specifically blocked BDNF rescue. Surprisingly, however, BDNF did not promote neuron survival by up-regulating mTOR-dependent protein synthesis or through mTOR-dependent suppression of caspase-3 activation. Instead, activated mTOR was responsible for BDNF''s suppression of autophagic flux. shRNA against the autophagic machinery Atg7 or Atg5 prolonged the survival of neurons co-treated with BDNF and rapamycin, suggesting that suppression of mTOR in BDNF-treated cells resulted in excessive autophagy. Finally, acting as a physiological analog of rapamycin, IL-1β impaired BDNF signaling by way of inhibiting mTOR activation as follows: the cytokine induced caspase-independent neuronal death and accelerated autophagic flux in BDNF-treated cells. These findings reveal a novel mechanism of BDNF neuroprotection; BDNF not only prevents apoptosis through inhibiting caspase activation but also promotes neuron survival through modulation of autophagy. This protection mechanism is vulnerable under chronic inflammation, which deregulates autophagy through impairing mTOR signaling. These results may be relevant to age-related changes observed in neurodegenerative diseases.     

The effect of brain-derived neurotrophic factor on neuritogenesis and synaptic plasticity in Aplysia neurons and the hippocampal cell line HiB5

Brain-derived neurotrophic factor (BDNF) plays a key role in the differentiation and neuritogenesis of developing neurons, and in the synaptic plasticity of mature neurons, in the mammalian nervous system. BDNF binds to the receptor tyrosine kinase TrkB and transmits neurotrophic signals by activating neuron-specific tyrosine phosphorylation pathways. However, the neurotrophic function of BDNF in Aplysia neurons is poorly understood. We examined the specific effect of BDNF on neurite outgrowth and synaptic plasticity in cultured Aplysia neurons and a multipotent rat hippocampal stem cell line (HiB5). Our study indicates that mammalian BDNF has no significant effect on the neuritogenesis, neurotransmitter release, excitability, and synaptic plasticity of cultured Aplysia neurons in our experimental conditions. In contrast, BDNF in combination with platelet-derived growth factor (PDGF) increases the length of the neurites and the number of spine-like structures in cells of HiB5.