脑源性神经营养因子的研究进展

近年来,科学研究发现神经营养因子是参与调控神经系统多种生理功能的一种蛋白质。其中,脑源性神经营养因子是一种在脑内合成的小分子二聚体蛋白质,对中枢系统神经元的生长、发育、分化、再生和修复具有重要作用。本文对脑源性神经营养因子的结构、功能、疾病相关性及临床应用前景进行了综述。     

2型糖尿病并发抑郁症与脑源性神经营养因子的相关性研究

目的探究2型糖尿病并发抑郁症与脑源性神经营养因子的相关性。方法将我院2009年4月至2011年4月之间收录的80例2型糖尿病并发抑郁症患者作为研究组,并选取同期的80例2型糖尿病非抑郁患者为对照1组,而选取同期80名健康对象为对照2组。三组的患者均空腹采血,并采取常规的蛋白酶K快速裂解法进行提取外周血的基因组DNA,然后采用聚合酶链式反应-限制性片段长度多态性法进行有效的检测脑源性神经营养因子基因Va166Met的多态性,并采取ELISA法进行测定血清中的脑源性神经营养因子的水平含量。结果通过三组的对比分析,研究组和对照1组及对照2组患者血清中的脑源性神经营养因子含量分别为(75.6±4.4)pg/mL、(79.5±5.3)pg/mL、(86.4±3.4)pg/mL,三组的数据比较具有明显的差异(P<0.05),统计学有意义。而三组的患者脑源性神经营养因子基因Va166Met的多态性基因型和等位基因的频率比较具有明显的差异(P<0.05),统计学有意义;不同脑源性神经营养因子基因Va166Met患者的脑源性神经营养因子含量比较比较明显的差异(P<0.05)。结论脑源性神经营养因子基因Va166Met的多态性是2型糖尿病并发抑郁症的易感因素,且携带Met/Met基因的纯合子患者较携带Val/Val基因的纯合子和Val/Met基因的杂合子患者更容易发生抑郁症,而且患者血清中的脑源性神经营养因子含量受到脑源性神经营养因子基因Va166Met多态性的影响,而且与糖尿病并发抑郁症的发生有关联。     

脑源性神经营养因子前体的研究进展

神经营养因子是一种分泌性多肽类生长因子家族,参与神经系统的多种生理功能活动,研究发现成熟的脑源性神经营养因子与其前体分子具有不同的生物学活性,它们的受体以及介导的细胞内信号通路也大相径庭。本文对近年来关于脑源性神经营养因子前体分子的研究进展予以综述,着重讨论其体内分布、生物合成与分泌、生物学活性以及与疾病的联系。研究脑源性神经营养因子前体分子在生理和病理状态下的作用将对未来的药物开发和神经系统疾病的治疗具有重要的意义。     

ZW1-2对局灶脑缺血小鼠纹状体、皮质及海马脑区BDNF和VEGF蛋白表达的影响

目的观察化合物zome wermel 1-2(ZW1-2)对小鼠永久性局灶脑缺血后的神经功能,以及对脑源性营养因子和血管内皮生长因子的影响。方法制备小鼠永久性局灶脑缺血模型,并分别于脑缺血后2.5 h和7.5 h,灌胃给予不同剂量的化合物ZW1-2,脑缺血后24 h采用免疫组化法测定小鼠各个脑缺血易损区的脑源性神经营养因子和血管内皮生长因子表达情况。结果 ZW1-2能够显著降低小鼠局灶性脑缺血导致的行为功能评分,可以显著提高皮质、纹状体和海马脑区的脑源性神经营养因子表达,显著降低这些脑区中的血管内皮生长因子蛋白表达。结论 ZW1-2具有抗实验性脑缺血作用,其作用机制可能通过调控脑源性神经营养因子以及血管内皮生长因子而起到对脑缺血损伤的治疗作用。     

脑源性神经营养因子与缺血性损伤

脑源性神经营养因子是神经营养因子(NTFS)中的一种，其在神经元损伤后再生修复和防止神经细胞退行性变等方面发挥了重要作用。许多研究表明，BDNF对限制脑缺血后分解代谢产物所产生的损伤级联反应有重要作用。本就其可能的作用机制及未来前景展望作一综述。     

硫化氢对阿尔采末病保护作用的研究进展

阿尔采末病是一种神经退行性疾病,在老年人疾病谱中的地位日益突出,其发病机制未完全明了,无理想的治疗药物。新近研究证实,硫化氢具有抗氧化、抗凋亡、抗炎作用,在阿尔采末病的发生、发展过程中扮演重要角色。本文综述了硫化氢的生物学特点及作用,特别强调了硫化氢在阿尔采末病病理生理学中的保护作用,旨在为后续研究该病的治疗药物提供新思路。     

小胶质细胞表达的受体与阿尔采末病

阿尔采末病(Alzheimer's disease,AD)是一种老年神经退行性疾病,其病因十分复杂,其中β-淀粉样蛋白(Aβ)毒性学说、tau蛋白过度磷酸化学说、基因突变、中枢胆碱能损伤学说等已得到普遍认可。近年来,由小胶质细胞介导的炎症学说也越来越受到重视。小胶质细胞是脑内先天性免疫反应的主要部位,在外源因子的刺激下可以表达大量受体,如TLRs、NLRs、RAGE等,这些受体在AD的发展过程中起重要作用。该文就由小胶质细胞激活所表达的受体与阿尔采末病的关系做一综述。     

脑源性神经营养因子在实验性糖尿病及其并发症中的表达及研究

脑源性神经营养因子（BDNF）属于一类神经营养因子,与对应受体TrkB相结合充分发挥有效生理作用能够促进神经系统发育、分化、生长,并促使神经元保持正常生理功能,与糖尿病存在较为密切相关性。本文分析BDNF与糖尿病及并发症相关性进行综述研究。     

脑内胶质细胞源性神经营养因子及其受体复合物研究进展

胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)在脑内广泛分布,通过其受体复合物介导激活细胞内信号转导通路,发挥维持神经元功能和损伤修复等作用。胶质细胞源性神经营养因子家族受体α(GD-NF family receptorα,GFRα)和RET是其受体复合物的主要成员。GDNF和其受体复合物可能参与多种脑部病变的病理生理过程,是潜在的治疗靶点之一。     

脑源性神经营养因子与抑郁症

脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)是神经营养家族中的重要成员。BDNF可促进神经系统的发育,维持神经系统的功能,在各种神经的生长发育以及再生中起重要作用。近年来的研究表明,BDNF在抑郁症及其并发症的诊治中发挥重要作用。该文综述了BDNF、BDNF受体和信号转导通路在抑郁症以及糖尿病、脑卒中、产后、慢性疼痛等并发抑郁症中的研究现状。     

Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer’s disease patients

Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition.This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25–59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively.The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p > 0.001) but not in AD patients (p = 0.1).     

Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer’s disease patients

Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition.This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25–59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively.The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p > 0.001) but not in AD patients (p = 0.1).     

蝎毒注射液对阿尔茨海默病模型大鼠学习记忆能力及海马BDNF/TrkB表达的影响

目的：探讨蝎毒注射液（scorpion venom injection，SVI）对阿尔茨海默病（Alzheimer’s disease，AD）模型大鼠的学习记忆能力以及海马组织中脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）和酪氨酸激酶受体B （tyrosine kinase receptor B，TrkB）表达的影响。方法： 36只智力正常的健康成年SD大鼠，每组12只，随机分为正常对照组、AD模型组与SVI治疗组。后两组采用双侧海马注射Aβ_25-35构建AD模型，SVI治疗组于造模后每日一次腹腔注射SVI，连续10 d。Morris水迷宫测试各组大鼠认知功能，之后取大鼠海马组织，RT-PCR法、免疫组化和Western Blot法分别检测海马组织中BDNF与TrkB的mRNA和蛋白表达情况。结果：与对照组相比，AD模型组大鼠认知能力降低，逃避潜伏期延长，空间探索次数减少，海马中BDNF、TrkB的mRNA和蛋白表达水平明显降低（P<0.05）。而与AD模型组相比，SVI治疗组大鼠的逃避潜伏期缩短，空间探索次数增加，海马中BDNF与TrkBmRNA和蛋白表达水平显著升高（P<0.05）。结论： SVI能够改善AD模型大鼠学习记忆能力，可能与激活脑内BDNF-TrkB信号通路、提高海马组织中BDNF和TrkB表达有关。     

Anti-depressant natural flavonols modulate BDNF and beta amyloid in neurons and hippocampus of double TgAD mice

Increasing evidence suggests that depression may be both a cause and consequence of neurological disorders such as Alzheimer's disease (AD), and that anti-depressants could provide an alternative strategy to current AD therapies. Association of side effect and herbal-drug interaction with conventional anti-depressant and St. John's wort warrant investigating new anti-depressant drugs. Anti-depressant effects of ginkgo biloba extract (EGb 761) have been demonstrated in animal models of depression and in human volunteers. We report here that ginkgo flavonols quercetin and kaempferol stimulates depression-related signaling pathways involving brain-derived neurotrophic factor BDNF/phosphorylation of cyclic AMP response element binding protein CREB/postsynaptic density proteins PSD95, and reduces amyloid-β peptide (Aβ) in neurons isolated from double transgenic AD mouse (TgAPPswe/PS1e9). In addition, enhanced BDNF expression and reduction of Aβ oligomers was confirmed in hippocampus of the double transgenic mice administered with flavonol, which correlates with cognitive improvement behaviors in these mice. The present results suggest that stimulating BDNF and reducing Aβ toxicity by natural flavonols provide a therapeutic implication for treatment of AD.     

Chronic caffeine prevents changes in inhibitory avoidance memory and hippocampal BDNF immunocontent in middle-aged rats

Beneficial effects of caffeine on memory processes have been observed in animal models relevant to neurodegenerative diseases and aging, although the underlying mechanisms remain unknown. Because brain-derived neurotrophic factor (BDNF) is associated with memory formation and BDNF's actions are modulated by adenosine receptors, the molecular targets for the psychostimulant actions of caffeine, we here compare the effects of chronic caffeine (1?mg/mL drinking solution for 30?days) on short- and long term memory and on levels of hippocampal proBDNF, mature BDNF, TrkB and CREB in young (3 month old) and middle-aged (12 month old) rats. Caffeine treatment substantially reduced i) age-related impairments in the two types of memory in an inhibitory avoidance paradigm, and ii) parallel increases in hippocampal BDNF levels. In addition, chronic caffeine increased proBDNF and CREB concentrations, and decreased TrkB levels, in hippocampus regardless of age. These data provide new evidence in favor of the hypothesis that modifications in BDNF and related proteins in the hippocampus contribute to the pro-cognitive effects of caffeine on age-associated losses in memory encoding. This article is part of a Special Issue entitled 'Cognitive Enhancers'.     

Neurotrophic factors--a tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases?

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) belong to the protein family of neurotrophins. They both display profound neuromodulatory functions and are essentially involved in the survival and homeostatic maintenance of central and peripheral neurons during development and adulthood. Moreover, NGF and BDNF are known to modulate immune cell function and thus serve as mediators in the reciprocal cross talk between neurons and immune cells. Neurotrophic factors have been implicated in pathophysiological mechanisms of many diseases of the nervous and the immune system, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), neuropathy, pain, allergic bronchial asthma (BA) and neurotrophic keratitis. For all these diseases research has reached the point of creating strategies for therapeutic intervention with neurotrophins. In this review, we present an overview of the pathophysiology, therapeutic interventions and strategies concerning NGF and BDNF in the mentioned diseases.     

Comparative studies of glial fibrillary acidic protein and brain-derived neurotrophic factor expression in two transgenic mouse models of Alzheimer’s disease

In Alzheimer’s disease (AD) glial fibrillary acidic protein (GFAP) is expressed by reactive astrocytes surrounding β-amyloid (Aβ) plaques, whereas brain-derived neurotrophic factor (BDNF) levels are typically reduced. We compared the expression of GFAP, BDNF, and its precursor proBDNF in the dorsal hippocampus of two transgenic AD mouse models. APPSwe YAC mice expressing the APPSwe transgene on a yeast artificial chromosome (YAC) were assessed at age 4 and 21 months, and APPSwe/PS1dE9 mice co-expressing mutant amyloid precursor protein (APPSwe) and presenilin-1 (PS1dE9) were assessed at age 4 and 9 months. Significantly increased (1.4-fold) GFAP expression was observed in APPSwe YAC c.f. wild-type (Wt) mice aged 21 months, when Aβ deposition was first evident in these mice. In APPSwe/PS1dE9 mice aged 4 and 9 months, GFAP expression was significantly increased (1.6- and 3.1-fold, respectively) c.f. Wt mice, and was associated with robust Aβ deposition at 9 months. BDNF expression was significantly lower in 4- and 21-month old APPSwe YAC mice (0.8- and 0.6-fold, respectively) c.f. age-matched Wt mice, whereas proBDNF expression was significantly higher (10-fold) in the APPSwe YAC c.f. Wt mice aged 21 months. In APPSwe/PS1dE9 mice aged 4 months, BDNF expression was significantly lower (0.4-fold) c.f. age-matched Wt mice and was equivalent to that in 9-month old mice of both genotypes; proBDNF expression mirrored that of BDNF in this strain. These findings support a role for reactive astrocytes and neuroinflammation, rather than BDNF, in the spatial memory deficits previously reported for APPSwe YAC and APPSwe/PS1dE9 mice.     

Methylene blue and Alzheimer's disease

The relationship between methylene blue (MB) and Alzheimer's disease (AD) has recently attracted increasing scientific attention since it has been suggested that MB may slow down the progression of this disease. In fact, MB, in addition to its well characterized inhibitory actions on the cGMP pathway, affects numerous cellular and molecular events closely related to the progression of AD. Currently, MB has been shown to attenuate the formations of amyloid plaques and neurofibrillary tangles, and to partially repair impairments in mitochondrial function and cellular metabolism. Furthermore, various neurotransmitter systems (cholinergic, serotonergic and glutamatergic), believed to play important roles in the pathogenesis of AD and other cognitive disorders, are also influenced by MB. Recent studies suggest that the combination of diverse actions of MB on these cellular functions is likely to mediate potential beneficial effects of MB. This has lead to attempts to develop novel MB-based treatment modalities for AD. In this review article, actions of MB on neurotransmitter systems and multiple cellular and molecular targets are summarized with regard to their relevance to AD.     

The role of BDNF in depression on the basis of its location in the neural circuitry

Depression is one of the most prevalent and life-threatening forms of mental illnesses and the neural circuitry underlying depression remains incompletely understood. Most attention in the field has focused on hippocampal and frontal cortical regions for their roles in depression and antidepressant action. While these regions no doubt play important roles in the mental illness, there is compelling evidence that other brain regions are also involved. Brain-derived neurotrophic factor (BDNF) is broadly expressed in the developing and adult mammalian brain and has been implicated in development, neural regeneration, synaptic transmission, synaptic plasticity and neurogenesis. Recently BDNF has been shown to play an important role in the pathophysiology of depression, however there are controversial reports about the effects of BDNF on depression. Here, we present an overview of the current knowledge concerning BDNF actions and associated intracellular signaling in hippocampus, prefrontal cortex, nucleus accumbens (NAc) and amygdala as their relation to depression.     

Reduced behavioral effects of cocaine in heterozygous brain-derived neurotrophic factor (BDNF) knockout mice.

Brain-derived neurotrophic factor (BDNF) affects the development of brain neurotransmitter systems, including dopamine and serotonin systems that are important for cocaine's rewarding and locomotor stimulatory properties. Human genomic markers within or near the BDNF locus have been linked to or associated with substance abuse. Post-mortem human brain specimens reveal individual differences in the levels of BDNF mRNA and in mRNA splicing patterns. To assess the effects of lifelong alterations in the levels of BDNF expression on a measure of psychostimulant reward, we have compared locomotor stimulant and rewarding effects of cocaine in heterozygous BDNF knockout mice with effects in their wild-type littermates. Heterozygous BDNF knockout mice displayed less locomotion during habituation and less locomotion after cocaine injections. Cocaine-conditioned place preferences were reduced in the BDNF heterozygotes. These mice displayed no significant difference from saline control values at a dose of 10 mg/kg s.c. cocaine, although they exhibited cocaine-induced preference at a 20 mg/kg dose. These data confirm important roles for BDNF in psychostimulant actions, presumably via neurotrophic effects on dopamine and serotonin systems. Furthermore, these data support suggestions that differences in human BDNF expression may underlie associations between markers near the human BDNF gene locus and drug addiction.