脑源性神经营养因子在阿尔茨海默病中的研究进展

脑源性神经营养因子足神经营养因子家族成员,对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重要作用的神经营养因子.阿尔茨海默病足一种常见的神经系统退行性疾病,其中Tau蛋白磷酸化促进了疾病的发生,而脑源性神经营养因子通过激活酪氨酸激酶受体可以阻止Tau蛋白磷酸化,从而影响疾病的发生发展.     

脑源性神经营养因子与阿尔茨海默病的关系

脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）是一种广泛分布于哺乳类动物脑中的一种蛋白。近年来的研究表明其对阿尔茨海默病（Alzheimer＇s disease,AD）的临床症状和病理改变有重要影响。此文就BNDF的基因、转录物、功能、与AD的关系、在AD时功能和表达降低的原因、及仍有待研究的问题作一综述。     

脑源性神经营养因子与阿尔茨海默病

脑源性神经营养因子(BDNF)能够支持多种神经元生存、发育、分化及修复,并通过调节海马突触传递和突触可塑性,诱发及维持突触前和突触后的长时程增强效应(LTP),改变海马神经元的形态可塑性等机制,参与海马依赖的学习和记忆过程。BDNF与阿尔茨海默病(AD)的发病密切相笑。研究发现AD患者海马和大脑皮质的BDNF含量下降;BDNF缺乏可能通过降低海马突触可塑性及减少对海马神经元的支持营养,从而导致学习记忆障碍;BDNF缺乏还与AD患者常见的精神症状有关。     

美金刚联合丰富环境对快速衰老小鼠海马脑源性神经营养因子、酪氨酸蛋白激酶受体B表达及学习记忆能力的影响

目的 探讨美金刚联合丰富环境对快速衰老小鼠(SAMP8)海马脑源性神经营养因子(BDNF)、酪氨酸蛋白激酶受体B(TrkB)表达及学习记忆能力的影响.方法 24只雄性SAMP8小鼠随机分为对照组、丰富环境治疗组(丰富环境组)、美金刚治疗组(美金刚组)和美金刚联合丰富环境组(联合治疗组),每组6只小鼠.治疗8周后,采用Morris水迷宫试验检测小鼠空间学习记忆能力,免疫印记法和实时定量PCR法检测小鼠海马组织中BDNF、TrkB的表达水平.结果 与对照组比较,丰富环境组、美金刚组小鼠在试验第3d起寻找到平台的潜伏期明显缩短,联合治疗组小鼠在试验第2d起的逃避潜伏期明显缩短(P＜0.05 ～0.01);且联合治疗组小鼠在试验第4d时的逃避潜伏期明显短于丰富环境组和美金刚组(均P＜0.05).与对照组比较,其余3组小鼠穿越平台次数明显增多(P ＜0.05 ～0.01);且联合治疗组小鼠穿越平台次数明显多于丰富环境组和美金刚组(均P＜0.01).与对照组比较,其余3组小鼠海马BDNF mRNA、BDNF蛋白和TrkB蛋白的表达均明显升高(P ＜0.05～0.01),其中联合治疗组明显高于丰富环境组与美金刚组(P＜0.05～0.01).各组小鼠海马TrkB mRNA表达的差异无统计学意义.结论 美金刚和丰富环境治疗能够有效地改善SAMP8小鼠学习记忆能力并增加海马BDNF和TrkB的表达,二者联合治疗时效果更显著.     

阿尔茨海默病患者血清脑源性神经营养因子水平研究

目的 探讨阿尔茨海默病（AD）与血清脑源性神经营养因子（BDNF）水平的关系。方法 采用酶联免疫吸附法对46例AD患者（研究组）和44例正常对照者（对照组）的外周血清进行BDNF水平检测。所有受试者均进行简易精神状态量表（MMSE）、Hachinski缺血指数（HIS）及汉密尔顿抑郁量表（HAMD）评定,AD患者用临床痴呆评定量表（CDR）进行痴呆严重程度分级。结果 研究组血清BDNF水平低于对照组（P〈0.01）。研究组轻度、中度与重度AD患者血清BDNF水平均低于对照组（P〈0.01）,重度AD血清BDNF水平低于轻度AD（P〈0.05）。研究组血清BDNF水平与年龄、病程呈负相关（P〈0.01）,与MMSE评分呈正相关（P〈0.01）。结论 AD患者存在血清BDNF水平降低,且与其年龄、病程及痴呆程度显著相关。     

远志总皂苷对阿尔茨海默病模型大鼠海马脑源性神经营养因子及酪氨酸蛋白激酶B表达的影响

目的观察远志总皂苷对阿尔茨海默病模型大鼠海马CA1区脑源性神经营养因子(BDNF)及其特异性受体酪氨酸蛋白激酶B(TrkB)表达的影响,探讨远志总皂苷对阿尔茨海默病的干预作用机制。方法雄性Wistar大鼠被随机分为生理盐水组(正常对照组)、阿尔茨海默病模型组(模型组),以及远志总皂苷低剂量(12.50 mg/ml)和高剂量(37.50 mg/ml)组;采用D-半乳糖致衰老联合鹅膏覃氨酸损毁基底前脑Meynert核法建立阿尔茨海默病大鼠模型,免疫组织化学染色检测大鼠海马CA1区BDNF及其受体TrkB表达水平。结果 BDNF和TrkB阳性物质呈棕黄色,主要表达于海马CA1区神经元胞膜。模型组大鼠海马CA1区BDNF及其受体TrkB表达水平为0.30±0.02和0.21±0.07,低于正常对照组的0.47±0.02和0.46±0.05(均P=0.000);与模型组相比,远志总皂苷低剂量组(0.35±0.05,0.32±0.07)和高剂量组(0.43±0.05,0.37±0.03)大鼠海马CA1区BDNF及其受体TrkB表达水平均显著升高(均P=0.000),但以高剂量组升高更为显著(均P=0.000)。结论远志总皂苷可以显著升高阿尔茨海默病模型大鼠海马CA1区BDNF及其受体TrkB表达水平,且具有剂量依赖性,这可能是其改善认知功能的机制之一。     

脑源性神经营养因子与精神分裂症

脑源性神经营养因子BDNF在精神分裂症发病中的作用得到了越来越广泛的关注。目前研究发现,BDNF与精神分裂症发病机制假说、分裂症动物模型的建立及分裂症治疗均存在相关性。通过综合评价该领域近年来的实验结果,对BDNF与精神分裂症的关系作一综述。     

脑源性神经营养因子和脑缺血

有证据表明BDNF在脑缺血的保护中起重要作用。BDNF保护缺血引起的神经细胞损伤的机制为(1)稳定细胞内钙离子水平,减少兴奋性氨基酸引起的损伤;(2)拮抗NO介导的细胞毒作用;(3)调节自由基代谢;(4)对损伤神经元具有修复作用。     

脑源性神经营养因子和抑郁症

抑郁症是以显著而持久的情绪低落或心境改变为主要特征的一组精神疾病。其高发病率、致死率、高疾病负担已引起社会各界的关注。然而,由于其发病机制的不详,患者很难获得完全治愈的机会。近年来,国内外研究者发现脑源性神经营养因子可能参与抑郁症的发病和治疗过程。脑源性神经营养因子(Brain-derived neurotrophic factor,BD-NF)在中枢神经系统及周围神经系统的多种神经元均有分布,尤以海马和皮层含量最高。其基因定位于11p13,酪氨酸激酶受体B(tyrosine kinase receptor,TrkB)是其特异性受体,当BDNF与TrkB结合时,受体分子二聚化,其多…     

脑源性神经营养因子与癫痫研究进展

癫痫发作后 ,脑内BDNF的表达升高 ,其在时间和地域分布上有一定规律 ,这与其维持神经元存活和再生的功能紧密相关 ;BDNF对癫痫动物模型的痫性发作有阻止作用 ;痫性发作后 ,BDNF的表达受到多种分子的影响     

BDNF及其受体TrkB mRNA在脑缺血后适应大鼠模型中的表达变化

目的检测脑源性性神经营养因子(BDNF)及其受体酪氨酸激酶B(TrkB)在脑缺血后适应大鼠模型再灌注不同时间窗的表达,探讨BDNF/TrkB在脑缺血后适应中的作用。方法 Wistar大鼠随机分成对照组、缺血-再灌注组(IR)和缺血后适应组(IP),后两组根据再灌注时间的不同各分为6h、12h、24h、48h、72h 5个亚组。线栓法建立局灶性脑缺血-再灌注模型。TTC染色测定脑梗死体积,原位杂交法检测BDNF/TrkB mRNA的表达。结果 IP组大鼠梗死体积较IR组明显减小(P0.05)。IP组各时间点BDNF mRNA及TrkB mRNA表达较IR组均明显升高(P0.05)。结论脑缺血后适应能增加脑缺血-再灌注后BDNF及TrkB的表达,减轻脑梗死体积,BDNF/TrkB在脑缺血后适应后脑缺血-再灌注损伤中发挥了重要保护作用。     

Effects of ginsenoside on brain-derived neurotrophic factor and tyrosine kinase B mRNA expression in the hippocampal formation of aged rats

BACKGROUND:There are a limited number of studies involving the effects of ginsenosides,the active component of ginseng,on expression of hippocampal TrkB mRNA in aged rats.OBJECTIVE:To observe expression of brain-derived neurotrophic factor(BDNF) and tyrosine kinase B (TrkB)mRNA in the hippocampal formation of aged rats,as well as changes after ginsenoside administrated.DESIGN,TIME AND SETTING:A randomized,controlled experiment was performed at the Department of Anatomy,College of Basic Medical Sciences,China Medical University in March 2005.MATERIALS:A total of 39 female,Wistar rats were randomly divided into 3 groups (n=13 each):young (3-5 months old),aged(27 months old),and ginsenoside group(received 25mg/kg/d ginsenoside in the drinking water between 17 and 27 months of age).METHODS:Following anesthesia,the rats were exsanguinated and perfused transcardially with chilled,heparinized,0.9% saline.The brains were removed and post-fixed in 40 g/L paraformaldehyde/phosphate buffer for 20 minutes,and further incubated in 30% sucrose/phosphate buffer overnight.MAIN OUTCOME MEASURES:In situ hybridization,immunohistochemistry,and image analysis were used to investigate expression of BDNF and Trk(B mRNA in the hippocampal formation.RESULTS:The expression levels of BDNF in the hippocampal CA3 and CA1 of aged rats was significantly less than the young group(t=2.879,1.814,1.984,P<0.05).BDNF expression was significantly greater in the dentate gyrus of the ginsenoside group,compared with the aging group(t=1.943,P<0.01).The expression of TrkB mRNA in the hippocampal CA3,CA1,and dentate gyrus of aged rats was less than the young group(t=3.540,3.629,17.905,P<0.01).TrkB mRNA expression in the CA3 region and dentate gyrus of the ginsenoside group was significantly greater compared with the aging group(t=1.293,3.386,P<0.05.0.01).CONCLUSION:BDNF and TrkB mRNA expression in the hippocampal formation were reduced in the aged group.However,ginsenosides can increase BDNF and TrkB mRNA expression in the hippocampal formation.     

Effects of ginsenoside on brain-derived neurotrophic factor and tyrosine kinase B mRNA expression in the hippocampal formation of aged rats*☆

BACKGROUND： There are a limited number of studies involving the effects of ginsenosides, the active component of ginseng, on expression of hippocampal TrkB mRNA in aged rats.
OBJECTIVE： To observe expression of brain-derived neurotrophic factor （BDNF） and tyrosine kinase B （TrkB） mRNA in the hippocampal formation of aged rats, as well as changes after ginsenoside administrated.
DESIGN, TIME AND SETTING： A randomized, controlled experiment was performed at the Department of Anatomy, College of Basic Medical Sciences, China Medical University in March 2005.
MATERIALS： A total of 39 female, Wistar rats were randomly divided into 3 groups （n = 13 each）： young （3-5 months old）, aged （27 months old）, and ginsenoside group （received 25mg/kg/d ginsenoside in the drinking water between 17 and 27 months of age）.
METHODS： Following anesthesia, the rats were exsanguinated and perfused transcardially with chilled, heparinized, 0.9% saline. The brains were removed and post-fixed in 40 g/L paraformaldehyde/phosphate buffer for 20 minutes, and further incubated in 30% sucrose/phosphate buffer overnight.
MAIN OUTCOME MEASURES： In situ hybridization, immunohistochemistry, and image analysis were used to investigate expression of BDNF and TrkB mRNA in the hippocampal formation. RESULTS： The expression levels of BDNF in the hippocampal CA3 and CA1 of aged rats was significantly less than the young group （t = 2.879, 1.814, 1.984, P 〈 0.05）. BDNF expression was significantly greater in the dentate gyrus of the ginsenoside group, compared with the aging group （t = 1.943, P 〈 0.01）. The expression of TrkB mRNA in the hippocampal CA3, CA1, and dentate gyrus of aged rats was less than the young group （t = 3.540, 3.629, 17.905, P 〈 0.01）. TrkB mRNA expression in the CA3 region and dentate gyrus of the ginsenoside group was significantly greater compared with the aging group （t = 1.293, 3.386, P 〈 0.05, 0.01 ）.
CONCLUSION： BDNF and TrkB mRNA expression in the hipp     

Infarct tolerance induced by intra-cerebral infusion of recombinant brain-derived neurotrophic factor

Neuronal expression of brain-derived neurotrophic factor (BDNF) has been implicated in the mechanism of infarct tolerance (resistance to stroke) (H. Yanamoto et al., Infarct tolerance accompanied enhanced BDNF-like immunoreactivity in neuronal nuclei, submitted to Brain Res.), a process that takes more than 7 days following a preconditioning of repetitive cortical spreading depression (CSD). To investigate whether an elevated level of BDNF protein in the brain solely protects neurons against temporary focal ischemia, recombinant (r)BDNF was infused into the rat neocortex. Recombinant BDNF (or vehicle: saline) was administered into the left neocortex via an implanted osmotic minipump for 2.5, 7, 10 or 14 days pre-ischemia, during ischemia and for 2 days post-ischemia (8 microgram in total) in male Sprague-Dawley rats (n=6 each). Temporary focal ischemia was induced in the left middle cerebral artery (MCA) territory by three-vessel occlusion of bilateral common carotid arteries (CCAs) and MCA for 2 h, and the cerebral infarct volume was analyzed 2 days after ischemia using TTC staining. Regional cerebral blood flow (rCBF) of the left neocortex was monitored after 14 days of intracerebral administration of BDNF or vehicle (n=10 each). The distribution of BDNF following different periods of rBDNF or vehicle-infusion was analyzed using immunohistochemical techniques (n=5 each). In the groups treated with 8 microgram of rhBDNF for 7, 10, or 14 days pre-ischemia, there were significant reductions of neocortical infarct volume compared to in the control or vehicle-treated groups (p<0.05). In the rCBF study, there was no significant change after the infusion of 8 microgram rhBDNF for 14 days. In the histological study, a wide distribution of BDNF-like immunoreactivity in the neuronal nuclei in the ipsilateral neocortex was demonstrated after the infusion of 8 microgram rhBDNF for 14 days. The BDNF-like immunoreactivity in the neuronal nuclei was enhanced at the time that the resistance to stroke was achieved by direct intra-cerebral infusion of exogenous rBDNF. Elucidating the function of the BDNF-like protein located in the neuronal nuclei should reveal a new strategy for neuroprotection against ischemic brain attack in humans.     

Effect of propofol on brain-derived neurotrophic factor and tyrosine kinase receptor B in the hippocampus of aged rats with chronic cerebral ischemia

We intraperitoneally injected 10 and 50 mg/kg of propofol for 7 consecutive days to treat a rat model of chronic cerebral ischemia. A low-dose of propofol promoted the expression of brain-derived neurotrophic factor, tyrosine kinase receptor B, phosphorylated cAMP response element binding protein, and cAMP in the hippocampus of aged rats with chronic cerebral ischemia, but a high-dose of propofol inhibited their expression. Results indicated that the protective effect of propofol against cerebral ischemia in aged rats is related to changes in the expression of brain-derived neurotrophic factor and tyrosine kinase receptor B in the hippocampus, and that the cAMP-cAMP responsive element binding protein pathway is involved in the regulatory effect of propofol on brain-derived neurotrophic factor expression.     

Hypothermia and brain-derived neurotrophic factor reduce glutamate synergistically in acute stroke

Moderate hypothermia and application of brain-derived neurotrophic factor (BDNF) have separately been identified as neuroprotective strategies in experimental cerebral ischemia. To assess their separate and combined effects on striatal glutamate release in the hyperacute phase of stroke, we inserted microdialysis probes into the striatum of rats 2 h before permanent middle cerebral artery occlusion (MCAO). The animals (N = 28) were randomly assigned to one of four treatment strategies commencing 30 min after MCAO: (1) hypothermia at 33 degrees C (n = 7); (2) intravenous BDNF infusion [300 microg/(kg/h) for 2 h, n = 7]; (3) combination of hypothermia and BDNF (n = 7); (4) control group (saline, n = 7). Infarct size at 5 h after MCAO was assessed with the silver-staining method. Total infarct volume was significantly reduced in the hypothermia (202.7 +/- 3.5 mm(3), P = 0.0002) and BDNF group (206.5 +/- 6.9 mm(3), P = 0.0006) as compared to control group (254.4 +/- 9.3 mm(3)). In the combination group, infarct size was further reduced with overall significance in post hoc tests (157.3 +/- 6.2 mm(3), P < 0.0001). Postischemic glutamate concentrations in the control group constantly remained significantly higher than in all other treatment groups. At 255 and 270 min after MCAO, striatal glutamate in the combination group decreased significantly more than in animals treated with hypothermia or BDNF alone.Combining hypothermia and BDNF therapy in the acute stage of ischemia has a synergistic effect in attenuating striatal glutamate release and reducing early infarct size.     

精神分裂症患者脑源性神经营养因子水平及其与临床症状的关系

目的探讨脑源性神经营养因子（BDNF）在精神分裂症病理生理机制中的可能作用。方法采用横断面病例一对照研究设计。患者组为48例精神分裂症患者，其中发病后从未治疗组31例，停止治疗组17例。正常对照组（以下简称对照组）为与患者组性别、年龄匹配的41名健康人。对患者组用阳性和阴性症状量表（PANSS）评定病情严重程度。血浆BDNF浓度用酶联免疫吸附试验测定。用多变量方差分析比较组间差异。结果从未治疗组[（4．5±2．2）μg/L]和停药组患者[（3．9±1．4）μg/L]血浆BDNF浓度均低于对照组[（6．5±2．2）μg/L]（F检验，P〈0．01）；而从未治疗组与停止治疗组的差异无统计学意义（P〉0．05）。患者组的血浆BDNF浓度与PANSS阴性症状因子分（r=-0．509；P〈0．01）及总病期呈负相关（r=-0．426；P〈0．01），与发病年龄、PANSS阳性因子分、总分的相关性均无统计学差异。结论精神分裂症患者BDNF浓度低于正常；BDNF可能是参与精神分裂症病理生理机制的一种重要物质。     

Local infusion of brain-derived neurotrophic factor modifies the firing pattern of dorsal raphé serotonergic neurons

Previous studies have reported a neuromodulatory effect of brain-derived neurotrophic factor (BDNF) on serotonin neurons in the central nervous system. In the present study, we examined the effects of local infusion of BDNF on the electrophysiological activity of serotonergic neurons in the rat dorsal raphé nucleus with extracellular single unit recording in vivo. Compared with vehicle-infused rats, chronic administration of BDNF (10–14 days) caused serotonergic neurons to fire in a significantly less regular pattern, without altering the mean firing rate or other measures of electrical activity. These results suggest that the ability of similar infusions of BDNF to produce behavioral effects (i.e. analgesia and an antidepressant-like effect) associated with elevated serotonin turnover may be in part the result of more irregular firing patterns of dorsal raphé neurons.     

姜黄素对肠易激综合征模型大鼠5-羟色胺和脑源性神经营养因子的影响

目的 从脑肠轴角度明确肠易激综合征(IBS)发病机制,观察姜黄素对IBS的疗效.方法 48只SD大鼠按随机数字表法分为6组:正常组,IBS模型组,姜低组、姜中组、姜高组(造模前分别灌胃给予姜黄素10、20、40 mg/kg),丙咪嗪组(造模前腹腔注射丙咪嗪10 mg/kg),每组各8只.采用大鼠慢急性联合应激模型模拟IBS.糖水消耗试验和内脏敏感性实验检测各组大鼠抑郁样行为和肠道敏感性,高效液相法及Western blotting分别测定大鼠大脑皮层和回肠5-羟色胺(5-HT)及脑源性神经营养因子(BDNF)的表达. 结果 IBS模型组大鼠糖水消耗量明显减少,肠道内脏敏感性明显升高,大脑额叶皮层5-HT、BDNF表达水平降低,回肠黏膜5-HT、BDNF表达水平明显升高,与正常组比较差异均有统计学意义(P＜0.05).给予不同剂量姜黄素后能逆转上述行为学改变及大脑皮层、回肠的5-HT 、BDNF水平变化,其中姜高组与IBS模型组比较差异均有统计学意义(P＜0.05).丙咪嗪组效果与姜高组类似. 结论 IBS大鼠脑肠内5-HT、BDNF表达异常说明IBS的发生存在脑肠改变的物质基础.姜黄素可能是通过调节5-HT、BDNF表达来改善IBS模型大鼠的行为学变化.