甲基苯丙胺成瘾者戒断期的脑源性神经营养因子变化研究进展

脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)参与了神经发生、神经可塑性及认知功能等多种神经活动,参与学习和记忆的过程,对神经可塑性的调节和损伤后修复具有重要影响,被认为是与成瘾行为相关的生物标志物.本文回顾了国内外BDNF与物质成瘾关系以及甲基苯丙胺成瘾者戒断期外周...     

神经生长因子和脑源性神经营养因子对神经干细胞迁移的影响

目的:探讨神经生长因子(nervegrowth factor,NGF)与脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)体外实验对神经干细胞迁移的影响.方法:体外应用半固体培养法连续14d观察不同浓度的NGF、BDNF及NGF +BDNF组合诱导神经干细胞迁移的情况.结果:体外条件下不同浓度的神经营养因子的组间和组内比较显示,100μg/L BDNF诱导神经干细胞迁移作用最明显.BDNF+NGF联合组在诱导神经干细胞迁移方面未见协同效应.结论:NGF、BDNF二者皆有诱导神经干细胞迁移的作用,100μ g/L BDNF组诱导迁移作用最明显.     

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。     

脑源性神经营养因子与脑缺血的研究进展

脑源性神经营养因子(brain derived neurotrophic factor,BDNF)是在脑内形成的一类神经营养因子。BDNF通过作用于其特异性受体TrkB、P75促进神经元的生长发育同时修复受损的神经元。BDNF对缺血性脑损伤的保护机制是通过下调钙离子浓度,减小Bax/Bcl-2比值,对抗NO毒性等途径实现的。该文介绍了BDNF的基本作用及其与脑缺血的相关作用研究,综述了BDNF的应用方法研究。     

脑源性神经营养因子在炎症性肠病中的作用

脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）是神经营养因子（neurotrophin,NT）家族中的重要成员,在神经元的维持和存活,保持突触完整性和突触可塑性中起重要作用,但其作用不仅限于此。研究发现BDNF在炎症性肠病（inflammatory bowel disease,IBD）中具有维持内脏超敏反应,促进肠道动力,维持肠道屏障,调节情绪障碍及心脏功能的作用,可能在IBD的发生发展中起重要作用。虽然目前大多限于基础研究,但已经取得了一定的成果,可以预见BDNF将有很好的临床应用前景,可能为IBD的临床治疗提供新的治疗思路。对此,本文作一简要综述。     

脑源性神经营养因子对离子通道的调节作用

脑源性神经营养因子（brain derived neurotrophic factor,BDNF）是神经营养因子（neurotrophicfactors,NTF）家族成员之一,对中枢和周围神经系统多种神经元的生长、发育、分化、维持和损伤修复起重要作用。BDNF还能够调节神经元静息膜电位、神经兴奋性和突触传递,在突触可塑性过程中起重要作用,这些作用与其对离子通道的调节有关。BDNF不仅可以与TrkB受体结合激活第二信使级联反应和蛋白磷酸化过程调节离子通道的性质,还可以直接调节钠通道活性。可见,BDNF还具有神经调质和兴奋性递质的作用。     

更年期妇女抑郁程度与脑源性神经营养因子水平的相关性研究

目的 通过观察更年期妇女汉密顿抑郁量表(HAMD)及血清脑源性神经营养因子(BDNF)水平,探讨更年期妇女抑郁程度与脑源性神经营养因子水平的相关性.方法 随机选取更年期妇女405名作为研究对象,采用HAMD进行评分及分组,同时采用ELISA法检测血清BDNF水平,进行统计学分析.结果 405名更年期妇女抑郁症状的检出率为32.3％(131/405).有抑郁症状组与无抑郁症状组比较,HAMD分值、血清BDNF水平差异有统计学意义(P＜0.01).更年期抑郁症妇女HAMD分值与血清BDNF水平呈显著负相关性(r=-0.497,P＜0.01).结论 近1/3更年期妇女存在抑郁症状,其抑郁程度与BDNF水平负相关;血清BDNF水平可作为判定更年期妇女抑郁程度及抗抑郁疗效的参考指标.     

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。     

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。     

褪黑素对SD大鼠胚胎中脑神经干细胞增殖和分化的影响

目的：脑内神经发生受多种病理生理因素调节，既往的研究表明褪黑素（Melatonin，MT）具有广泛的神经营养和神经保护作用，本研究观察MT对SD大鼠胚胎中脑神经干细胞（NSCs）增殖和分化的影响。方法：分离培养孕13-14天SD大鼠胚胎的中脑NSCs，用MTS方法测定MT对NSCs增殖的影响；通过RT-PCR、Western blot和免疫荧光方法检测MT对NSCs分化方向的调节作用；RT-PCR和Western blot方法检测NSCs上MT受体及脑源神经营养因子（BDNF）和胶质细胞源性神经营养因子（GDNF）的表达。结果：MT（0．05、0．1和1nM）均可促进NSCs的增殖，与对照组相比具有显著性差异（P〈0．05或P〈O．01）；而且，MT明显促进中脑NSCs分化时多巴胺能神经元标志蛋白酪氨酸羟化酶（TH）表达（P〈O．05），抑制胶质纤维酸性蛋白（GFAP）的表达；此外，MT可使NSCs内BDNF和GDNF的表达水平显著提高（P〈0．01）；同时我们还发现MT受体的两个亚型MTl和MT2在中脑NSCs均有表达，提示可能参与了对NSCs的调节作用。结论：本研究发现，MT不仅可以促进中脑NSCs的增殖，还显著提高NSCs向多巴胺能神经元方向的分化，而抑制其向星形胶质细胞的分化，这可能与MT上调BDNF和GDNF的表达有关。以上结果可为MT临床治疗某些老年性神经疾患并改善部分临床症状的作用机理提供线索。     

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'.     

GABAA Receptor Blockade Enhances Memory Consolidation by Increasing Hippocampal BDNF Levels

Memory consolidation is the process by which acquired information is converted to something concrete to be retrieved later. Here we examined a potential role for brain-derived neurotrophic factor (BDNF) in mediating the enhanced memory consolidation induced by the GABA_A receptor antagonist, bicuculline methiodide. With the administration of an acquisition trial in naïve mice using a passive avoidance task, mature BDNF (mBDNF) levels were temporally changed in the hippocampal CA1 region, and the lowest levels were observed 9 h after the acquisition trial. In the passive avoidance task, bicuculline methiodide administration within 1 h of training but not after 3 h significantly increased latency time in the retention trial 24 h after the acquisition trial. Concomitantly, 1 h post-training administration of bicuculline methiodide, which enhanced memory consolidation, significantly increased mBDNF levels 9 h after training compared to those of the vehicle-treated control group. In addition, exogenous human recombinant BDNF (hrBDNF) administration 9 h after training into the hippocampal CA1 region facilitated memory consolidation confirming that the increase in mBDNF at around 9 h after training plays a key role in the enhancement of memory consolidation. Moreover, the increases in latency time and immediate early gene expressions by bicuculline methiodide or hrBDNF were significantly blocked by anisomycin, a protein synthesis inhibitor, K252a, a tyrosine receptor kinase (Trk) inhibitor, or anti-TrkB IgG. These findings suggest that the increase in the level of mBDNF and its function during a restricted time window after training are required for the enhancement of memory consolidation by GABA_A receptor blockade.     

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.     

Disruption of synaptic expression pattern and age-related DNA oxidation in a neuronal model of lead-induced toxicity

Lead (Pb) is recognized as a potent inducer of synaptic toxicity generally associated with reduced synaptic transmission and increased neuronal fiber excitability, becoming an environmental risk for neurodegenerative processes. Despite numerous toxicological studies on Pb have been directed to the developing brain, attention concerning long-term consequences of pubertal chronic Pb exposure on neuronal activity is still lacking. Thus, we exposed 4-week-old male mice to 0.2 % lead acetate solution for one month, then, conducted behavioral tests or extracted brain homogenate from mice prefrontal cortex (PFC) and hippocampus at the age of 4, 13 and 16-month-old respectively. Our results showed that treated mice exhibited an evident increase in latency to reach platform following pubertal Pb exposure and aging. The increase of 8-OHdG revealed evident neural DNA oxidative damage across time upon pubertal Pb exposure. In the hippocampus of lead exposed mice at three age nodes, the expression of brain-derived neurotrophic factor precursor (proBDNF) increased, while that of mature BDNF (mBDNF), cAMP-response element binding protein (CREB) and phosphorylated CREB (pCREB) decreased compared with the control group. Furthermore, the expression of BACE1 protein and tau phosphorylation level in PFC and hippocampus increased, APP mRNAs in PFC and prolonged induction of BACE1 in hippocampus. Our results show that chronic Pb exposure from pubertal stage onward can either initiate divergent synaptic-related gene expression patterns in adulthood or trigger time-course of neurodegenerative profile within the PFC or hippocampus, which can contribute consistent deficits of cognition across subsequent age-nodes.     

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。     

Protection by [6]-shogaol against lipopolysaccharide-induced toxicity in murine astrocytes is related to production of brain-derived neurotrophic factor

[6]-Shogaol has beneficial effects in spinal neuronal regeneration, but associated molecules and mechanisms are not identified. Neurotrophic factors, including brain-derived neurotrophic factor (BDNF), are associated with proliferation and differentiation of neuronal cells and exert a neuroprotective effect in neurodegenerative models. We investigated whether treatment with [6]-shogaol increases BDNF expression in lipopolysaccharide (LPS)-treated astrocytes, and examined the effect of [6]-shogaol on neuronal protection. [6]-Shogaol significantly attenuated the cell death induced by LPS. Western blotting showed that [6]-shogaol treatment reduced Bax expression and increased B-cell lymphoma (Bcl)-2 and BclxL expression in LPS-treated cells, consistent with the effects of BDNF treatment. Furthermore, K252a, a blocker of neurotrophic factors, attenuated the cellular protective effects of [6]-shogaol and BDNF. This study provides the first evidence that [6]-shogaol increases the expression of BDNF in LPS-treated astrocytes. Furthermore, these experimental results indicate that production of BDNF in astrocytes might be related to altered cell viability following [6]-shogaol treatment. Thus, the neuroprotective effects of [6]-shogaol is mediated by up-regulation of BDNF.     

Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator

The effects of a novel AMPA receptor potentiator (LY392098) on the expression of brain-derived neurotrophic factor (BDNF) were examined in primary neuron culture. The addition of either AMPA or LY392098 to cortical neurons elicited a time and concentration dependent increase in mRNA encoding BDNF. Moreover, co-addition of subeffective concentrations of AMPA (1 μM) and LY392098 (1 μM) resulted in dramatic increases in both BDNF mRNA (>25-fold) and protein (7-fold) levels, whilst no changes in either NT-3 or NT-4 mRNA were detected. More modest (1.5–2.5-fold) elevations in BDNF mRNA and protein expression were also produced by combinations of AMPA and LY392098 in cerebellar granule cell neurons. In contrast, AMPA and LY392098, either alone or in combination, did not elevate BDNF mRNA levels in primary astroglial cultures. Maximum elevations in BDNF mRNA and protein were produced by 6–12 h of AMPA receptor activation 1–3 h of AMPA receptor activation were required to elevate BDNF mRNA levels. AMPA receptor-mediated increases in BDNF mRNA and protein were abolished by the AMPA antagonist, NBQX, but were unaffected by the NMDA antagonist, MK-801. In cortical neuron cultures, activation of both L-type Ca⁺² channels and mitogen-activated protein (MAP) kinases contribute to AMPA receptor-mediated increases in BDNF mRNA. The ability of LY392098 to increase the expression of BDNF in primary neuron culture indicates this and related biarylpropylsulfonamides may be useful in the treatment of neuropsychiatric disorders.     

BDNF plasma levels after antidepressant treatment with sertraline and transcranial direct current stimulation: Results from a factorial,randomized, sham-controlled trial

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention that modifies cortical excitability according to the stimulation parameters. Preclinical and clinical studies in healthy volunteers suggest that tDCS induces neuroplastic alterations of cortical excitability, which might explain its clinical effects in major depressive disorder (MDD). We therefore examined whether tDCS, as compared to the antidepressant sertraline, increases plasma brain-derived neurotrophic factor (BDNF) levels, a neurotrophin associated with neuroplasticity. Patients (n=73) with major depressive disorder were randomized to active/sham tDCS and sertraline/placebo (four groups) in this 6-week, double-blind, placebo-controlled trial. We measured BDNF plasma levels at baseline and endpoint, observing no significant changes of BDNF levels after treatment. In addition, no significant changes were observed in responders and non-responders as well as no relationships between BDNF levels and clinical and psychopathological variables related to depression. Thus, in one of the few placebo-controlled trials evaluating BDNF changes over an antidepressant treatment course, we did not observe BDNF increase regardless of clinical improvement in depressed patients. Regarding tDCS, BDNF plasma levels might not be a good candidate biomarker to evaluate depression improvement or be a predictor of response in patients treated with tDCS, as our results showed that BDNF increase was not necessary to induce clinical response. Finally, our findings do not support a relationship between BDNF and improvement of depression.     

Low-Dose Memantine Attenuated Morphine Addictive Behavior Through its Anti-Inflammation and Neurotrophic Effects in Rats

Opioid abuse and dependency are international problems. Studies have shown that neuronal inflammation and degeneration might be related to the development of opioid addiction. Thus, using neuroprotective agents might be beneficial for treating opioid addiction. Memantine, an Alzheimer's disease medication, has neuroprotective effects in vitro and in vivo. In this study, we evaluated whether a low dose of memantine prevents opioid-induced drug-seeking behavior in rats and analyzed its mechanism. A conditioned-place-preference test was used to investigate the morphine-induced drug-seeking behaviors in rats. We found that a low-dose (0.2-1?mg/kg) of subcutaneous memantine significantly attenuated the chronic morphine-induced place-preference in rats. To clarify the effects of chronic morphine and low-dose memantine, serum and brain levels of cytokines and brain-derived neurotrophic factor (BDNF) were measured. After 6?days of morphine treatment, cytokine (IL-1β, IL-6) levels had significantly increased in serum; IL-1β and IL-6 mRNA levels had significantly increased in the nucleus accumbens and medial prefrontal cortex, both addiction-related brain areas; and BDNF levels had significantly decreased, both in serum and in addiction-related brain areas. Pretreatment with low-dose memantine significantly attenuated chronic morphine-induced increases in serum and brain cytokines. Low-dose memantine also significantly potentiated serum and brain BDNF levels. We hypothesize that neuronal inflammation and BDNF downregulation are related to the progression of opioid addiction. We hypothesize that the mechanism low-dose memantine uses to attenuate morphine-induced addiction behavior is its anti-inflammatory and neurotrophic effects.