脑源性神经营养因子失平衡在神经退行性疾病中的作用及治疗应用研究进展

脑源性神经营养因子(BDNF)的两种形式——成熟型BDNF(mBDNF)和BDNF前体(proBDNF)与相应的受体结合可介导一系列的生物信号, 对神经元的增殖、存活和凋亡均起着重要作用。目前已有越来越多的研究关注proBDNF向mBDNF的不平衡转化在阿尔茨海默病(AD)、帕金森病(PD)等神经退行性疾病中的作用, 以及它们作为疾病的生物标记物和治疗靶点方面的潜能。本文现围绕近年来BDNF及proBDNF/mBDNF失平衡在上述神经退行性疾病中的作用及治疗应用研究进展进行综述, 以期为AD、PD等神经退行性疾病的发病机制、早期诊断及治疗研究提供新的视角和途径。     

抑郁症的tPA-纤溶酶原系统功能紊乱假说

抑郁症的发病机制尚不明确,有学者提出"t PA-纤溶酶原系统功能紊乱假说",本文将近年来相关研究予以综述,着重讨论提出该假说的依据及t PA-纤溶酶原系统参与抑郁症的发病及抗抑郁治疗的可能机制。     

抑郁症与组织型纤溶酶原激活物及纤溶酶原系统功能紊乱

抑郁症是常见的精神疾病之一,普通人群的终身患病率一般在15％左右,女性高达25％.半个世纪以来,抑郁症生物学基础的主要解释是单胺递质异常假说,主要涉及去甲肾上腺素及5-羟色胺.近年来,多层面的研究显示,神经营养因子家族中的脑源性神经营养因子( brain derived neurotrophic factor,BDNF)在抑郁症发病以及抗抑郁药治疗机制中均起着重要作用[1]. 动物研究显示,环境应激可降低海马区BDNF的表达,而这一现象可被抗抑郁药逆转[2 ],并增加神经再生能力[3];给予应激抑郁模型动物外源性BDNF,也能产生抗抑郁作用.尸检研究显示,与生前未经抗抑郁药治疗的抑郁症患者相比,经药物治疗的患者海马区BDNF的免疫活性增加[4].临床研究显示,未接受抗抑郁药治疗的患者血清BDNF水平低于正常人,而抗抑郁药或电抽搐治疗后可恢复到正常范围[5-6].上述研究均提示,BDNF功能受损可能存在于抑郁症和应激相关的情感障碍,而上调BDNF可能是抗抑郁药发挥治疗作用的一个重要因素[7].因此,近年来围绕着抑郁症神经再生障碍假说和神经营养因子假说展开了大量的研究,其中抑郁症的组织型纤溶酶原激活物( tissue-type plasminogen activator,tPA)及纤溶酶原系统功能紊乱假说刚刚引起重视.本文就这一问题进行综述.     

脑源性神经营养因子在急性冠脉综合征合并抑郁症患者中的研究进展

脑源性神经营养因子(Brain-Derived Neurotrophic Factor,BDNF)为神经营养因子家族中一员,可调节血管及神经元的生成、存活和维持,研究发现BDNF与急性冠脉综合征(acute coronarysyndrome,ACS)及抑郁症相互关联,有望成为ACS合并抑郁症的生物学标志物,现就BDNF在急性冠脉综合征合并抑郁症患者中的研究进展做一综述。     

抑郁症大鼠海马BDNF及其受体TrkB和p75NTR的表达及米氮平的调节作用

目的观察抑郁症模型大鼠学习记忆力改变情况,研究海马脑源性神经营养因子(BDNF)、酪氨酸激酶受体B(TrkB)和神经营养因子低亲和力受体(p75NTR)蛋白的表达变化,以及米氮平的调节作用。方法制备抑郁症大鼠模型;采用Morris水迷宫实验方法记录大鼠游动距离变化;免疫组化染色方法测定海马BDNF、TrkB和p75NTR表达阳性区吸光度值。结果抑郁症模型大鼠在目标象限游动距离减少,海马BDNF及TrkB蛋白表达减少,p75NTR蛋白表达增加;米氮平逆转上述行为学异常及蛋白表达异常(p﹤0.01)。结论抑郁症模型大鼠可能存在BDNF-p75NTR通路信息传递增强,而抗抑郁治疗用药可能通过BDNFTrkB信号通路的改变引起相应行为学改善。     

抑郁症患者自杀行为与血清脑源性神经营养因子水平的关系

目的:探讨血清脑源性神经营养因子(BDNF)水平与抑郁症患者自杀行为之间的关系.方法:采用酶联吸附反应方法对有自杀行为的21例抑郁症患者(自杀组)、无自杀行为的52例抑郁症患者(非自杀组)以及80例正常人(对照组)血清的BDNF进行检测,应用汉密尔顿抑郁量表(HAMD)对抑郁症患者的抑郁症状进行评定. 结果:抑郁症患者...     

亨廷顿蛋白相关蛋白1与脑源性神经营养因子的胞吞关系的机制研究

目的探讨亨廷顿蛋白相关蛋白1(HAP1)与脑源性神经营养因子(mBDNF)胞吞的相关性和可能的机制。方法神经营养因子(NGF)诱导分化PC 1 2细胞,将荧光质粒HAP1A-CFP和(或)mBDNF-ds-red转染进入细胞,培养4 8 h后在含有BDNF或p7 5NTR抗体的培养基中继续培养,激光共聚焦显微镜观察荧光的表达情况及其在细胞中的定位;利用小鼠皮层神经元(正常型和HAP1基因敲除型)在生物素标记mBDNF的培养基中孵育6 0 m in,激光共聚焦显微镜观察皮层神经元免疫荧光的效果。结果共转染HAP1A-CFP和mBDNF-ds-red质粒的细胞,2种荧光蛋白存在部分共定位3 4%。共转染的细胞在抗BDNF培养基孵育下,或者单转染HAP1A-CFP质粒的细胞在mBDNF-ds-red荧光蛋白+抗BD-NF/抗p7 5NTR培养基孵育下,2种荧光蛋白几乎没有共定位现象。单转染HAP1A-CFP质粒的细胞在mBDNF-ds-red荧光蛋白培养基孵育下,mBDNF与HAP1蛋白的共定位比例高达9 3%。正常新生小鼠皮层神经元内可见内吞的mBDNF免疫荧光,HAP1基因敲除小鼠的皮层神经元内未见。结论 mBDNF的胞吞必需HAP1的表达和参与。     

脑源性神经营养因子与抑郁症

神经营养因子是神经元网络形成和可塑性的重要调节因子,以脑源性神经营养因子(BDNF)最受关注。抗抑郁治疗通过提高BDNF表达来促进神经元可塑性,从而取得疗效。本文从临床前研究、临床研究和基因多态性等方面对BDNF与抑郁症作一综述。     

抑郁症患者血清脑源性神经营养因子水平及其相关因素

目的 探讨抑郁症患者血清脑源性神经营养因子水平及其相关因素,为防治抑郁症提供重要依据.方法 采用酶联免疫吸附法和汉密尔顿抑郁量表分别测定40例抑郁症患者(患者组)的血清BDNF水平和抑郁严重程度,并与49名正常者(对照组)进行对比分析.结果 患者组治疗前血清BDNF水平明显降低,与对照组比较差异有统计学意义(P＜0.01).患者组治疗8周末血清BDNF水平明显升高,HAMD总分明显降低,与治疗前比较差异有统计学意义(P＜0.05).患者组治疗前后血清BDNF水平与性别及年龄均呈负相关,差异具有统计学意义(P＜0.05),与受教育程度、病程及HAMD总分比较无统计学意义(P＞0.05).结论 抑郁症患者存在血清BDNF水平的下降,抗抑郁治疗可改善抑郁症状,并显著提高血清BDNF水平.     

晚发性抑郁症患者血浆脑源性神经营养因子水平与认知功能

目的 探讨晚发性抑郁症患者血浆脑源性神经营养因子(BDNF)水平与抑郁症发病及认知功能之间的关系.方法 采用酶联免疫吸附法测定34例未经治疗的晚发性抑郁症患者(患者组)和32名正常对照(对照组)血浆BDNF水平;对患者组及对照组进行17项汉密尔顿抑郁量表( HAMD17)评估及神经心理学测试;对患者组的血浆BDNF水平及HAMD17总分与认知功能进行Pearson相关分析.结果 患者组治疗前的神经认知测试成绩显著差于对照组(P＜0.01);患者组的血浆BDNF水平[(3.24±2.67) μg/L]低于对照组[(6.71±3.16)μg/L,P＜0.01].血浆BDNF水平与各项认知成绩、HAMD17总分值均无显著相关性(P＞0.05).结论 部分晚发性抑郁症患者存在认知功能广泛受损;血浆BDNF水平低下与晚发性抑郁症发病密切相关,与认知功能可能无直接相关性.     

Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor

Morphine has been shown to increase the expression of brain-derived neurotrophic factor (BDNF) in the brain. However, little is known about the effect of morphine withdrawal on BDNF and its precursor protein, or proBDNF, which induces neuronal apoptosis. In this work, we examined whether BDNF and proBDNF levels change in rats chronically injected with escalating doses of morphine and those who undergo spontaneous withdrawal for 60 h. We observed, in the frontal cortex and striatum, that the ratio of BDNF to proBDNF changed depending upon the experimental paradigm. Morphine treatment and morphine withdrawal increased both BDNF and proBDNF levels. However, the increase in proBDNF immunoreactivity in withdrawal rats was more robust than that observed in morphine-treated rats. proBDNF is processed either intracellularly by furin or extracellularly by the tissue plasminogen activator (tPA)/plasminogen system or matrix metalloproteases (MMPs). To examine the mechanisms whereby chronic morphine treatment and morphine withdrawal differentially affects BDNF/proBDNF, the levels MMP-3 and MMP-7, furin, and tPA were analyzed. We found that morphine increases tPA levels, whereas withdrawal causes a decrease. To confirm the involvement of tPA in the morphine-mediated effect on BDNF/proBDNF, we exposed cortical neurons to morphine in the presence of the tPA inhibitor plasminogen activator inhibitor-1 (PAI-1). This inhibitor reversed the morphine-mediated decrease in proBDNF, supporting the hypothesis that morphine increases the availability of BDNF by promoting the extracellular processing of proBDNF by tPA. Because proBDNF could negatively influence synaptic repair, preventing withdrawal is crucial for reducing neurotoxic mechanisms associated with opioid abuse.     

Plasminogen activator inhibitor 1 gene polymorphisms and mirtazapine responses in Koreans with major depression

Introduction: Brain‐derived neurotrophic factor (BDNF) is involved in the pathophysiology of mental disorders and in the mechanism of action of antidepressant medications. The mature form of BDNF is derived from proBDNF through tissue type plasminogen activator (tPA) and the plasminogen system in the brain, which is regulated by an endogenous inhibitor, plasminogen activator inhibitor (PAI). Therefore, PAI may be involved in the development of major depressive disorder (MDD) and its response to antidepressant treatment. The present study determined the relationship between the 4G/5G polymorphism in the PAI1 gene and the clinical outcome of mirtazapine treatment in 271 Korean MDD patients. Methods: We tested the association between the polymorphism and response to mirtazapine treatment or percentage decrease of the 21‐item Hamilton Depression Rating (HAMD21) scores using multiple logistic and linear regression analysis. Results: PAI1 4G/5G genotypes and allele distributions were comparable between responders and non‐responders during the treatment period. Similarly, linear regression showed no association between genotypes or alleles and the percentage decline in total HAMD21 with mirtazapine treatment. In the analysis of symptomatic subscores, the percentage decline in the psychic anxiety and delusion scores after 4 weeks of mirtazapine treatment showed a statistical trend to a difference among genotypes, although it was not statistically significance. Discussion: In this first pharmacogenetics study of the PAI1 4G/5G polymorphism and mirtazapine treatment response, our results do not support the hypothesis that this polymorphism is involved in the therapeutic response to mirtazapine.     

Plasma BDNF and tPA are associated with late‐onset geriatric depression

Aims: Studies in the recent decade have shown that brain‐derived neurotrophic factor (BDNF) may play an important role in the pathogenesis of major depressive disorder (MDD). Tissue‐type plasminogen activator (tPA) has been implicated in the control of the direction of BDNF action. The aim of the study was therefore to investigate the changes of BDNF/tPA levels and their clinical meanings in geriatric depression. Methods: Plasma BDNF and tPA levels were measured in late‐onset geriatric depression (LGD) before treatment (n = 24) and after 6 weeks of antidepressant treatment (n = 24) compared with control subjects (n = 30) using enzyme‐linked immunosorbent assay. The severity of depression was assessed with the Hamilton Depression Rating Scale. Results: Baseline plasma BDNF and tPA levels were significantly lower in LGD patients compared to controls (P = 0.037 and P = 0.000, respectively). There was a heightening tendency of plasma BDNF level after treatment. Conclusions: Plasma BDNF and tPA levels are associated with LGD. The complex mechanism of BDNF and tPA in LGD should be further explored in future studies.     

Brain‐derived neurotrophic factor as a biomarker for mood disorders: An historical overview and future directions

Mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BPD), are the most prevalent psychiatric conditions, and are also among the most severe and debilitating. However, the precise neurobiology underlying these disorders is currently unknown. One way to combat these disorders is to discover novel biomarkers for them. The development of such biomarkers will aid both in the diagnosis of mood disorders and in the development of effective psychiatric medications to treat them. A number of preclinical studies have suggested that the brain‐derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of MDD. In 2003, we reported that serum levels of BDNF in antidepressant‐naive patients with MDD were significantly lower than those of patients medicated with antidepressants and normal controls, and that serum BDNF levels were negatively correlated with the severity of depression. Additionally, we found that decreased serum levels of BDNF in antidepressant‐naive patients recovered to normal levels associated with the recovery of depression after treatment with antidepressant medication. This review article will provide an historical overview of the role played by BDNF in the pathophysiology of mood disorders and in the mechanism of action of therapeutic agents. Particular focus will be given to the potential use of BDNF as a biomarker for mood disorders. BDNF is initially synthesized as a precursor protein proBDNF, and then proBDNF is proteolytically cleaved to the mature BDNF. Finally, future perspectives on the use of proBDNF as a novel biomarker for mood disorders will be discussed.     

Brain-derived neurotrophic factor and inflammation in depression: Pathogenic partners in crime?

Major depressive disorder is a debilitating disorder affecting millions of people each year. Brain-derived neurotrophic factor (BDNF) and inflammation are two prominent biologic risk factors in the pathogenesis of depression that have received considerable attention. Many clinical and animal studies have highlighted associations between low levels of BDNF or high levels of inflammatory markers and the development of behavioral symptoms of depression. However, less is known about potential interaction between BDNF and inflammation, particularly within the central nervous system. Emerging evidence suggests that there is bidirectional regulation between these factors with important implications for the development of depressive symptoms and anti-depressant response. Elevated levels of inflammatory mediators have been shown to reduce expression of BDNF, and BDNF may play an important negative regulatory role on inflammation within the brain. Understanding this interaction more fully within the context of neuropsychiatric disease is important for both developing a fuller understanding of biological pathogenesis of depression and for identifying novel therapeutic opportunities. Here we review these two prominent risk factors for depression with a particular focus on pathogenic implications of their interaction.     

Injection of Anti-proBDNF in Anterior Cingulate Cortex (ACC) Reverses Chronic Stress-Induced Adverse Mood Behaviors in Mice

Foraging behavior is a species-specific behavior which is considered to involve the decision making and higher cognitive functions. We previously established a novel method to detect the foraging behavior in chronic unpredictable mild stress (CUMS)-induced depression mice, in which the food foraging activity of mice was significantly reduced. Furthermore, it is generally assumed that the bilateral anterior cingulate cortex (ACC) is related to foraging activity in rat. Brain-derived neurotrophic factor (BDNF) is widely expressed in many regions of the brain and is down-regulated in depressive patients. However, the relationship between the precursor of brain-derived neurotrophic factor (proBDNF) and depression has not been fully elucidated. The results showed that CUMS in mice induced anxiety- and depression-like behaviors and significant reduction in BDNF messenger RNA (mRNA) in the brain. In this study, we evaluated the effect of anti-BDNF and anti-proBDNF in the ACC on the CUMS-induced depression mice. In contrast to the normal IgG group (normal IgG microinjection into the ACC), bilateral ACC treatment with anti-proBDNF microinjection not only reversed depressive activity but also significantly increased the amount of foraged food and BDNF mRNA in the brain. There was no significant alteration in the group of anti-BDNF microinjection into the ACC. Our data indicate that the proBDNF signaling pathway might down-regulate the foraging activity in CUMS rodents and be involved in the depression.     

Fibrin-dependent fibrinolytic activity during extracorporeal circulation

Cardiopulmonary By-Pass (CPB) Surgery may at times induce a haemostatic defect, at present not too well understood, causing severe bleeding from the operative site and chest tube drain. We present here some data on antigen increase in tissue Plasminogen Activator (tPA) and D 2 Dimer (D2D) detected during CPB and apparently not compensated by enhanced Plasminogen Activator Inhibitor type 1 (PAI 1) activity. tPA concentration (antigenic) ranged around 6.15 ng/ml (SD 5.6) before thoracotomy and 5.8 g/ml (SD 4.74) 5-10 minutes after a heparin 250 IU/Kg bolus injection. During CPB, tPA increased to 20.34 ng/ml (SD 9.17) before protamine infusion, and 16.93 ng/ml (SD 8.13) after heparin neutralization. As the D2D went up to 2000-4000 ng/ml (before/after protamine) and it was not correlated by fibrinogen consumption or FDP production, we find these observations suggestive of fibrin-dependent fibrinolytic activity, as an acquired haemostatic defect developed during CPB.     

Production of plasminogen activator and plasminogen activator inhibitor by bovine lymphatic endothelial cells: modulation by TNF-alpha

We have investigated whether lymphatic endothelial cells in culture produce plasminogen activators (PAs) and their inhibitors (PAIs) and if these activities can be modulated by the inflammatory cytokine Tumor Necrosis Factor alpha (TNF-alpha). Examination by reverse fibrin autography of the conditioned medium from these cells revealed a PAI of Mr 50 kDa. Also evident by fibrin autography were two species of PAs, of Mr 110 kDa and Mr 60 kDa. The 110 kDa protein co-migrated with the PA-PAI complexes and the 60 kDa protein co-migrated with tissue Plasminogen Activator (tPA). Functional and immunological assays indicated the human TNF-alpha increased the type 1 plasminogen activator inhibitor (PAI-1) in a time dependent manner. Treatment of the cells with recombinant human TNF-alpha for 24 hours resulted in a 3 to 7 fold increase in the amount of PAI released into the conditioned media. Immunoblot analysis identified the PAI in the TNF-alpha treated cell conditioned media, as PAI-1. Deposition of PAI-1 in the extracellular matrix then became apparent. TNF-alpha increased 4 fold the amount of tPA-PAI-1 complexes (Mr 110 kDa) detected in the conditioned media. Free tPA (Mr 60 kDa) decreased to 1/5 of control. Net fibrinolytic activity, as determined by a chromogenic substrate assay, decreased after TNF-alpha treatment. No urokinase type Plasminogen Activator (uPA) activity was detected in control or treated cells. This fibrinolytic activity may be important in maintaining free fluid movement in the interstitium and lymphatic vessels and in inflammatory states this potential may be decreased by the increase in PAI-1.     

Neurotrophic factors and Alzheimer's disease: are we focusing on the wrong molecule?

Brain derived neurotrophic factor (BDNF) promotes cholinergic neuron function and survival. In Alzheimer's disease, BDNF mRNA and protein are decreased in basal forebrain cholinergic neuron target tissues such as cortex and hippocampus. Using RT-PCR, we demonstrate that BDNF is synthesized in basal forebrain, supplying cholinergic neurons with a local as well as a target-derived source of this factor. BDNF mRNA levels are decreased 50% in nucleus basalis of Alzheimer disease patients compared to controls. Thus, not only do the basal forebrain cholinergic neurons have a reduced supply of target-derived BDNF, but also of local BDNF. We also show by Western blotting that human CNS tissue contains both proBDNF and mature BDNF protein. Moreover, we demonstrate a significant (2.25-fold) deficit in proBDNF protein in Alzheimer's disease parietal cortex compared to controls. Thus, reduced BDNF mRNA and protein levels in Alzheimer's disease suggests that BDNF administration may be an effective therapeutic strategy for this disorder.     

Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer's disease

Brain-derived neurotrophic factor (BDNF) promotes the function and survival of the major neuronal types affected in Alzheimer disease, such as hippocampal, cortical and basal forebrain cholinergic neurons. We and others have demonstrated a reduction in BDNF mRNA expression in Alzheimer's disease hippocampus and cortex, which may help to explain the selective vulnerability of these neurons. Several studies have also shown decreased BDNF protein in Alzheimer's disease. BDNF protein is synthesized as a precursor, proBDNF, which is cleaved to the mature 14-kDa form. We demonstrate here that BDNF exists as a mixture of proBDNF and mature BDNF in all regions tested of human brain. Using Western blotting, we observe a 40% reduction in proBDNF levels in Alzheimer's disease parietal cortex compared to controls. Thus, decreased BDNF protein measured by ELISA and immunohistochemistry likely represents a mixture of the two BDNF forms, and previously reported decreases in BDNF protein may be due, at least in part, to a significant reduction in proBDNF levels. Although the biological activity of proBDNF is unknown, reduced proBDNF may have functional consequences for the selective neuronal degeneration in Alzheimer's disease brain.