神经营养因子及其对神经系统疾病治疗作用的研究进展

本文就近年来神经营养因子(NTFs)及其受体的分类、编码基因及作用机理等方面作了综述,并评价了NTFs对神经系统疾病的治疗作用。     

神经营养因子与帕金森病

神经营养因子（ＮＴＦ_ｓ）及其基因对帕金森病（ＰＤ）的保护作用研究是目前研究的前沿领域。本文对ＮＴＦ_ｓ的家族与生物特性,ＮＴＦ_ｓ受体,ＮＴＦ_ｓ与帕金森病的相互关系及其对ＰＤ的保护机制等方面的研究作一综述。     

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…     

胶质细胞源性营养因子及内皮素B受体基因共转染小鼠神经干细胞*☆

背景：胶质细胞源性神经营养因子与内皮素B受体基因的缺失将导致肠神经系统发育异常。神经干细胞移植不仅可以从解剖和功能上修复神经系统,还可以作为基因转染的载体。 目的：拟将携带胶质细胞源性神经营养因子和内皮素B受体基因的重组腺病毒转染至小鼠神经干细胞,并观察目的基因的表达。 设计：细胞-基因学观察。 材料：新生昆明小鼠由华中科技大学同济医学院动物实验中心提供。jetPEI转染试剂为PolyPlus 公司产品;携带绿色荧光蛋白的胶质细胞源性神经营养因子、内皮素B受体基因共表达腺病毒由本室孙念峰博士和张景辉博士构建并惠赠。 方法：无菌条件下取新生小鼠脑组织,制备单细胞悬液。取携带绿色荧光蛋白的胶质细胞源性神经营养因子和内皮素B受体基因共表达腺病毒,溶解于NaCl中制备JetPEI/DNA复合体。用DMEM/F12完全培养基调整次代神经干细胞密度为5×108 L-1,向24孔板中每孔加入400 μL细胞悬液、100 μL JetPEI/DNA复合体,置37 ℃、体积分数为5%的CO2培养箱中,分别于转染24,48,72 h后收集神经干细胞。 主要观察指标：采用荧光显微镜、流式细胞仪检测转染效率,RT-PCR检测目的基因在神经干细胞内的表达。 结果：转染24 h后即可在荧光显微镜下观察到绿色荧光蛋白的表达,转染24,48,72 h后绿色荧光蛋白阳性率分别为15.36%,24.67%,25.73%。各转染时间点神经干细胞均表达胶质细胞源性神经营养因子及内皮素B受体基因,转染24 h条带亮度较低,72 h时外源基因表达水平最高。 结论：运用jetPEI试剂成功将目的基因转染至小鼠神经干细胞内,且胶质细胞源性神经营养因子和内皮素B受体基因在靶细胞中得到有效转录和表达。     

胶质源性神经营养因子和精神分裂症相关性的研究进展

目前神经发育异常假说认为精神分裂症是脑组织发育异常的结果。胶质细胞源性神经营养因子(GDNF)对神经细胞的生长、分化、存活、可塑性及损伤后修复有重要作用。GDNF基因敲除小鼠表现出异常的海马突触传递,GDNF及其受体在海马、前额皮质均有高表达,而这些脑区与精神分裂症的发生与治疗有关。故本文对GDNF和精神分裂症的关系作一综述。     

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.     

神经营养因子的两类受体:Trks及p75(综述)

此文简要回顾了神经营养因子的两类受体——酪氨酸激酶受体家族 (Trks)及 p75的分子结构、分布、相互作用 ,与神经营养因子的结合及其后的信号传导路径     

精神分裂症与神经营养因子

精神分裂症的神经发育障碍假说认为，神经发育障碍可能是导致精神分裂症的重要原因，而神经营养因子系统在神经发育过程中起重要作用，本文就精神分裂症与神经营养因子的研究进行综述。     

脑源性神经营养因子在神经系统疾病中的应用

脑源性神经营养因子在神经系统疾病中的应用曲伸综述路长林审校神经营养因子（Ｎｅｕｒｏｔｒｏｐｈｉｃｆａｃｔｏｒ，ＮＴＦ）是靶组织分泌的一组特异性的蛋白分子，有促进和维持神经细胞生长、存活、分化和执行功能的作用，它对神经元有一定的特异性，但不刺激细胞分裂...     

神经营养因子3基因修饰神经干细胞移植脊髓损伤的相关蛋白表达☆

背景：研究表明神经干细胞和神经营养因子3基因修饰的神经细胞联合移植能够在移植后存活并有效促进脊髓横断后脊髓的功能恢复,但神经营养因子3基因修饰的神经干细胞能否在脊髓受损部位发挥功能并促进脊髓损伤大鼠的功能恢复? 目的：观察神经营养因子3基因修饰胚胎脊髓神经干细胞移植后脊髓损伤大鼠的功能恢复情况及损伤局部的基因表达。 方法：将30只SD大鼠在T9水平进行脊髓半切后,随机分为3组,分别在受损脊髓内植入细胞培养液、神经干细胞及神经营养因子3基因修饰神经干细胞。另取10只仅行椎板切除设置为空白对照。移植后通过行为学测试评价脊髓功能的恢复,RT-PCR和Western blot检测脊髓损伤部位神经营养因子3和髓鞘碱性蛋白的表达。 结果与结论：移植神经营养因子3基因修饰神经干细胞组行为学测试结果最好,移植细胞培养液组行为学测试最差。与移植细胞培养液组相比,移植神经干细胞及神经营养因子3基因修饰神经干细胞组大鼠脊髓组织中神经营养因子3基因和髓鞘碱性蛋白基因的mRNA水平明显上调,在蛋白水平也有类似的结果,且神经营养因子3基因修饰神经干细胞组效果更明显。提示移植神经营养因子3基因修饰神经干细胞能促进脊髓受损部位出现更多向少突胶质细胞分化的细胞,并能更强的表达神经营养因子3。     

Cognitive disorder and changes in cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor following brain injury*★

BACKGROUND: Learning and memory damage is one of the most permanent and the severest symptoms of traumatic brain injury; it can seriously influence the normal life and work of patients. Some research has demonstrated that cognitive disorder is closely related to nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor. OBJECTIVE: To summarize the cognitive disorder and changes in nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor following brain injury. RETRIEVAL STRATEGY: A computer-based online search was conducted in PUBMED for English language publications containing the key words “brain injured, cognitive handicap, acetylcholine, N-methyl-D aspartate receptors, neural cell adhesion molecule, brain-derived neurotrophic factor” from January 2000 to December 2007. There were 44 papers in total. Inclusion criteria: ① articles about changes in nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor following brain injury; ② articles in the same researching circle published in authoritative journals or recently published. Exclusion criteria: duplicated articles. LITERATURE EVALUATION: References were mainly derived from research on changes in these four factors following brain injury. The 20 included papers were clinical or basic experimental studies. DATA SYNTHESIS: After craniocerebral injury, changes in these four factors in brain were similar to those during recovery from cognitive disorder, to a certain degree. Some data have indicated that activation of nicotine cholinergic receptors, N-methyl-D aspartate receptors, neural cell adhesion molecule, and brain-derived neurotrophic factor could greatly improve cognitive disorder following brain injury. However, there are still a lot of questions remaining; for example, how do these factors change at different time points after brain injury, and what is the relationship between associated factors and cognitive disorder. CONCLUSION: It is necessary to comprehensively study some associated factors, to analyze their changes and their relationship with cognitive disorder following brain injury, and to investigate their effects at different time points after brain injury. Key Words: brain injured; cognitive handicap; acetylcholine; N-methyl-D aspartate receptors; neural cell adhesion molecule; brain-derived neurotrophic factor     

Ciliary neurotrophic factor enhances nicotinic synaptic transmission in sympathetic neurons

Nicotinic acetylcholine receptors mediate fast synaptic transmission in both central and peripheral nervous systems. These receptors play important roles in various physiological functions and are involved in different neurological diseases. A disruption in nicotinic receptor‐mediated synaptic transmission due to the loss of nAChRs was detected in the brains of patients with Parkinson's disease and Alzheimer's disease. Although ciliary neurotrophic factor (CNTF) has been reported to promote the cholinergic properties by increasing the production and storage of acetylcholine, it is still unclear whether CNTF can enhance nicotinic synaptic neurotransmission. In this study, we found that CNTF dramatically enhanced the frequency and amplitude of nicotinic excitatory post‐synaptic currents in rat superior cervical ganglion neurons maintained in a medium supplemented with nerve growth factor. Moreover, the number of neurons displaying nicotinic synaptic currents was also significantly increased by CNTF. These results suggest that CNTF could enhance nicotinic synaptic transmission via both presynaptic and postsynaptic mechanisms. The findings of this study reinforce the rationale for the usage of combinations of different neurotrophic factors for the therapy of neurodegenerative diseases. © 2009 Wiley‐Liss, Inc.     

Expression of brain-derived neurotrophic factor protein in activated microglia of human immunodeficiency virus type 1 encephalitis

The role of neurotrophic factors and their therapeutic potential have been investigated in various neurodegenerative disorders. In neurodegeneration associated with human immunodeficiency virus (HIV) infection, neuronal function and survival may be affected by abnormal neurotrophic regulation involving HIV-infected microglia and reactive astrocytes. To characterize the cellular localization of brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor, trkB, proteins in HIV-1 encephalitis, we examined post-mortem brains from patients with acquired immunodeficiency syndrome and brains from non-HIV-infected controls. Using double immunofluorescent confocal microscopy, we found that BDNF immunoreactivity was distributed in neocortical neuronal perikarya and neuritic processes, while in the striatum only neurites were BDNF-immunoreactive. Additionally, the striatum with HIV infection was characterized by BDNF immunoreactivity in infiltrating activated microglia/macrophages and multinucleated giant cells. Catalytic trkB receptor immunoreactivity was observed in neuronal perikarya in the neocortex and striatum, as well as in reactive astrocytes within HIV-infected regions. Our findings suggest that expression of BDNF by activated microglia in HIV-1 encephalitis may affect neuronal survival and astroglial response through corresponding trkB receptors.     

Parallel expression of neurotrophic factors and their receptors in chronic inflammatory demyelinating polyneuropathy

The mRNA levels of nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and interleukin-6 (IL-6) were examined in sural nerves of 22 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The mRNAs for NGF, GDNF, LIF, and IL-6 were upregulated, whereas CNTF mRNA was downregulated significantly in the nerves. The NGF, GDNF, and CNTF, but not LIF mRNA expressions were parallel to those of the cognate receptors, suggesting that these cognate soluble receptors effectively present these factors to maintain and regenerate the axons. Furthermore, IL-6 mRNA expression was significantly parallel to both binding and signal-transducing receptor expression, implying a role of the IL-6 signal for non-neuronal cells in CIDP. These findings indicate that multiple neurotrophic growth factors and cytokines are expressed cooperatively with their concomitant receptors in the nerve lesions of CIDP and play an important role particularly in nerve repair.     

Ciliary neurotrophic factor selectively protects human oligodendrocytes from tumor necrosis factor-mediated injury

Oligodendrocytes (OLs) and their myelin membranes are the apparent injury targets in the putative human autoimmune disease multiple sclerosis. The basis for this selective injury remains to be defined. OLs in vitro have been shown to be susceptible to both tumor necrosis factor (TNF) and non-TNF-dependent immune effector mechanisms. The former involves initial nuclear injury (apoptosis); the latter, when mediated by activated T cells, involves initial cell membrane injury (lysis). In the current study, we determined whether human adult CNS-derived OLs could be protected from the above immune effector mechanisms by selected neurotrophic factors (CNTF, BDNF, NGF, NT-3, and NT-4/5) or cytokines demonstrated to protect from human or experimental autoimmune demyelinating diseases (β-interferon [IFN], IL-10, and TGF-β). Nuclear injury was assessed in terms of DNA fragmentation using a DNA nick-end-labelling technique; cell membrane injury was assessed by lactate dehydrogenase or chromium 51 release. MTT and cell counting assays were used to assess cell viability and cell loss, respectively. Amongst the neurotrophic factors and cytokines tested, only CNTF significantly protected the OLs from TNF-mediated injury. CNTF also protected the OLs from serum deprivation-induced apoptosis. CNTF, however, did not protect the OLs from injury induced by activated CD4⁺ T cells. CNTF also did not protect human fetal cortical neurons from serum deprivation or TNF-induced DNA fragmentation, nor did it protect the U251 human glioma cell line from DNA fragmentation induced by a combination of TNF and reduced serum concentration in the culture media. Our results indicate that potential protective effects of neurotrophic factors or cytokines on neural cell populations can be selective both for cell type involved and mechanism of immune-mediated injury. CNTF is the protective factor selective for nuclear-directed injury of OLs. © 1996 Wiley-Liss, Inc.     

Secretion of nerve growth factor,brain-derived neurotrophic factor,and glial cell-line derived neurotrophic factor in co-culture of four cell types in cerebrospinal fluid-containing medium

The present study co-cultured human embryonic olfactory ensheathing cells, human Schwann cells, human amniotic epithelial cells and human vascular endothelial cells in complete culture medium- containing cerebrospinal fluid. Enzyme linked immunosorbent assay was used to detect nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor secretion in the supernatant of co-cultured cells. Results showed that the number of all cell types reached a peak at 7-10 days, and the expression of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor peaked at 9 days. Levels of secreted nerve growth factor were four-fold higher than brain-derived neurotrophic factor, which was three-fold higher than glial cell line-derived neurotrophic factor. Increasing concentrations of cerebrospinal fluid (10%, 20% and 30%) in the growth medium caused a decrease of neurotrophic factor secretion Results indicated co-culture of human embryonic olfactory ensheathing cells, human Schwann cells human amniotic epithelial cells and human vascular endothelial cells improved the expression of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor. The reduction of cerebrospinal fluid extravasation at the transplant site after spinal cord injury is beneficial for the survival and secretion of neurotrophic factors from transplanted cells.     

Apoptosis and neurotrophic factors

Neurotrophic factors are endogenous soluble proteins regulating development, differentiation, and survival of neurons. They are secreted from target cells or surrounding glial cells and act on the neurons via their receptors on the cell membranes. Several factors are reported to promote survival of motor neurons in vitro and to rescue developing motor neurons from naturally occurring cell death. Administration of the factors has also been shown to rescue motor neurons from degeneration after axotomy in adult as well as neonatal rodents. On the basis of these lines of evidence, neurotrophic factors have been considered to be potential candidates for drugs alleviating human motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Although some factors such as ciliary neurotrophic factor and brain-derived neurotrophic factor slowed down the disease progression in animal models of motor neuron disease, phase III clinical trials showed no therapeutic effects for ALS patients treated with these factors. There may be some reasons for this lack of success in humans. Several important issues remain to be resolved such as the drug delivery systems for neurotrophic factors and combination of neurotrophic factors with complementary effects.     

Brain-derived neurotrophic factor in Huntington disease

Trophic factors, administered systemically or delivered via genetically-modified cells grafted into target regions, have been proposed as putative therapeutic agents in human neurodegenerative disorders. In parallel to the study of the beneficial effects in experimental models of particular diseases, a crucial aspect of the study of trophic factors is the gathering of information about the actual trophic factor expression in human diseased states. Brain-derived neurotrophic factor (BDNF) promotes survival and growth of various nerve cell populations during normal development and following various insults in the developing and adult brain. In particular, BDNF prevents cell death of certain striatal populations in excitotoxic models of Huntington disease (HD) following intrastriatal injection of quinolinic acid to the adult rodent brain. The present study examines BDNF expression, by gel electrophoresis and Western blotting, and immunohistochemistry, in the brains of patients who had suffered from HD. Reduced BDNF expression, ranging from 53 to 82%, has been found in the caudate and putamen in HD when compared with age-matched controls. No modifications in BDNF expression levels have been seen in the parietal cortex, temporal cortex and hippocampus. Furthermore, immunohistochemistry has shown reduced BDNF immunoreactivity in caudate neurons, but not in cortical neurons in HD when compared with controls. These data demonstrate selective BDNF decay in regions that are vulnerable to HD, and suggest, in combination with results in experimental models, that a BDNF surplus may have beneficial effects in the treatment of HD.     

Brain-derived neurotrophic factor and substantia nigra dopaminergic neurons in Parkinson''s disease

BACKGROUND:Parkinson's disease (PD) is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor (BDNF) mRNA (20%) than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.