蛛网膜下隙注射胶质细胞源性神经营养因子抑制脊神经结扎大鼠脊髓背角胶质原纤维酸性蛋白表达

目的观察蛛网膜下隙注射胶质细胞源性神经营养因子(GDNF)对脊神经结扎(SNL)大鼠脊髓背角胶质原纤维酸性蛋白(GFAP)的影响。方法采用结扎SD大鼠第5~第6腰脊神经(L5~L6)制备SNL模型。术后隔日一次性蛛网膜下隙注射10μl GDNF2 g·L-1组。术后第3,7和14天采用免疫组织化学和Western免疫印迹法测定脊髓背角处GFAP蛋白表达。结果免疫组化结果显示,SNL组在术后第3天、第7天和第14天脊髓GFAP阳性细胞数目明显增加,可持续至第14天,而正常对照组与假手术组的星形胶质细胞未发生此种改变。GDNF组的阳性细胞显著减少。Western印迹结果显示,正常对照组和假手术组脊髓背角均出现GFAP免疫阳性条带,灰度值较低;SNL在术后第3天即可诱导脊髓背角GFAP蛋白的表达,随着时间的延长,GFAP蛋白的灰度值逐渐升高,术后第3,7,14天分别为2.55±0.33,2.88±0.79和3.12±0.75(P<0.01)。与SNL模型组比较,GDNF可显著降低GFAP的表达水平,术后第3,7,14天分别为1.61±0.38,1.65±0.64和1.57±0.41(P<0.01)。结论蛛网膜下隙注射GDNF减轻大鼠神经病理性疼痛机制可能与其抑制脊髓背角GFAP蛋白表达有关。     

简便快速获取鼠胶质细胞源性神经营养因子基因的RT-PCR方法

目的：建立一种简便快速地获取鼠胶质细胞源性神经营养因子（GDNF）基因的RT-PCR方法。方法：Gene Bank中调出鼠的GDNF基因全序列设计引物，提取鼠基因组总RNA做模板进行RT-PCR，经酶切和凝胶电泳鉴定产物。结果：扩增出650bp鼠的GDNF基因，经EcoR Ⅰ酶切可见预期的650bp片段，证实获得正确的产物。结论：成功建立一种简便快速地从鼠基因组总RNA获取鼠GDNF基因的RT-PCR。     

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。     

临床孤立综合征患者血清和脑脊液中脑源性与胶质细胞源性神经营养因子水平及其神经保护作用研究

目的 探讨多发性硬化（MS）的早期表现--临床孤立综合征（CIS）患者血清及脑脊液中脑源性神经营养因子（BDNF）、胶质细胞源性神经营养因子（GDNF）水平及其神经保护作用.方法 对27例CIS患者及21例对照者进行研究,CIS患者发作期进行扩展残疾状态量表（EDSS）评分、寡克隆带测定及MRI检查,液相芯片分析技术检测血清及脑脊液BDNF、GDNF浓度.结果 CIS患者发作期血清及脑脊液BDNF[分别为（5.981±0.995）和（0.178±0.008）μg/L]、GDNF浓度[分别为（0.039±0.007）和（0.082±0.011）μg/L]与对照组[血清：（4.374±0.501）、（0.042±0.007）μg/L;脑脊液：（0.152±0.011）、（0.065±0.013）μg/L]比较差异均无统计学意义（均P＞0.05）;脑脊液BDNF与GDNF浓度呈正相关（r=0.777,P=0.000）,血清BDNF与GDNF浓度无相关性（r=-0.375,P=0.126）.血清及脑脊液BDNF、GDNF浓度与EDSS评分、血脑屏障指数、Delpech指数、Tourtellotte合成率及脑萎缩无明显相关性（P＞0.05）.结论 CIS患者体内BDNF与GDNF水平相关,二者可能具有协同的神经保护作用.BDNF及GDNF与CIS患者血脑屏障破坏及中枢神经系统内IgG合成无关,与神经功能残疾及脑萎缩的关系仍需研究.     

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。     

胶质细胞源性神经营养因子的表达、功能和在药物依赖中的作用

1993年,Lin等[1]从大鼠胶质细胞株B49中提纯到一种可促进胚胎中脑多巴胺能神经元存活的神经营养因子,并命名为胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF).GDNF和后来发现的neurturin(NRTN)、persephin(PSPN)、artemin(ARTN)在结构和功能上有很大的相似性,共同构成一个家族,称为GDNF家族.     

胶质细胞源性神经营养因子在人脑胶质瘤的表达及意义

目的从基因表达的水平探讨胶质细胞源性神经营养因子(GDNF)与人脑胶质细胞瘤发生发展的关系。方法采用原位杂交的方法用特异性探针结合59例胶质瘤标本和20例正常脑组织中的GDNFmRNA,观察GDNFmRNA的表达情况。结果GDNFmRNA在正常脑组织和胶质瘤标本中均有表达,但胶质瘤中的表达明显高于正常脑组织,GDNFmRNA在不同级别胶质瘤中的表达也存在显著性差异,恶性程度越高,GDNFmRNA表达强度越强。结论GDNF可能作为一种重要的因子参与胶质瘤的恶性增殖过程,影响胶质瘤的发生、发展及其他生物学特性。     

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抑郁症发生和治疗中的研究进展

目前临床常用的抗抑郁药主要通过增加脑内突触间隙单胺类递质的浓度、增强单胺类神经的功能而起效,但这一机制不能很好地解释抗抑郁药存在的起效时间长等现象.近年提出,抗抑郁药可能还通过增加海马区域脑源性神经营养因子(BDNF)基因表达起效.抗抑郁药能增加受试动物海马区BDNF基因表达,抑郁患者接受抗抑郁药治疗,其血清BDNF水平上升;BDNF基因的单核苷酸多态性也与抑郁症的发生有关;抗抑郁药可能还通过激活丝裂原活化蛋白激酶(MAPK)信号通路,磷酸化cAMP反应序列结合(cREB)蛋白,最终使BDNF基因表达上调.这一机制的提出为抑郁症生物学病因的阐明提供了必要信息,同时也有助于抗抑郁新药的开发,为研制安全、有效的新药提供新的思路.     

脑源性神经营养因子与中枢神经损伤

<正>脑源性神经营养因子(Brain-derived neurotrophie factor,BDNF)由Barde等于1982年首次从猪脑提取液中获得,是相对分子质量为1213kD的碱性蛋白,为神经营养素家族成员之一,广泛分布于中枢神经系统(Central nervous system,CNS)。目前国内外已经对BDNF的生物学作用进行了广泛的研究,证实它不仅在中枢神经系统发育过程中对神经元的生存、分化、生长和维持神经元正常的生理功能起     

脑源性神经营养因子与脑卒中后疼痛和抑郁的关系

脑源性神经营养因子（BDNF）是成人脑内含量最丰富的神经营养因子,具有显著的脑损伤修复能力。最近的多项研究表明,BNDF在脑卒中后的多种并发症的发生发展中起到了重要的作用,有希望成为新的卒中治疗方法的晚期靶点,但它的作用机制尚不明确。本文就BDNF的生物学特性、在卒中后并发症的作用机制以及最新的研究进展进行综述,从而为...     

Decreased expression of glial cell line-derived neurotrophic factor signaling in rat models of neuropathic pain

1. In an attempt to clarify whether glial cell line-derived neurotrophic factor (GDNF), a survival factor for subpopulations of primary afferent neurons, is involved in the states of neuropathic pain, we observed changes in the expressions of GDNF and its signal-transducing receptor Ret after nerve injury in two rat models of neuropathic pain. 2. In the rats treated with sciatic nerve ligation (chronic constrictive injury (CCI) model) or spinal nerve ligation at L5 (SNL model), the thresholds of paw withdrawal in response to mechanical or heat stimuli began to decrease on the injured side within the first week after the operation and the decreases in the thresholds persisted for more than 2 weeks. 3. In CCI-treated rats, the GDNF contents in L4 and L5 dorsal root ganglia (DRGs) on the injured side were markedly decreased at day 7 after the operation and stayed at low levels at day 14. In SNL-treated rats, comparable reductions of GDNF levels in L4 and L5 DRGs on the injured side were observed at 14 postoperative days. 4. Significant decreases of the percentages of DRG neurons expressing Ret were also observed at L4 DRGs in CCI-treated rats at 7 and 14 postoperative days and in SNL-treated rats at 14 days. 5. In CCI- or SNL-treated rats, continuous intrathecal administration of GDNF (12 microg day-1) using an osmotic pump suppressed the increased sensitivities to nociceptive stimuli to control levels. 6. The present results suggested that the dysfunction of GDNF signaling in the nociceptive afferent system may contribute to the development and/or maintenance of neuropathic pain states.     

Glial cell line-derived neurotrophic factormediated enhancement of noradrenergic descending inhibition in the locus coeruleus exerts prolonged analgesia in neuropathic pain

Background and Purpose

The locus coeruleus (LC) is the principal nucleus containing the noradrenergic neurons and is a major endogenous source of pain modulation in the brain. Glial cell line-derived neurotrophic factor (GDNF), a well-established neurotrophic factor for noradrenergic neurons, is a major pain modulator in the spinal cord and primary sensory neurons. However, it is unknown whether GDNF is involved in pain modulation in the LC.

Experimental Approach

Rats with chronic constriction injury (CCI) of the left sciatic nerve were used as a model of neuropathic pain. GDNF was injected into the left LC of rats with CCI for 3 consecutive days and changes in mechanical allodynia and thermal hyperalgesia were assessed. The α₂-adrenoceptor antagonist yohimbine was injected intrathecally to assess the involvement of descending inhibition in GDNF-mediated analgesia. The MEK inhibitor U0126 was used to investigate whether the ERK signalling pathway plays a role in the analgesic effects of GDNF.

Key Results

Both mechanical allodynia and thermal hyperalgesia were attenuated 24 h after the first GDNF injection. GDNF increased the noradrenaline content in the dorsal spinal cord. The analgesic effects continued for at least 3 days after the last injection. Yohimbine abolished these effects of GDNF. The analgesic effects of GDNF were partly, but significantly, inhibited by prior injection of U0126 into the LC.

Conclusions and Implications

GDNF injection into the LC exerts prolonged analgesic effects on neuropathic pain in rats by enhancing descending noradrenergic inhibition.     

Adenoviral Vector-Mediated Delivery Of Glial Cell Line-Derived Neurotrophic Factor Provides Neuroprotection In The Aged Parkinsonian Rat

1. The long-term delivery of neurotrophic factors to specific regions of the central nervous system via gene therapy offers a new strategy for the treatment of neurodegenerative disorders. 2. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) is a potent dopaminergic (DA) trophic factor that ameliorates the behavioural and histological consequences of lesioning DA neurons in rodent and primate models of Parkinson's disease. 3. Glial cell line-derived neurotrophic factor gene therapy may have a potential use in the clinical treatment of Parkinson's disease. 4. We examined whether injection of an adenoviral vector encoding human GDNF preproprotein (Ad GDNF) could protect the rat nigrostriatal DA system from progressive neuronal degeneration. Because Parkinson's disease occurs primarily in the elderly population, we studied the effect of GDNF gene delivery in an aged rat model of Parkinson's disease. 5. In the aged (20 month) Fischer 344 rat, Ad GDNF was injected either near DA cell bodies in the substantia nigra (SN) or at the DA terminals in the striatum. One week following gene delivery, the neurotoxin 6-hydroxydopamine (6-OHDA) was injected unilaterally into the striatum to cause progressive degeneration of the DA neurons. 6. Injection of GDNF vector into either the striatum or the SN provided significant cell protection against 6-OHDA. However, only striatal injection of Ad GDNF protected against the development of behavioural and neurochemical changes that occur in the DA-depleted brain. 7. The results of this study are reviewed here and the behavioural and cellular effects of GDNF gene delivery into striatal versus mesencephalic sites are discussed.     

Emerging drugs in neuropathic pain

Neuropathic pain is a personally devastating and costly condition affecting 3 – 8% of the population. Existing treatments have limited effectiveness and produce relatively frequent adverse effects. Preclinical research has identified many promising pharmacological targets; however, reliable predictors of success in humans remain elusive. At least 50 new molecular entities have reached clinical development including: glutamate antagonists, cytokine inhibitors, vanilloid-receptor agonists, catecholamine modulators, ion-channel blockers, anticonvulsants, opioids, cannabinoids, COX inhibitors, acteylcholine modulators, adenosine receptor agonists and several miscellaneous drugs. Eight drugs are in Phase III trials at present. Strategies that may show promise over existing treatments include topical therapies, analgesic combinations and, in future, gene-related therapies. Recent years have heralded an explosion of pharmaceutical development in neuropathic pain, reflecting advanced knowledge of neurobiology and a heightened perception of the commercial value of neuropathic pain therapeutics. In the interest of improving patient care, the authors recommend implementing comparative studies throughout the development process in order to demonstrate the increased value of novel agents.     

神经病理性疼痛动物模型

神经病理性疼痛动物模型的不断发展极大地促进了对神经病理性疼痛机制的研究。但是,目前的动物模型仍有很多缺陷,需要不断地完善,对疼痛的观察方法也需要改进。