Adenoviral vector-mediated delivery of glial cell line-derived neurotrophic factor provides neuroprotection in the aged parkinsonian rat
Adenoviral vector-mediated delivery of glial cell line-derived neurotrophic factor provides neuroprotection in the aged parkinsonian rat
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DOI：
10.1046/j.1440-1681.2001.03544.x
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发表时间：
2001-11-01
影响因子：
2.9
通讯作者：
Connor, B
中科院分区：
文献类型：
--
作者：
Connor, B
1. 通过基因治疗将神经营养因子长期输送到中枢神经系统的特定区域，为神经退行性疾病的治疗提供了一种新的策略。神经营养因子胶质细胞系衍生的神经营养因子（GDNF）是一种有效的多巴胺能（DA）营养因子，可改善帕金森病啮齿动物和灵长类动物DA神经元损伤的行为和组织学后果。神经胶质细胞系来源的神经营养因子基因疗法可能在帕金森病的临床治疗中有潜在的应用。我们检测了注射一种编码人GDNF前蛋白（Ad GDNF）的腺病毒载体是否能保护大鼠黑纹状体DA系统免受进行性神经元变性的影响。由于帕金森病主要发生在老年人群中，我们研究了GDNF基因在老年帕金森病大鼠模型中的作用。老龄（20月龄）Fischer 344大鼠，在黑质DA细胞体附近或纹状体DA末梢注射Ad GDNF。基因传递一周后，将神经毒素6-羟多巴胺（6-OHDA）单侧注射到纹状体，导致DA神经元进行性变性。将GDNF载体注射到纹状体或SN中，对6-OHDA具有显著的细胞保护作用。然而，只有纹状体注射Ad - GDNF才能防止在da缺乏的大脑中发生的行为和神经化学变化。本文综述了本研究的结果，并讨论了GDNF基因传递到纹状体和中脑部位的行为和细胞效应。
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.