HSV amplicon delivery of glial cell line-derived neurotrophic factor is neuroprotective against ischemic injury
HSV amplicon delivery of glial cell line-derived neurotrophic factor is neuroprotective against ischemic injury
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DOI：
10.1016/s0014-4886(03)00080-3
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发表时间：
2003-09-01
影响因子：
5.3
通讯作者：
Federoff, HJ
中科院分区：
文献类型：
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作者：
Harvey, BK;Chang, CF;Federoff, HJ
直接脑内给予神经胶质细胞源性神经营养因子（GDNF）可对缺血引起的脑损伤具有神经保护作用。利用病毒载体传递和表达治疗基因提供了在不断发展的梗塞局部区域内产生 GDNF 的机会。我们研究了编码 GDNF (HSVgdnf) 的基于单纯疱疹病毒 (HSV) 扩增子的载体是否可以保护神经元免受缺血性损伤。在原代皮质培养物中，与对照载体 HSVlac 相比，HSVgdnf 减少了氧化剂诱导的损伤。为了测试体内保护作用，在单侧大脑中动脉闭塞 60 分钟前 4 天或 3 天后，将 HSVgdnf 或 HSVlac 注射到大脑皮层。对照中风动物出现运动迟缓和运动不对称； HSVgdnf 预处理显着减少了这种运动缺陷。在缺血性损伤后接受HSVlac或HSVgdnf的动物没有表现出任何行为改善。中风后 1 个月进行的组织学分析显示，用 HSVgdnf 预处理的大鼠缺血性组织损失减少。同样，这些动物的神经胶质原纤维酸性蛋白和凋亡标记 caspase-3 的免疫染色较少。总而言之，我们的数据表明 HSVgdnf 预处理可提供针对脑缺血的保护，并支持利用 HSV 扩增子将营养因子治疗性递送至 CNS。 (C) 2003 年爱思唯尔科学（美国）。版权所有。
Direct intracerebral administration of glial cell line-derived neurotrophic factor (GDNF) is neuroprotective against ischemia-induced cerebral injury. Utilizing viral vectors to deliver and express therapeutic genes presents an opportunity to produce GDNF within localized regions of an evolving infarct. We investigated whether a herpes simplex virus (HSV) amplicon-based vector encoding GDNF (HSVgdnf) would protect neurons against ischemic injury. In primary cortical cultures HSVgdnf reduced oxidant-induced injury compared to the control vector HSVlac. To test protective effects in vivo, HSVgdnf or HSVlac was injected into the cerebral cortex 4 days prior to, or 3 days, after a 60-min unilateral occlusion of the middle cerebral artery. Control stroke animals developed bradykinesia and motor asymmetry; pretreatment with HSVgdnf significantly reduced such motor deficits. Animals receiving HSVlac or HSVgdnf after the ischemic insult did not exhibit any behavioral improvement. Histological analyses performed 1 month after stroke revealed a reduction in ischemic tissue loss in rats pretreated with HSVgdnf. Similarly, these animals exhibited less immunostaining for glial fibrillary acidic protein and the apoptotic marker caspase-3. Taken together, our data indicate that HSVgdnf pretreatment provides protection against cerebral ischemia and supports the utilization of the HSV amplicon for therapeutic delivery of trophic factors to the CNS. (C) 2003 Elsevier Science (USA). All rights reserved.