Gene Transfer of Hepatocyte Growth Factor Gene Improves Learning and Memory in the Chronic Stage of Cerebral Infarction
Gene Transfer of Hepatocyte Growth Factor Gene Improves Learning and Memory in the Chronic Stage of Cerebral Infarction
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DOI：
10.1161/01.hyp.0000208598.57687.3e
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发表时间：
2006-04
期刊：
影响因子：
8.3
通讯作者：
M. Shimamura;N. Sato;S. Waguri;Y. Uchiyama;Takuya Hayashi;H. Iida;Toshikazu Nakamura;T. Ogihara;Y. Kaneda;R. Morishita
中科院分区：
文献类型：
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作者：
M. Shimamura;N. Sato;S. Waguri;Y. Uchiyama;Takuya Hayashi;H. Iida;Toshikazu Nakamura;T. Ogihara;Y. Kaneda;R. Morishita
没有特定的治疗方法可以改善缺血性中风慢性阶段的功能恢复。为了提供新的治疗选择，我们通过使用日本包膜载体血凝病毒将HGF基因转移到大脑中，检查了肝细胞生长因子（HGF）过度表达在脑梗塞慢性阶段的效果。六十只大鼠接受永久性大脑中动脉闭塞（第一天）。根据第7天的感觉运动缺陷，将大鼠平均分为对照载体或HGF治疗的大鼠。第56天，转染HGF基因的大鼠在Morris水迷宫测试（对照向量50±4 s；HGF 33±5 s；P<0.05）和被动回避任务（对照向量132.4±37.5 s；HGF 214.8±26.5 s；P<0.05）中表现出学习记忆的显着恢复。尽管脑梗塞的总体积与结果无关，但梗塞周围区域的 Cdc42 和突触素的免疫组织化学分析表明，HGF 增强了神经突延伸并增加了突触。神经胶质纤维酸性蛋白的免疫组织化学显示，HGF 基因治疗也可以预防神经胶质疤痕的形成。此外，第 56 天时 HGF 组的动脉数量有所增加。这些数据表明，HGF 通过神经细胞生成、改善微循环和预防神经胶质增生，对脑梗塞后的功能恢复具有关键作用。我们的结果也为脑梗塞慢性期基因治疗的可行性提供了证据。
There is no specific treatment to improve the functional recovery in the chronic stage of ischemic stroke. To provide the new therapeutic options, we examined the effect of overexpression of hepatocyte growth factor (HGF) in the chronic stage of cerebral infarction by transferring the HGF gene into the brain using hemagglutinating virus of Japan envelope vector. Sixty rats were exposed to permanent middle cerebral artery occlusion (day 1). Based on the sensorimotor deficits at day 7, the rats were divided equally into control vector or HGF-treated rats. At day 56, rats transfected with the HGF gene showed a significant recovery of learning and memory in Morris water maze tests (control vector 50±4 s; HGF 33±5 s; P<0.05) and passive avoidance task (control vector 132.4±37.5 s; HGF 214.8±26.5 s; P<0.05). Although the total volume of cerebral infarction was not related to the outcome, immunohistochemical analysis for Cdc42 and synaptophysin in the peri-infarct region revealed that HGF enhanced the neurite extension and increased synapses. Immunohistochemistry for glial fibriary acidic protein revealed that the formation of glial scar was also prevented by HGF gene treatment. Additionally, the number of the arteries was increased in the HGF group at day 56. These data demonstrated that HGF has a pivotal role for the functional recovery after cerebral infarction through neuritogenesis, improved microcirculation, and the prevention of gliosis. Our results also provide evidence for the feasibility of gene therapy in the chronic stage of cerebral infarction.