Published Online
on February 27, 2006

A more recent version of this article appeared on April 1, 2006

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Submitted on October 23, 2005
Revised on November 14, 2005

Gene Transfer of Hepatocyte Growth Factor Gene Improves Learning and Memory in the Chronic Stage of Cerebral Infarction

Munehisa Shimamura; Naoyuki Sato; Satoshi Waguri; Yasuo Uchiyama; Takuya Hayashi; Hidehiro Iida; Toshikazu Nakamura; Toshio Ogihara; Yasufumi Kaneda; and Ryuichi Morishita^*

From the Division of Clinical Gene Therapy (M.S., N.S., R.M.), Department of Cell Biology and Neuroscience (S.W., Y.U.), Division of Molecular Regenerative Medicine (T.N.), Department of Geriatric Medicine (T.O.), and Division of Gene Therapy Science (Y.K.), Graduate School of Medicine, Osaka University, Osaka; Department of Advanced Clinical Science and Therapeutics (M.S.), Graduate School of Medicine, Tokyo University, Tokyo; and Department of Investigative Radiology (T.H., H.I.), National Cardiovascular Center, Research Institute, Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: morishit{at}cgt.med.osaka-u.ac.jp.

Abstract--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.

Key words: cerebral ischemia • genes • microcirculation • rats

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