title: Gene transfer of hepatocyte growth factor gene improves learning and memory in the chronic stage of cerebral infarction.
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.
authors.affiliation: Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Munehisa
authors.initials: M
authors.lastname: Shimamura
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Sato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Waguri
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.forename: Takuya
authors.initials: T
authors.lastname: Hayashi
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Iida
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000818:Animals; D002544:Cerebral Infarction / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002908:Chronic Disease; D002921:Cicatrix / Q000517:prevention & control; D018014:Gene Transfer Techniques; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000494:pharmacology; D006801:Humans; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D008833:Microcirculation / Q000187:drug effects; D016501:Neurites / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects; D013997:Time Factors
chemical_list: D017228:Hepatocyte Growth Factor