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(Circulation. 2004;109:424-431.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Novel Therapeutic Strategy to Treat Brain Ischemia

Overexpression of Hepatocyte Growth Factor Gene Reduced Ischemic Injury Without Cerebral Edema in Rat Model

Munehisa Shimamura, MD; Naoyuki Sato, MD, PhD; Kazuo Oshima, MD; Motokuni Aoki, MD, PhD; Hitomi Kurinami, MD, PhD; Satoshi Waguri, MD, PhD; Yasuo Uchiyama, MD, PhD; Toshio Ogihara, MD, PhD; Yasufumi Kaneda, MD, PhD; Ryuichi Morishita, MD, PhD

From the Division of Clinical Gene Therapy (M.S., N.S., H.K., R.M.), Division of Gene Therapy Science (M.S., K.O., Y.K.), Department of Geriatric Medicine (M.A., T.O.), and Department of Cell Biology and Neuroscience (A1) (S.W., Y.U.), Graduate School of Medicine, Osaka University, Suita, Japan.

Correspondence to Ryuichi Morishita, MD, PhD, Professor, Division of Clinical Gene Therapy, Osaka University, Graduate School of Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan. E-mail morishit{at}cgt.med.osaka-u.ac.jp

Received July 23, 2003; revision received September 19, 2003; accepted September 22, 2003.

Background— Although cerebral occlusive disease leads to cerebral ischemic events, an effective treatment has not yet been established. An ideal therapeutic approach to treat ischemia might have both aspects of enhancement of collateral formation and prevention of neuronal death. Hepatocyte growth factor (HGF) is a potent angiogenic factor that also acts as a neurotrophic factor. Thus, in this study, we examined the therapeutic effects of HGF on brain injury in a rat permanent middle cerebral artery occlusion model.

Methods and Results— Gene transfer into the brain was performed by injection of human HGF gene with hemagglutinating virus of Japan–envelope vector into the cerebrospinal fluid via the cisterna magna. Overexpression of the HGF gene resulted in a significant decrease in the infarcted brain area as assessed by triphenyltetrazolium chloride staining, whereas rats transfected with control vector exhibited a wide area of brain death after 24 hours of ischemia. Consistently, the decrease in neurological deficit was significantly attenuated in rats transfected with the HGF gene at 24 hours after the ischemic event. Stimulation of angiogenesis was also detected in rats transfected with the HGF gene compared with controls. Of importance, no cerebral edema or destruction of the blood-brain barrier was observed in rats transfected with the HGF gene.

Conclusions— Overall, the present study demonstrated that overexpression of the HGF gene attenuated brain ischemic injury in a rat model, without cerebral edema, through angiogenic and neuroprotective actions. In particular, the reduction of brain injury by HGF may provide a new therapeutic option to treat cerebrovascular disease.

Key Words: gene therapy • nervous system • stroke • cerebral ischemia • angiogenesis

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