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(Circulation. 2005;111:913-919.)
© 2005 American Heart Association, Inc.

Stroke

Postischemic Gene Transfer of Interleukin-10 Protects Against Both Focal and Global Brain Ischemia

Hiroaki Ooboshi, MD, PhD; Setsuro Ibayashi, MD, PhD; Takashi Shichita, MD; Yasuhiro Kumai, MD; Junichi Takada, MD; Tetsuro Ago, MD, PhD; Shuji Arakawa, MD, PhD; Hiroshi Sugimori, MD, PhD; Masahiro Kamouchi, MD, PhD; Takanari Kitazono, MD, PhD; Mitsuo Iida, MD, PhD

From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Correspondence to Hiroaki Ooboshi, MD, PhD, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. E-mail ooboshi{at}intmed2.med.kyushu-u.ac.jp

Received August 28, 2004; revision received October 3, 2004; accepted October 26, 2004.

Background— Gene therapy may be a promising approach for treatment of brain ischemia, although the efficiency of postischemic gene therapy is not established. Our goal in this study was to examine the effects of gene transfer of interleukin-10 (IL-10), an antiinflammatory cytokine, after induction of brain ischemia.

Methods and Results— Brain ischemia was produced by either photochemical occlusion of distal middle cerebral artery for focal ischemia or bilateral carotid occlusion for global ischemia in spontaneously hypertensive rats. Adenoviral vectors encoding human IL-10 (AdIL10) or ß-galactosidase (control) were injected into the lateral ventricle 90 or 60 minutes after focal or global ischemia. Five days after ischemia, IL-10, IL-1ß, or tissue necrosis factor- in the cerebrospinal fluid, infarct volume, infiltrations of leukocytes/macrophages in the infarct area, or hippocampal neuronal damages were determined. The transduced IL-10 was released to the cerebrospinal fluid from the ventricular wall and increased to 7623±2965 pg/mL 5 days after AdIL10 transfection. Cerebral blood flow during ischemia was not different between treatments in either focal or global ischemia. Brain infarction of the AdIL10 group was significantly smaller and infiltrations of leukocytes and macrophages were fewer in the IL-10 treatment than control. Hippocampal neurons after global ischemia were more preserved, and the terminal deoxynucleotidyl transferase–mediated dUTP-biotin in situ nick end labeling–positive cells were diminished by the IL-10 gene transfer with attenuated IL-1ß and augmented tissue necrosis factor-.

Conclusions— Postischemic gene transfer of IL-10 into the lateral ventricle attenuated brain infarction and hippocampal damages, suggesting the promise for treatment of brain ischemia.

Key Words: apoptosis • cerebral ischemia • gene therapy • inflammation • interleukins

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