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(Stroke. 2009;40:e598.)
© 2009 American Heart Association, Inc.

Original Contributions

Electrical Stimulation of the Cerebral Cortex Exerts Antiapoptotic, Angiogenic, and Anti-Inflammatory Effects in Ischemic Stroke Rats Through Phosphoinositide 3-Kinase/Akt Signaling Pathway

Tanefumi Baba, MD; Masahiro Kameda, MD, PhD; Takao Yasuhara, MD, PhD; Takamasa Morimoto; Akihiko Kondo, MD; Tetsuro Shingo, MD, PhD; Naoki Tajiri; Feifei Wang; Yasuyuki Miyoshi, MD, PhD; Cesario V. Borlongan, PhD; Mitsunori Matsumae, MD, PhD Isao Date, MD, PhD

From the Department of Neurological Surgery (T.B., M.K., T.Y., T.M., A.K., T.S., N.T., F.W., Y.M., I.D.), Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; the Department of Neurosurgery (T.B., M.M.), Tokai University, Kanagawa, Japan; and the Department of Neurosurgery (C.V.B.), University of South Florida College of Medicine, Tampa, Fla.

Correspondence to Takao Yasuhara, MD, PhD, Assistant Professor, Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama, 700-8558, Japan. E-mail tyasu37{at}cc.okayama-u.ac.jp

Background and Purpose— Neuroprotective effects of electric stimulation have been recently shown in ischemic stroke, but the underlying mechanisms remain poorly understood.

Methods— Adult Wistar rats weighing 200 to 250 g received occlusion of the right middle cerebral artery for 90 minutes. At 1 hour after reperfusion, electrodes were implanted to rats on the right frontal epidural space. Electric stimulation, at preset current (0 to 200 µA) and frequency (0 to 50 Hz), was performed for 1 week. Stroke animals were subjected to behavioral tests at 3 days and 1 week postmiddle cerebral artery and then immediately euthanized for protein and immunohistochemical assays. After demonstration of behavioral and histological benefits, subsequent experiments pursued the mechanistic hypothesis that electric stimulation exerted antiapoptotic effects through the phosphoinositide 3-kinase-dependent pathway; thus, cortical stimulation was performed in the presence or absence of specific inhibitors of phosphoinositide 3-kinase (LY294002) in stroke rats.

Results— Cortical stimulation abrogated the ischemia-associated increase in apoptotic cells in the injured cortex by activating antiapoptotic cascades, which was reversed by the phosphoinositide 3-kinase inhibitor LY294002 as reflected behaviorally and immunohistochemically. Furthermore, brain levels of neurotrophic factors (glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, vascular endothelial growth factor) were upregulated, which coincided with enhanced angiogenesis and suppressed proliferation of inflammatory cells in the ischemic cortex.

Conclusions— These results suggest that electric stimulation prevents apoptosis through the phosphoinositide 3-kinase pathway. Consequently, the ischemic brain might have been rendered as a nurturing microenvironment characterized by robust angiogenesis and diminished microglial/astrocytic proliferation, resulting in the reduction of infarct volumes and behavioral recovery. Electric stimulation is a novel and potent therapeutic tool for cerebral ischemia.

Key Words: angiogenesis • apoptosis • neurotrophic factor • regenerative therapy • stroke