Published Online
on January 16, 2003

A more recent version of this article appeared on February 1, 2003

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Submitted on August 26, 2002
Accepted on August 26, 2002

Intravenous Administration of Bone Morphogenetic Protein-7 After Ischemia Improves Motor Function in Stroke Rats

Chen-Fu Chang MD; Shinn-Zong Lin MD, PhD; Yung-Hsiao Chiang MD, PhD; Marisela Morales PhD; Jenny Chou BS; Pamela Lein PhD; Hui-Ling Chen MS; Barry J. Hoffer MD, PhD; and Yun Wang MD, PhD^*

From the National Institute on Drug Abuse, National Institutes of Health, Baltimore, Md (C-F.C., M.M., J.C., H-L.C., B.J.H., Y.W.); Tri-Service General Hospital (C-F.C., S-Z.L., Y-H.C.) and Graduate Institute of Life Sciences (H-L.C.), National Defense Medical Center, Taiwan, Republic of China; and Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Md (P.L.).

^* To whom correspondence should be addressed. E-mail: ywang{at}intra.nida.nih.gov.

Background and Purpose--We and others have previously reported that bone morphogenetic protein-7 (BMP-7), given before middle cerebral artery occlusion (MCAO), reduces ischemic injury in brain. Recent studies have indicated that receptors for BMP are upregulated after brain ischemia. It is possible that this upregulation may facilitate endogenous neurorepair in the ischemic brain. The purpose of this study was to determine the neuroregenerative effects of BMP-7 given parenterally after ischemia/reperfusion injury.

Methods--Adult Sprague-Dawley rats were anesthetized with chloral hydrate. The middle cerebral artery was transiently occluded by a filament inserted through the right internal carotid artery. The filament was removed after 60-minute ischemia to allow reperfusion. Some animals were killed 24 hours after MCAO to examine BMP-7 mRNA expression. Other animals received a single dose of intravenous BMP-7 or vehicle at 24 hours after MCAO and were used for subsequent behavioral studies and BMP-7 immunostaining.

Results--BMP-7 mRNA was upregulated 24 hours after MCAO in untreated animals. BMP-7 immunoreactivity was dose-dependently increased on the ischemic side of the hippocampus/dentate on day 6 after MCAO in animals receiving intravenous injection of BMP-7. Animals receiving BMP-7 also showed a decrease in body asymmetry from day 7 to day 14 and an increase in locomotor activity on day 14 after MCAO.

Conclusions--Our data indicate that BMP-7, given parenterally after stroke, can pass through the blood-brain barrier on the ischemic side and induce behavioral recovery in stroke animals at longer testing times.

Key words: bone morphogenetic proteins • growth factors • nerve regeneration • stroke

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