Published Online
on February 3, 2005

A more recent version of this article appeared on March 1, 2005

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Submitted on November 8, 2004
Accepted on November 25, 2004

Inosine Reduces Ischemic Brain Injury in Rats

Hui Shen MD; Guann-Juh Chen MD; Brandon K. Harvey PhD; Paula C. Bickford PhD; and Yun Wang MD, PhD^*

From the National Institute on Drug Abuse (H.S., G.-J.C., B.K.H., P.C.B., Y.W.), National Institutes of Health, Baltimore, Md; and the Center for Aging and Brain Repair (B.K.H., P.C.B.), University of South Florida, Tampa, Fla.

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

Background and Purpose--Purinergic nucleoside inosine elicits protection and regeneration during various injuries. The purpose of this study was to examine the protective effects of inosine against cerebral ischemia.

Methods--Adult Sprague-Dawley rats were anesthetized. Inosine, hypoxathine, or vehicle was administered intracerebroventricularly before transient right middle cerebral artery occlusion (MCAo). Animals were placed in behavioral chambers 2 days to 2 weeks after MCAo and then euthanized for tri-phenyl-tetrazolium chloride staining. Glutamate release was measured by microdialysis/high-performance liquid chromatography, and single-unit action potentials were recorded from neurons in the parietal cortex.

Results--Stroke animals receiving inosine pretreatment demonstrated a higher level of locomotor activity and less cerebral infarction. Intracerebroventricular administration of the same dose of hypoxanthine did not confer protection. Coadministration of selective A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1, 4-(±)-dihydropyridine-3,5-dicarboxylate (MRS1191) significantly reduced inosine-mediated protection. Inosine did not alter basal glutamate release, nor did it reduce ischemia-evoked glutamate overflow from cerebral cortex. However, inosine antagonized glutamate-induced electrophysiological excitation in cerebral cortical neurons.

Conclusions--Inosine inhibits glutamate postsynaptic responses and reduces cerebral infarction. Its protective effect against ischemia/reperfusion-related insults may involve activation of adenosine A3 receptors.

Key words: inosine, adenosine • neuroprotection • stroke

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