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NEUROPHARMACOLOGY

Cell Death Mechanism and Protective Effect of Erythropoietin after Focal Ischemia in the Whisker-Barrel Cortex of Neonatal Rats

Departments of Pathology and Laboratory Medicine (L.W., Y.L., C.L.K., S.P.Y.) and Pharmaceutical Sciences (S.P.Y.), Medical University of South Carolina, Charleston, South Carolina; Department of Neurology, Molecular Biology and Pharmacology, Hope Center for Neurological Disorders, Washington University, St. Louis, Missouri (L.W., B.H.H., D.M.H.); and Department of Manufacturing Pharmacy, Seoul National University, Seoul, South Korea (B.H.H.)

Cell death induced by the combined insult of hypoxia-ischemia in neonatal rodents has been extensively investigated. Ischemia-only-induced cell death, however, has been much less characterized. Based on the notion that 1) ischemic stroke is a relatively common disorder in human neonates, and 2) developing cells are more susceptible to apoptosis, the present study examined whether typical apoptosis was induced by cerebral ischemia in a new neonatal rat model. Erythropoietin (EPO; Epoetin) was tested for its protective effect against ischemia-induced cell death. Postnatal day 7 rats were subjected to permanent occlusion of the middle cerebral artery branch supplying the right whisker-barrel cortex. Terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeled-positive cells in the ischemic region were detectable 4 h after ischemia and reached a peak level 16 h later. The cell death was preceded by caspase activation and cytochrome c release. Cell body shrinkage was evident among damaged cells. Agarose gel electrophoresis showed DNA damage with a smear pattern as well as DNA laddering. Electron microscopy demonstrated apoptotic features such as cell shrinkage, chromatin condensation, and fragmentation; meanwhile, necrotic alterations coexisted in the cytoplasm. EPO treatment increased signal transducers and activators of transcription-5 and Bcl-2 levels, markedly attenuated apoptotic cell death, and reduced ischemic infarct in the cortex. It is suggested that focal ischemia in the developing brain causes cell death with prominent apoptotic features coexisting with some characteristics of necrosis. This is consistent with the concept of hybrid death described previously in cultures and adult or developing brain. EPO may be explored as a potential therapy for neonatal ischemic stroke.

Address correspondence to: Dr. Shan Ping Yu, Department of Pharmaceutical Sciences, 280 Calhoun St., Medical University of South Carolina, Charleston, SC 29425. E-mail: yusp{at}musc.edu

This article has been cited by other articles:

				C. L. Keogh, S. P. Yu, and L. Wei The Effect of Recombinant Human Erythropoietin on Neurovasculature Repair after Focal Ischemic Stroke in Neonatal Rats J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 521 - 528. [Abstract] [Full Text] [PDF]