Protection of rat spinal cord from ischemia with dextrorphan and cycloheximide: Effects on necrosis and apoptosis

H. Kato, G. K. Kanellopoulos, S. Matsuo, Y. J. Wu, M. F. Jacquin, C. Y. Hsu, D. W. Choi, N. T. Kouchoukos

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Objective: We examined the characteristics of neuronal cell death after transient spinal cord ischemia in the rat and the effects of an N-methyl-D- aspartate antagonist, dextrorphan, and a protein synthesis inhibitor, cycloheximide. Methods: Spinal cord ischemia was induced for 15 minutes in Long-Evans rats with use of a 2F Fogarty catheter, which was passed through the left carotid artery and occluded the descending aorta, combined with a blood volume reduction distal to the occlusion. The rats were killed after 1, 2, and 7 days. Other groups of rats were pretreated with dextrorphan (30 mg/kg, intraperitoneally, n = 7), cycloheximide (30 mg, intrathecally, n = 7), or vehicle (saline solution, n = 12) and killed after 2 days. Results: This model reliably produced paraplegia and histopathologically distinct morphologic changes consistent with necrosis or apoptosis by light and electron microscopic criteria in different neuronal populations in the lumbar cord. Scattered necrotic neurons were seen in the intermediate gray matter (laminae 3 to 7) after 1, 2, and 7 days, whereas apoptotic neurons were seen in the dorsal horn laminae 1 to 3 after 1 and 2 days. Deoxyribonucleic acid extracted from lumbar cord showed internucleosomal fragmentation (laddering) on gel electrophoresis indicative of apoptosis. The severity of paraplegia in the rats treated with dextrorphan and cycloheximide was attenuated 1 day and 2 days after ischemia. The numbers of both necrotic and apoptotic neurons were markedly reduced in both dextrorphan- and cycloheximide-treated rats. Conclusions: The results suggest that both N-methyl-D-aspartate receptor- mediated excitotoxicity and apoptosis contribute to spinal cord neuronal death after ischemia and that pharmacologic treatments directed at blocking both of these processes may have therapeutic utility in reducing spinal cord ischemic injury.

Original languageEnglish
Pages (from-to)609-618
Number of pages10
JournalJournal of Thoracic and Cardiovascular Surgery
Volume114
Issue number4
DOIs
StatePublished - Jan 1 1997
Externally publishedYes

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