R N Auer1. 1. Department of Pathology, University of Calgary, Alberta, Canada.
Abstract
BACKGROUND AND PURPOSE: Although N-methyl-D-aspartate (NMDA) antagonism may be a useful therapeutic approach in stroke treatment, it has been found that these pharmacological agents cause neuronal necrosis in restricted cortical regions of the rodent brain. METHODS: To test the hypothesis that age and sex influence NMDA antagonist-induced neuronal necrosis, male and female rats were studied at 2 months (young), 12 months (middle-aged), and 24 months (old) of age. A dose of 5 mg/kg MK-801 was administered, followed by quantitation of neuronal necrosis at nine coronal levels in the cingulate and retrosplenial cortex at 1 week of survival. RESULTS: Mortality was dependent on age but not sex and was higher in the old rats (P<.01). The number of necrotic neurons per hemisphere was greater in female than in male rats at all ages (P<.0001). Female rats also showed increasing neuronal necrosis with age (P<.05). CONCLUSIONS: The results indicate a major sex difference in neuronal cytotoxicity caused by NMDA antagonists and a minor increase in susceptibility with increasing age in females. The findings may be relevant to development of drugs with NMDA antagonist properties for use in human stroke.
BACKGROUND AND PURPOSE: Although N-methyl-D-aspartate (NMDA) antagonism may be a useful therapeutic approach in stroke treatment, it has been found that these pharmacological agents cause neuronal necrosis in restricted cortical regions of the rodent brain. METHODS: To test the hypothesis that age and sex influence NMDA antagonist-induced neuronal necrosis, male and female rats were studied at 2 months (young), 12 months (middle-aged), and 24 months (old) of age. A dose of 5 mg/kg MK-801 was administered, followed by quantitation of neuronal necrosis at nine coronal levels in the cingulate and retrosplenial cortex at 1 week of survival. RESULTS: Mortality was dependent on age but not sex and was higher in the old rats (P<.01). The number of necrotic neurons per hemisphere was greater in female than in male rats at all ages (P<.0001). Female rats also showed increasing neuronal necrosis with age (P<.05). CONCLUSIONS: The results indicate a major sex difference in neuronal cytotoxicity caused by NMDA antagonists and a minor increase in susceptibility with increasing age in females. The findings may be relevant to development of drugs with NMDA antagonist properties for use in humanstroke.
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