EFFECT OF AGE AND SEX ON N-METHYL-D-ASPARTATE ANTAGONIST-INDUCED NEURONAL NECROSIS IN RATS

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 re stricted cortical regions of the rodent brain. Methods To test the hyp othesis that age and sex influence NMDA antagonist-induced neuronal ne crosis, male and female rats were studied at 2 months (young), 12 mont hs (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 ni ne coronal levels in the cingulate and retrosplenial cortex at 1 week of survival. Results Mortality was dependent on age but not sex and wa s higher in the old rats (P<.01) The number of necrotic neurons per he misphere was greater in female than in male rats at all ages (P<.0001) . Female rats also showed increasing neuronal necrosis with age (P<0.5 ). Conclusions The results indicate a major sex difference in neuronal cytotoxicity caused by NMDA antagonists and a minor increase in susce ptibility with increasing age in females. The findings may be relevant to development of drugs with NMDA antagonist properties for use in hu man stroke.