NEURONAL LOSS AND CYTOSKELETAL DISRUPTION FOLLOWING INTRAHIPPOCAMPAL ADMINISTRATION OF THE METABOLIC INHIBITOR MALONATE - LACK OF PROTECTION BY MK-801

Impaired energy metabolism may contribute to the pathogenesis of late- onset neurodegenerative disorders such as Alzheimer's disease by incre asing neuronal vulnerability to excitotoxic damage through the NMDA re ceptor. The effects of metabolic impairment on the striatum have been extensively examined, but relatively little is known regarding the vul nerability of the hippocampus. To examine the effect of metabolic impa irment on the hippocampal formation, malonate (0.25-2.5 mu mol), a rev ersible inhibitor of succinate dehydrogenase, was administered by ster eotaxic injection into the hippocampus of male Sprague-Dawley rats. Ne uronal loss was assessed by Nissl stain, and immunocytochemistry was u sed to examine cytoskeletal disruption. Malonate produced a dose-depen dent lesion in which CA1 pyramidal neurons were most vulnerable, follo wed by CA3 and dentate gyrus. Cytoskeletal alterations included the lo ss of microtubule-associated protein 2 (MAP2) and dendritic MAP1B immu noreactivity, whereas axonal MAP1B and tau proteins were relatively sp ared. Spatially and temporally correlated with the loss of MAP2 was an increase in the immunoreactivity of calpain-cleaved spectrin. A simil ar pattern of neuronal damage and cytoskeletal disruption was produced by intrahippocampal injection of quinolinate (0.1 mu mol), an NMDA ag onist. Although these results are consistent with the hypothesis that metabolic impairment results in excitotoxic death, NK-801 (dizocilpine maleate), a noncompetitive NMDA receptor antagonist, did not attenuat e the lesions produced by malonate but was effective against quinolina te. The results suggest that NMDA receptor activation is not required for malonate-induced damage in the hippocampal formation.