EVALUATION OF THE ROLE OF NMDA-MEDIATED EXCITOTOXICITY IN THE SELECTIVE NEURONAL LOSS IN EXPERIMENTAL WERNICKE ENCEPHALOPATHY

The goal of the studies described was to evaluate the role of NMDA rec eptor-mediated glutamate excitotoxicity in the pathogenesis of selecti ve neuronal loss due to thiamine deficiency, Administration of the cen tral thiamine antagonist pyrithiamine to adult male rats resulted in a sequence of neurological symptoms including ataxia and loss of righti ng reflex followed by convulsions, Prior to the onset of convulsions, neuropathologic evaluation revealed significant neuronal loss in the v entral posterior medial thalamic nucleus. However, in vivo cerebral mi crodialysis at preconvulsive stages did not demonstrate significant in creases of extracellular glutamate in this region and pretreatment wit h the NMDA receptor antagonist MK801 (1 mg/kg/12 h, ip) did not afford significant neuroprotection. Following the onset of convulsions, micr odialysate glutamate concentrations were increased fivefold (P > 0.05) and MK801 treatment resulted in significant attenuation of neuronal l oss in some thalamic nuclei. A comparable degree of neuroprotection wa s afforded by pretreatment with an anticonvulsant dose of diazepam (10 mg/kg/12 h, ip) a compound whose action is not NMDA receptor mediated . These findings suggest that NMDA receptor-mediated excitotoxicity is not responsible for early selective neuronal loss in this model of th iamine deficiency encephalopathy and that the neuroprotective effect o f MK801 at later stages are at least in part a consequence of its anti convulsant properties. (C) 1998 Academic Press.