The goal of the studies described was to evaluate the role of
NMDA receptor-mediated
glutamate excitotoxicity in the pathogenesis of selective neuronal loss due to
thiamine deficiency. Administration of the central
thiamine antagonist
pyrithiamine to adult male rats resulted in a sequence of neurological symptoms including
ataxia and loss of righting reflex followed by convulsions. Prior to the onset of convulsions, neuropathologic evaluation revealed significant neuronal loss in the ventral posterior medial thalamic nucleus. However, in vivo cerebral microdialysis at preconvulsive stages did not demonstrate significant increases of extracellular
glutamate in this region and pretreatment with the
NMDA receptor antagonist
MK801 (1 mg/ kg/12 h, i.p.) did not afford significant neuroprotection. Following the onset of convulsions, microdialysate
glutamate concentrations were increased fivefold (P > 0.05) and
MK801 treatment resulted in significant attenuation of neuronal loss in some thalamic nuclei. A comparable degree of neuroprotection was afforded by pretreatment with an
anticonvulsant dose of
diazepam (10 mg/kg/12 h, i.p.) 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
thiamine deficiency encephalopathy and that the
neuroprotective effect of
MK801 at later stages are at least in part a consequence of its
anticonvulsant properties.