Disseminated corticolimbic neuronal degeneration induced in rat brain by MK-801: Potential relevance to Alzheimer's disease

Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors by MK-801 induc es neuronal degeneration in the posterior cingulate/retrosplenial cortex an d other corticolimbic regions although damage in the latter has not been ad equately characterized. This disseminated corticolimbic damage is of intere st since NMDA hypofunction, the mechanism that triggers this neurodegenerat ive syndrome, has been postulated to play a role in the pathophysiology of Alzheimer's disease (AD). Several histological methods, including electron microscopy, were used to evaluate the neurotoxic changes in various cortico limbic regions of rat brain following MK-801 or a combination of MK-801 plu s pilocarpine. We found that MK-801 triggers neuronal degeneration in a wid espread pattern similar to that induced by phencyclidine and that females s howed more damage than males. The neurotoxic reaction involved additional b rain regions when muscarinic receptors were hyperactivated by administering pilocarpine with MK-801.. Ultrastructural evaluation revealed that a major feature of the neurotoxic action involves degeneration of dendritic spines which entails loss of synaptic complexes. The ultrastructural appearance o f degenerating neurons was generally inconsistent with an apoptotic mechani sm, although evidence equivocally consistent with apoptosis was observed in some instances. The cell death process evolved relatively slowly and was s till ongoing 7 days posttreatment. Relevance of these results to AD is disc ussed. (C) 1998 Academic Press.