PATHOMORPHOLOGIC EFFECTS OF N-METHYL-D-ASPARTATE ANTAGONISTS IN THE RAT POSTERIOR CINGULATE RETROSPLENIAL CEREBRAL-CORTEX - A REVIEW/

This review discusses available information on the neurotoxicity of N- methyl-D-aspartate (NMDA) antagonists in the posterior cingulate/retro splenial (PC/RS) cortex of rats. NMDA antagonists block the NMDA recep tor, a central nervous system ionotropic glutamate receptor, and are n europrotective since they reduce injury in animal models of ischemia. There is interest in the development and use of NMDA antagonists in tr eating human cerebrovascular diseases. However, with certain NMDA anta gonists, dose-dependent vacuolization of neurons in the neuroanatomica lly localized PC/RS cortex occurs as a side effect in rats. NMDA antag onists that cause vacuolization also appear to induce heat shock prote in expression and heightened glucose metabolism in the same cortical r egion. Electron microscopy has shown that after treatment with MK-801 (dizocilpine maleate), a prototypic noncompetitive NMDA antagonist, th e onset of vacuolization is very rapid. Additional studies with MK-801 have indicated that susceptibility to vacuolization increases between 30 and 90 days of age. Histologic time course studies have demonstrat ed that as the dose of MK-801 is increased, some vacuolated neurons be come necrotic. Necrotic neurons are readily evident by light microscop y in routine preparations. At a given dose of MK-801, neuronal necrosi s is more extensive in female rats than male rats. Furthermore, necros is increases along an anterior to posterior gradient within the suscep tible PC/RS cortex. A number of compounds with varied central nervous system (CNS) pharmacologic activity (anticholinergics, GABAmimetics, a ntipsychotics, and general anesthetics) partially or completely preven t neuronal vacuolization. These data suggest a complex pathogenesis fo r NMDA antagonist-mediated neurotoxicity and indicate variables which require consideration when designing and interpreting studies with the se compounds. Since recent reports have described failure of some NMDA antagonists to produce these side effects, the issues discussed in th is review may or may not apply to all NMDA antagonists. (C) 1994 Wiley -Liss, Inc.