MK-801 INDUCES APOPTOTIC NEURONAL DEATH IN THE RAT RETROSPLENIAL CORTEX - PREVENTION BY CYCLOHEXIMIDE AND R(-)-2-HEXYL-N-METHYLPROPARGYLAMINE

MK-801 is a non-competitive N-methyl-D-aspartate (NMDA) receptor antag onist which can prevent excitatory neuronal death, At higher concentra tions, however, it can also induce neuronal death in the limbic system , This MK-801-induced selective neurotoxicity has been proposed as an animal model for dementia and psychosis, We have investigated the effe cts of the protein synthesis inhibitor cycloheximide and the neuroresc ue agent 2-hexyl-N-methylpropargylamine [R(-)-2HxMP] on MK-801-induced neuronal death in the retrosplenial cortex in the rat. Cycloheximide [2 mg/kg, subcutaneously (sc)] administered either 1 hr before, or aft er, injection of MK-801 (5 mg/kg, sc) prevented almost completely neur onal shrinkage and nuclear condensation of the granular retrosplenial cortex as assessed by hematoxylin-eosin staining, The results suggest that the MK-801-induced neuronal death was apoptotic, This neurorescue effect by cycloheximide was time dependent: after 4 hr the effect was reduced to about 50% and by 8 hr had disappeared, R(-)-2HxMP (0.25 mg /kg, sc), which does not inhibit protein synthesis in vitro, was also found to be effective at preventing MK-801-induced neuronal death. (C) 1996 Wiley-Liss, Inc.