MK-801 induces apoptotic neuronal death in the rat retrosplenial cortex: prevention by cycloheximide and R(-)-2-hexyl-N-methylpropargylamine.

摘要

MK-801 is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist which can prevent excitatory neuronal death. At higher concentrations, however, it can also induce neuronal death in the limbic system. This MK-801-induced selective neuro-toxicity has been proposed as an animal model for dementia and psychosis. We have investigated the effects of the protein synthesis inhibitor cycloheximide and the neurorescue agent 2-hexyl-N-methylpro-pargylamine [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 after, injection of MK-801 (5 mg/kg, sc) prevented almost completely neuronal 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.