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 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.
Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada.
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Zhang
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Boulton
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Zuo
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Yu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D011437:Propylamines / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D011437:Propylamines; D011500:Protein Synthesis Inhibitors; C094098:N-2-hexyl-N-methylpropargylamine; D016291:Dizocilpine Maleate; D003513:Cycloheximide