INFLUENCE OF KETAMINE ON THE NEURONAL DEATH CAUSED BY NMDA IN THE RATHIPPOCAMPUS

The protection provided by ketamine against the neuronal cytotoxicity of NMDA was investigated and compared with that provided by dizocilpin e (MK 801). A massive anaesthetic dose of ketamine (180 mg/kg) was req uired for substantial protection (about 70%) of rat dorsal hippocampal neurons. Protection was markedly decreased if the ketamine was given in three divided doses of 60 mg/kg over a period of 2 hr, rather than as a bolus injection of 180 mg/kg. A lower dose (60 mg/kg i.p.) gave n o protection when given 10 min prior to NMDA, but some protection (up to 30%) was found when administration was delayed for 1-2 hr. After 3 hr, ketamine at this dose did not protect. In comparison, the toxicity of NMDA was reduced by about 70% by prior treatment with dizocilpine at 1 mg/kg, and completely eliminated at 10 mg/kg. The lack of protect ion when ketamine at 60 mg/kg was administered prior to NMDA may be du e to a proconvulsant action of ketamine, as diazepam in the presence b ut not in the absence of ketamine significantly reduced the toxicity o f NMDA. However, there was no behavioural or histological evidence of increased seizure activity in the presence of ketamine. Neuroprotectan t effects may prevail with massive anaesthetic doses of ketamine or wh en diffusion has reduced the concentration of NMDA. The heroic doses o f ketamine required for protection diminish its attractiveness as a po tential anti-ischaemic agent.