Influence of ketamine on the neuronal death caused by NMDA in the rat hippocampus

Abstract

The protection provided by ketamine against the neuronal cytotoxicity of NMDA was investigated and compared with that provided by dizocilpine (MK 801). A massive anaesthetic dose of ketamine (180 mg/kg) was required 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 no 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 protection when ketamine at 60 mg/kg was administered prior to NMDA may be due to a proconvulsant action of ketamine, as diazepam in the presence but not in the absence of ketamine significantly reduced the toxicity of NMDA. However, there was no behavioural or histological evidence of increased seizure activity in the presence of ketamine. Neuroprotectant effects may prevail with massive anaesthetic doses of ketamine or when diffusion has reduced the concentration of NMDA. The heroic doses of ketamine required for protection diminish its attractiveness as a potential anti-ischaemic agent.