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.