The effects of ketamine-isomers on neuronal injury and regeneration in rat hippocampal neurons

There is a difference in the relative anesthetic potency of the isomers of ketamine. Neuroprotective differences may therefore also exist. After an 8-min exposure to 500 mu M glutamate or axonal transection, cultured rat hippocampal neurons were maintained untreated or in the presence of ketamine-racemate, S(+)-ketamine, or R(-)-ketamine (10(-4) M, 10(-5) M, 10(-6) M). Cell survival was examined by dye inclusion/esterase activity, morphology by phase contrast and immunofluorescence microscopy, and [H-3]arachidonic acid (ARA) release by liquid scintillation spectrometry. Seven days after glutamate exposure, survival decreased to 30% in the damaged, untreated group. Extracellular [H-3]ARA increased fivefold. Dendritic length and branching decreased to a quarter and axonal extensions to the half. Ketamine-racemate 10(-4) M increased survival to 65%, and induced longer dendrites (P less than or equal to 0.05). S(+)-Ketamine 10(-4) M increased survival to 80%, reduced [H-3]ARA threefold, and preserved cytoskeletal arborizations (P less than or equal to 0.05). Axotomy decreased survival to 60% and caused a minor increase in [H-3]ARA after 7 days. Survival was 80% after 10(-4) M ketamine-racemate and 90% after 10(-4) M S(+)-ketamine (P less than or equal to 0.05). Only S(+)-ketamine supported axonal re-outgrowth and decreased [H-3]ARA (P less than or equal to 0.05). R(-)-Ketamine was ineffective after both types of injury. Ketamine-racemate and S(+)-ketamine attenuated injury after glutamate exposure or axonal transection in hippocampal neurons in vitro. Neuroregenerative effects were uniquely demonstrated by S(+)-ketamine.