[Neuroprotection by ketamine at the cellular level]

A key question in cellular neuroprotection is how pharmacologic agents may protect neurons when applied after injury in clinically relevant concentrations. Of special importance is the N-methyl-D-aspartate (NMDA) antagonist ketamine, which offers the potential for regulation of intracellular calcium levels and pathophysiological NO induction by blocking excessive NMDA-receptor stimulation. This may reduce progressive neuronal degeneration and cell death. Initial evidence for ketamine's neuroprotective effects came from cell culture studies demonstrating increased neuronal and astroglial viability, preserved cellular morphology, and reduced cell swelling subsequent to anoxia-hypoxia or glutamate injury and ketamine application. Moreover, ketamine was found to protect cellular energy status after ischaemic insults and maintained ATP production, glucose metabolism, and mitochondrial transmembrane potentials. Subsequent studies have revealed ketamine's regulating effects on intracellular ion homeostasis, thus stabilising neuronal electrophysiological functions. In addition, ketamine was reported to maintain a glutamate-associated induction of intrinsic-neuronal protective nerve growth factors, and recent evidence suggests that S(+)-ketamine has a greater neuroprotective potential than ketamine racemate. S(+)-ketamine demonstrated a unique neuroregenerative potential that was associated with greater re-outgrowth of axonal neurites after mechanical injury and increased expression of growth-associated proteins after glutamate damage. S(+)-ketamine has a two- to four-fold higher affinity for the phencyclidine receptor of the NMDA receptor complex than ketamine racemate, and it is conceivable that the induction of a differentiated pattern of genes induces cellular growth activities via ketamine-mediated NMDA-receptor activation or blockade. However, further investigations elucidating ketamine's effects in animals and humans have to be performed before final decisions regarding a potential application of ketamine as a neuroprotective agent in the clinical setting can be made.