Phencyclidine receptor ligands attenuate cortical neuronal injury after N-methyl-D-aspartate exposure or hypoxia

Phencyclidine (PCP) and related noncompetitive antagonists of N-methyl-D-aspartate (NMDA) receptor neuroexcitation were tested for their ability to attenuate either NMDA- or hypoxia-induced neuronal loss in dissociated cell cultures prepared from mouse neocortex. 10 μM PCP or MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] selectively blocked the neurotoxicity produced by application of NMDA or the endogenous NMDA agonist quinolinate, without altering kainate or quisqualate neurotoxicity. Blockade of NMDA toxicity was concentration-dependent in the submicromolar and micromolar range, with a potency order (MK-801 > PCP > SKF 10,047 > pentazocine) consistent with primary mediation at PCP sites rather than at sigma sites. PCP reduced the toxicity of high NMDA concentrations, consistent with a noncompetitive mechanism of antagonism. PCP ligands also potently attenuated neuronal injury after exposure of the cultures to hypoxia. The effective concentrations and drug potency order for blockade of hypoxic injury were quantitatively similar to results obtained against the application of exogenous NMDA. These observations provide further support for the hypothesis that excessive activation of NMDA receptors may participate importantly in the pathogenesis of hypoxic brain injury.