σ Receptor ligands attenuate N-methyl-D-aspartate cytotoxicity in dopaminergic neurons of mesencephalic slice cultures

We investigated the potential neuroprotective effects of several σ receptor ligands in organotypic midbrain slice cultures as an excitotoxicity model system. When challenged with 100-μM N-methyl-D-aspartate (NMDA) for 24 h, dopaminergic neurons in midbrain slice cultures degenerated, and this was prevented by (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]-cyclohepten-5,10-imine (MK-801; 1-10 μM). Concomitant application of ifenprodil (1-10 μM) or haloperidol (1-10 μM), both of which are high-affinity σ receptor ligands, significantly attenuated the neurotoxicity of 100 μM NMDA. The σ₁ receptor-selective ligand (+)-N-allylnormetazocine ((+)-SKF 10047; 1-10 μM) was also effective in attenuating the toxicity of NMDA. The effect of R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane hydrochloride ((-)-PPAP), a σ receptor ligand with negligible affinity for the phencyclidine site of NMDA receptors, was also examined. (-)-PPAP (3-100 μM) caused a concentration-dependent reduction of NMDA cytotoxicity, with significant protection at concentrations of 30 and 100 μM. In contrast, (+)-SKF 10047 (10 μM) and (-)-PPAP (100 μM) showed no protective effects against cell death induced by the Ca²⁺ ionophore ionomycin (1-3 μM). These results indicate that σ receptor ligands attenuate the cytotoxic effects of NMDA on midbrain dopaminergic neurons, possibly via inhibition of NMDA receptor functions. Copyright (C) 2000 Elsevier Science B.V.