Involvement of direct inhibition of NMDA receptors in the effects of sigma-receptor ligands on glutamate neurotoxicity in vitro

This study was performed to examine the roles: of the N-methyl-D-aspartate (NMDA) receptor/phencyclidine (PCP) channel complex in the protective effec ts of sigma-receptor ligands against glutamate neurotoxicity in cultured co rtical neurons derived from fetal rats. A 1-h exposure of cultures to gluta mate caused a marked loss of viability, as determined by Trypan blue exclus ion. This acute neurotoxicity of glutamate was prevented by NMDA receptor a ntagonists. Expression of sigma(1) receptor mRNA in cortical cultures was c onfirmed by reverse transcription polymerase chain reaction (RT-PCR). sigma Receptor ligands with affinity for NMDA receptor channels including the PC F site, such as (+)-N-allylnormetazocine ((+)-SKF10,047), haloperidol, and R(-)-N-(3-phenyl-1-propyl)-1-phenyl-2-aminopropane ((-)-PPAF), prevented gl utamate neurotoxicity in a concentration-dependent manner. In contrast, oth er sigma-receptor ligands without affinity fur NMDA receptors. such as carb etapentane and R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine ((+)-3-PPP). did not show neuroprotective effects. putative endogenous sigma receptor ligan ds such as pregnenolone, progesterone, and dehydroepiandrosterone did not a ffect glutamate neurotoxicity. The protective effects of(+)-SKF10,047. halo peridol, and (-)-PPAP were not affected by the sigma(1) receptor antagonist rimcazole. These results suggested that a direct interaction with NMDA rec eptors but not with sigma receptors plays a crucial role in the neuroprotec tive effects of sigma receptor ligands with affinity for NMDA receptors. (C ) 2000 Elsevier Science B.V. All rights reserved.