DISTINCT NEUROPROTECTIVE PROFILES FOR SIGMA-LIGANDS AGAINST N-METHYL-D-ASPARTATE (NMDA), AND HYPOXIA-MEDIATED NEUROTOXICITY IN NEURONAL CULTURE TOXICITY STUDIES

Substantiating evidence has raised the possibility that sigma ligands may have therapeutic potential as neuroprotective agents in brain isch emia. It has been suggested that the neuroprotective capacity of sigma ligands is related primarily to their affinity for the NMDA receptor complex and not to any selective action at the sigma binding site. How ever, sigma specific ligands, devoid of significant affinity for the N MDA receptor, are also neuroprotective via an inhibition of the ischem ic-induced presynaptic release of excitotoxic amino acids. In the pres ent study, we have investigated the potential neuroprotective effect o f a comprehensive series of a ligands, with either significant (sigma/ PCP) or negligible (sigma) affinity for the PCP site of the NMDA recep tor, in order to delineate a selective sigma site-dependent neuroprote ctive effect. For this aim, we have employed two different neuronal cu lture toxicity paradigms implicating either postsynaptic-mediated neur otoxicity, (brief exposure of cultures to a low concentration of NMDA or Kainate) or pre- and postsynaptic mechanisms (exposure to hypoxic/h ypoglycemic conditions). Only sigma ligands with affinity for the NMDA receptor [(+) and (-) cyclazocine, (+) pentazocine, (+) SKF-10047, if enprodil and haloperidol] were capable of attenuating NMDA-induced tox icity whereas the sigma [(+)BMY-14802, DTG, JO1784, JO1783, and (+)3-P PP] and kappa-opioid [CI-977, U-50488H] ligands, with very low affinit y for the NMDA receptor, were inactive. The rank order of potency, bas ed on the 50% protective concentration (PC50) value, of sigma/PCP liga nds against NMDA-mediated neurotoxicity correlates with their affinity for the PCP site of the NMDA receptor, and not with their affinity fo r the sigma site. In addition (sigma/PCP, a or kappa-opioid ligands fa iled to attenuate kainate-mediated neurotoxicity. On the other hand, s igma/PCP, sigma and kappa-opioid ligands were potent inhibitors of hyp oxia/hypoglycemia-induced neurotoxicity, although their neuroprotectiv e potency did not correlate with their affinity for either the sigma o r PCP binding sites. In conclusion, the ability of sigma and kappa-Opi oid ligands to attenuate hypoxia/hypoglycemia, but not NMDA or kainate -induced toxicity, suggests that these drugs exert their neuroprotecti ve role by a predominantly presynaptic mechanism possibly by inhibitin g ischemic-mediated glutamate release.