Distinct neuroprotective profiles for σ ligands against N-methyl- d-aspartate (NMDA), and hypoxia-mediated neurotoxicity in neuronal culture toxicity studies

Substantiating evidence has raised the possibility that σ ligands may have therapeutic potential as neuroprotective agents in brain ischemia. It has been suggested that the neuroprotective capacity of σ ligands is related primarily to their affinity for the NMDA receptor complex and not to any selective action at the σ binding site. However, σ specific ligands, devoid of significant affinity for the NMDA receptor, are also neuroprotective via an inhibition of the ischemic-induced presynaptic release of excitotoxic amino acids. In the present study, we have investigated the potential neuroprotective effect of a comprehensive series of σ ligands, with either significant (σ/PCP) or negligible (σ) affinity for the PCP site of the NMDA receptor, in order to delineate a selective σ site-dependent neuroprotective effect. For this aim, we have employed two different neuronal culture toxicity paradigms implicating either postsynaptic-mediated neurotoxicity, (brief exposure of cultures to a low concentration of NMDA or Kainate) or pre- and postsynaptic mechanisms (exposure to hypoxic/hypoglycemic conditions). Only σ ligands with affinity for the NMDA receptor [(+) and (−) cyclazocine, (+) pentazocine, (+) SKF-10047, ifenprodil and haloperidol] were capable of attenuating NMDA-induced toxicity whereas the σ [(+)BMY-14802, DTG, JO1784, JO1783, and (+)3-PPP] and κ-opioid [CI-977, U-50488H] ligands, with very low affinity for the NMDA receptor, were inactive. The rank order of potency, based on the 50% protective concentration (PC 50) value, of σ/PCP ligands against NMDA-mediated neurotoxicity correlates with their affinity for the PCP site of the NMDA receptor, and not with their affinity for the σ site. In addition σ/PCP, σ or κ-opioid ligands failed to attenuate kainate-mediated neurotoxicity. On the other hand, σ/PCP, σ and κ-opioid ligands were potent inhibitors of hypoxia/hypoglycemia-induced neurotoxicity, although their neuroprotective potency did not correlate with their affinity for either the σ or PCP binding sites. In conclusion, the ability of σ and κ-opioid ligands to attenuate hypoxia/hypoglycemia, but not NMDA or kainate-induced toxicity, suggests that these drugs exert their neuroprotective role by a predominantly presynaptic mechanism possibly by inhibiting ischemic-mediated glutamate release.