Lockhart B P, Soulard P, Benicourt C, Privat A, Junien J L
INSERM U-336, Développement, Plastieité et Vieillissement du Système Nerveux, Ecole Nationale Supérieure de Chimie, Montpellier, France.
Brain Res. 1995 Mar 27;675(1-2):110-20. doi: 10.1016/0006-8993(95)00049-v.
Substantiating evidence has raised the possibility that sigma ligands may have therapeutic potential as neuroprotective agents in brain ischemia. 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. However, sigma 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 sigma ligands, with either significant (sigma/PCP) or negligible (sigma) affinity for the PCP site of the NMDA receptor, in order to delineate a selective sigma 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 sigma ligands with affinity for the NMDA receptor [(+) and (-) cyclazocine, (+) pentazocine, (+) SKF-10047, ifenprodil and haloperidol] were capable of attenuating NMDA-induced toxicity whereas the sigma [(+)BMY-14802, DTG, JO1784, JO1783, and (+)3-PPP] and kappa-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 (PC50) value, of sigma/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 sigma site. In addition sigma/PCP, sigma or kappa-opioid ligands failed to attenuate kainate-mediated neurotoxicity. On the other hand, sigma/PCP, sigma and kappa-opioid ligands were potent inhibitors of hypoxia/hypoglycemia-induced neurotoxicity, although their neuroprotective potency did not correlate with their affinity for either the sigma or PCP binding sites. In conclusion, the ability of sigma and kappa-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.
确证性证据表明，σ配体作为脑缺血中的神经保护剂可能具有治疗潜力。有人提出，σ配体的神经保护能力主要与其对NMDA受体复合物的亲和力有关，而非与在σ结合位点的任何选择性作用有关。然而，对NMDA受体缺乏显著亲和力的σ特异性配体，也可通过抑制缺血诱导的兴奋性毒性氨基酸的突触前释放而发挥神经保护作用。在本研究中，我们研究了一系列对NMDA受体的PCP位点具有显著（σ/PCP）或可忽略不计（σ）亲和力的σ配体的潜在神经保护作用，以阐明一种选择性的依赖于σ位点的神经保护作用。为此，我们采用了两种不同的神经元培养毒性模型，一种涉及突触后介导的神经毒性（将培养物短暂暴露于低浓度的NMDA或海人藻酸），另一种涉及突触前和突触后机制（暴露于缺氧/低血糖条件）。只有对NMDA受体具有亲和力的σ配体[（+）和（-）环唑辛、（+）喷他佐辛、（+）SKF-10047、艾芬地尔和氟哌啶醇]能够减轻NMDA诱导的毒性，而对NMDA受体亲和力极低的σ配体[（+）BMY-14802、DTG、JO1784、JO1783和（+）3-PPP]以及κ-阿片样物质配体[CI-977、U-50488H]则无活性。基于50%保护浓度（PC50）值，σ/PCP配体对NMDA介导的神经毒性的效力排序与其对NMDA受体PCP位点的亲和力相关，而与其对σ位点的亲和力无关。此外，σ/PCP、σ或κ-阿片样物质配体均不能减轻海人藻酸介导的神经毒性。另一方面，σ/PCP配体、σ配体和κ-阿片样物质配体是缺氧/低血糖诱导的神经毒性的有效抑制剂，尽管它们的神经保护效力与其对σ或PCP结合位点的亲和力无关。总之，σ配体和κ-阿片样物质配体能够减轻缺氧/低血糖，但不能减轻NMDA或海人藻酸诱导的毒性，这表明这些药物主要通过突触前机制发挥神经保护作用，可能是通过抑制缺血介导的谷氨酸释放。
