Shalaby I A, Chenard B L, Prochniak M A, Butler T W
Department of Neuroscience, Pfizer Inc., Groton, Connecticut.
J Pharmacol Exp Ther. 1992 Feb;260(2):925-32.
The N-methyl-D-aspartate (NMDA) antagonists ifenprodil and SL-82,0715 were examined for neuroprotective efficacy against glutamate toxicity of hippocampal neurons in culture. Hippocampal cells were grown on 96-well culture plates for 2 to 3 weeks and then exposed for a 15-min period to glutamate or NMDA. Neurodegeneration was quantified 24 hr after the excitotoxin exposure, by measuring the activity of lactate dehydrogenase leaked into the culture medium by the damaged cells. Glutamate induced a concentration-dependent increase in lactate dehydrogenase that reached 3-fold the activity of control cultures. The NMDA antagonists MK-801 and AP-7 blocked this neurotoxicity when added either during or after the glutamate exposure. Ifenprodil and SL-82,0715 blocked the neurotoxicity only when added during the excitotoxin exposure. Ifenprodil was 3 times more potent than SL-82,0715 in blocking glutamate or NMDA-induced neurotoxicity. Glycine did not reverse the neuroprotective effects of these antagonists. The neuroprotective effect of ifenprodil or SL-82,0715 did not appear to result from actions at alpha-1 adrenergic or sigma receptor sites because the alpha-1 adrenergic antagonist prazosin and the sigma ligands haloperidol, 3-(3-hydroxyphenyl)-N-propylpiperidine) and 1,3-di-o-tolylguanidine) showed no neuroprotective activity. We conclude that ifenprodil and SL-82,0715 protect cultured hippocampal neurons from excitotoxic damage by antagonizing NMDA receptors.
研究了 N-甲基-D-天冬氨酸（NMDA）拮抗剂艾芬地尔和 SL-82,0715 对培养的海马神经元谷氨酸毒性的神经保护作用。将海马细胞接种于 96 孔培养板上培养 2 至 3 周，然后暴露于谷氨酸或 NMDA 中 15 分钟。在兴奋性毒素暴露 24 小时后，通过测量受损细胞泄漏到培养基中的乳酸脱氢酶活性来量化神经变性。谷氨酸诱导乳酸脱氢酶浓度依赖性增加，其活性达到对照培养物的 3 倍。当在谷氨酸暴露期间或之后添加 NMDA 拮抗剂 MK-801 和 AP-7 时，可阻断这种神经毒性。仅在兴奋性毒素暴露期间添加艾芬地尔和 SL-82,0715 时可阻断神经毒性。在阻断谷氨酸或 NMDA 诱导的神经毒性方面，艾芬地尔的效力是 SL-82,0715 的 3 倍。甘氨酸不能逆转这些拮抗剂的神经保护作用。艾芬地尔或 SL-82,0715 的神经保护作用似乎不是由其作用于α-1 肾上腺素能或σ受体位点所致，因为α-1 肾上腺素能拮抗剂哌唑嗪和σ配体氟哌啶醇、3-(3-羟基苯基)-N-丙基哌啶和 1,3-二邻甲苯基胍均无神经保护活性。我们得出结论，艾芬地尔和 SL-82,0715 通过拮抗 NMDA 受体保护培养的海马神经元免受兴奋性毒性损伤。
