Takada-Takatori Yuki, Kume Toshiaki, Sugimoto Mitsuhiro, Katsuki Hiroshi, Niidome Tetsuhiro, Sugimoto Hachiro, Fujii Takeshi, Okabe Susumu, Akaike Akinori
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Eur J Pharmacol. 2006 Nov 7;549(1-3):19-26. doi: 10.1016/j.ejphar.2006.08.017. Epub 2006 Aug 23.
We examined the mechanisms of the neuroprotective effects of two central-type acetylcholinesterase inhibitors, galanthamine and tacrine, on nitric oxide-mediated glutamate neurotoxicity using primary cultures from the cerebral cortex of fetal rats. Galanthamine and tacrine showed prominent protective effects against glutamate neurotoxicity. Mecamylamine, a nicotinic acetylcholine receptor antagonist, but not scopolamine, a muscarinic acetylcholine receptor antagonist, inhibited the protective effects of these inhibitors on glutamate neurotoxicity. Furthermore, dihydro-beta-erythroidine, an alpha4-nicotinic receptor antagonist, and methyllycaconitine, an alpha7-nicotinic receptor antagonist, inhibited the neuroprotective effects of galanthamine but not tacrine. Next, we investigated the site of action where galanthamine and tacrine prevent glutamate neurotoxicity. Both these acetylcholinesterase inhibitors prevented glutamate- and ionomycin-induced neurotoxicity, but only tacrine prevented S-nitrosocysteine-induced neurotoxicity. These results suggest that galanthamine and tacrine protect cortical neurons from glutamate neurotoxicity via different mechanisms.
我们使用胎鼠大脑皮层的原代培养物，研究了两种中枢型乙酰胆碱酯酶抑制剂加兰他敏和他克林对一氧化氮介导的谷氨酸神经毒性的神经保护作用机制。加兰他敏和他克林对谷氨酸神经毒性显示出显著的保护作用。烟碱型乙酰胆碱受体拮抗剂美加明，而非毒蕈碱型乙酰胆碱受体拮抗剂东莨菪碱，抑制了这些抑制剂对谷氨酸神经毒性的保护作用。此外，α4烟碱型受体拮抗剂二氢β刺桐啶和α7烟碱型受体拮抗剂甲基牛扁碱抑制了加兰他敏的神经保护作用，但未抑制他克林的神经保护作用。接下来，我们研究了加兰他敏和他克林预防谷氨酸神经毒性的作用位点。这两种乙酰胆碱酯酶抑制剂均能预防谷氨酸和离子霉素诱导的神经毒性，但只有他克林能预防S-亚硝基半胱氨酸诱导的神经毒性。这些结果表明，加兰他敏和他克林通过不同机制保护皮层神经元免受谷氨酸神经毒性。
