Department of Pharmacy, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
Bosn J Basic Med Sci. 2013 Aug;13(3):146-52. doi: 10.17305/bjbms.2013.2346.
Lesatropane, a synthesized chiral tropane (3S, 6S-isomer of satropane), is a novel muscarinic agonist, and is being under preclinical development in China for the treatment of primary glaucoma. The reports concerning that activation of muscarinic acetylcholine receptors (mAChRs) could protect cells against apoptosis prompted us to study the neuroprotective effects of lesatropane and the mechanism. We found that lesatropane could protect PC12 cells from glutamate-induced neurotoxicity and reverse the decreased ERK1/2 activation caused by glutamate. Atropine or pirenzepine, antagonist of mAChR or M1 mAChR, antagonized the protective effects of lesatropane respectively and suppressed the lesatropane's effects on ERK1/2. Furthermore, chelerythrine, a PKC inhibitor, partially suppressed ERK1/2 activation induced by lesatropane. The results indicated that the specific M1 mAChR via PKC-ERK1/2 pathway might be involved in the neuroprotective effects of lesatropane. While M1 mAChR is a therapeutic target of Alzheimer's disease (AD), the results of this paper contribute to further information concerning the activation of M1 mAChR as a therapeutic target in AD.
左旋山莨菪碱是一种合成的手性托烷（3S,6S-异构体），是一种新型的毒蕈碱激动剂，目前正在中国进行临床前研究，用于治疗原发性青光眼。有报道称，毒蕈碱乙酰胆碱受体（mAChR）的激活可以保护细胞免受细胞凋亡的影响，这促使我们研究左旋山莨菪碱的神经保护作用及其机制。我们发现，左旋山莨菪碱可以保护 PC12 细胞免受谷氨酸诱导的神经毒性，并逆转谷氨酸引起的 ERK1/2 激活减少。阿托品或哌仑西平，mAChR 或 M1 mAChR 的拮抗剂，分别拮抗左旋山莨菪碱的保护作用，并抑制左旋山莨菪碱对 ERK1/2 的作用。此外，PKC 抑制剂 Chelerythrine 部分抑制了左旋山莨菪碱诱导的 ERK1/2 激活。结果表明，特定的 M1 mAChR 通过 PKC-ERK1/2 通路可能参与了左旋山莨菪碱的神经保护作用。虽然 M1 mAChR 是阿尔茨海默病（AD）的治疗靶点，但本文的结果为进一步了解 AD 中 M1 mAChR 的激活作为治疗靶点提供了信息。
