Activation of M1 mAChRs by lesatropane rescues glutamate neurotoxicity in PC12 cells via PKC-mediated phosphorylation of ERK1/2

摘要

Lesatropane, a synthesized chiral tropane (?S, ?S-isomer of satropane), is a novel muscarinic agonist, and is being under preclinical development in China for the treatment of primary glaucoma. Th e reports concerning that activation of muscarinic acetylcholine receptors (mAChRs) could protect cells against apoptosis prompted us to study the neuroprotective eff ects of lesatropane and the mechanism. We found that lesatropane could protect PC?? cells from glutamate-induced neurotoxicity and reverse the decreased ERK?/? activation caused by glutamate. Atropine or pirenzepine, antagonist of mAChR or M? mAChR, antagonized the protective eff ects of lesatropane respectively and suppressed the lesatropane’s eff ects on ERK?/?. Furthermore, chelerythrine, a PKC inhibitor, partially suppressed ERK?/? activation induced by lesatropane. Th e results indicated that the specifi c M? mAChR via PKC-ERK?/? pathway might be involved in the neuroprotective eff ects of lesatropane. While M? mAChR is a therapeutic target of Alzheimer’s disease (AD), the results of this paper contribute to further information concerning the activation of M? mAChR as a therapeutic target in AD.