title: Activation of M1 mAChRs by lesatropane rescues glutamate neurotoxicity in PC12 cells via PKC-mediated phosphorylation of ERK1/2.
abstract: 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.
authors.affiliation: Department of Pharmacy, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ma
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Yang
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Yang
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000737:chemistry*; D016716:PC12 Cells; D010766:Phosphorylation; D010890:Pirenzepine / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D043643:Receptor, Muscarinic M1 / Q000187:drug effects*; D014326:Tropanes / Q000737:chemistry*
chemical_list: D018696:Neuroprotective Agents; D043643:Receptor, Muscarinic M1; D014326:Tropanes; C535253:satropane; D010890:Pirenzepine; D018698:Glutamic Acid; D001285:Atropine; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases