title: Peripheral cholinoceptor antagonist anisodamine counteracts cholinergic adverse effects and facilitates cognitive amelioration of rivastigmine.
abstract: Rivastigmine is a potent acetyl- and butyrylcholinesterase inhibitor widely used for cognitive improvement in Alzheimer's disease (AD) therapy. However, dose-limiting adverse effects restrict its tolerability and clinical outcomes. This study explored new combined therapy, in which peripheral cholinergic adverse effects and central cognitive amelioration of rivastigmine were differentiated by a peripheral cholinoceptor antagonist anisodamine. The results demonstrated that rivastigmine (0.75 and 2.0 mg/kg) could significantly reverse the scopolamine-induced cognitive deficit in mice through passive avoidance test. Nevertheless, a high dose of rivastigmine (3.25 mg/kg) would compromise cognitive amelioration and produce obvious adverse effects, including hypersalivation, intestinal hyperperistalsis and muscle cramp. Interestingly, concomitant administration of anisodamine (10 mg/kg) effectively counteracted both the muscarinergic and nicotinergic adverse effects, while facilitating cognitive amelioration of rivastigmine (3.25 mg/kg). These findings provide an insight into the feasibility of combined therapy with cholinesterase inhibitors and peripheral cholinoceptor antagonists for the treatment of AD.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, 200025 Shanghai, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Zhang
authors.forename: Zu-Peng
authors.initials: ZP
authors.lastname: Xu
authors.forename: Yong-Yao
authors.initials: YY
authors.lastname: Cui
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Ming-Ke
authors.initials: MK
authors.lastname: Song
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Bi-Yun
authors.initials: BY
authors.lastname: Shao
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D018680:Cholinergic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D007422:Intestines / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009120:Muscle Cramp / Q000139:chemically induced / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000009:adverse effects*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy*; D048448:Phenylcarbamates / Q000008:administration & dosage / Q000009:adverse effects*; D011897:Random Allocation; D000068836:Rivastigmine; D012472:Salivation / Q000187:drug effects; D012601:Scopolamine; D012991:Solanaceous Alkaloids / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D018680:Cholinergic Antagonists; D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D012991:Solanaceous Alkaloids; C003922:anisodamine; D012601:Scopolamine; D000068836:Rivastigmine