Open AccessCholinesterase inhibitor rivastigmine enhances nerve growth factor-induced neurite outgrowth in PC12 cells via sigma-1 and sigma-2 receptors
Author(s) -
Kazuki Terada,
Keisuke Migita,
Yukari Matsushima,
Yukihiko Sugimoto,
Chiaki Kamei,
Taichi Matsumoto,
Masayoshi Mori,
Kazuhisa Matsunaga,
Jiro Takata,
Yoshiharu Karube
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0209250
Subject(s) - neurite , nerve growth factor , acetylcholinesterase , tropomyosin receptor kinase a , butyrylcholinesterase , chemistry , pharmacology , rivastigmine , receptor , receptor antagonist , antagonist , biology , medicine , in vitro , biochemistry , aché , donepezil , enzyme , disease , dementia
Rivastigmine (Riv) is a potent and selective cholinesterase (acetylcholinesterase, AChE and butyrylcholinesterase, BuChE) inhibitor developed for the treatment of Alzheimer’s disease (AD). To elucidate whether Riv causes neuronal differentiation, we examined its effect on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. At concentrations of 0–100 μM, Riv was non-toxic in PC12 cells. Riv caused dose-dependent (10–100 μM) enhancement of NGF-induced neurite outgrowth, which was completely inhibited by the TrkA antagonist GW-441756. By contrast, Riv-mediated enhancement of neurite outgrowth was not blocked by the acetylcholine receptor antagonists, scopolamine and hexamethonium. However, the sigma-1 receptor (Sig-1R) antagonist NE-100 and sigma-2 receptor (Sig-2R) antagonist SM-21 each blocked about half of the Riv-mediated enhancement of NGF-induced neurite outgrowth. Interestingly, the simultaneous application of NE-100 and SM-21 completely blocked the enhancement of NGF-induced neurite outgrowth by Riv. These findings suggest that both Sig-1R and Sig-2R play important roles in NGF-induced neurite outgrowth through TrkA and that Riv may contribute to neuronal repair via Sig-1R and Sig-2R in AD therapy.