Cholinesterase inhibitor rivastigmine enhances nerve growth factor-induced neurite outgrowth in PC12 cells via sigma-1 and sigma-2 receptors

Abstract

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.

Role of TrkA signaling during tadpole tail regeneration and early embryonic development in Xenopus laevis

“…To confirm Trk involvement and identify the Trk family member(s) responsible for tadpole tail regeneration, tail-amputated tadpoles were treated with control DMSO or GW-441756, a potent selective TrkA inhibitor (Wood et al, 2004), for 5 days. GW-441756 significantly reduced the regenerated tail length (Figure 4e,f) at the dose (1 μM) used for TrkA inhibition in previous studies (Terada et al, 2018;Waetzig et al, 2017;Zhang et al, 2014), suggesting that TrkA is required for full tail regeneration.…”

“…GW-441756 has been developed and used as a TrkA inhibitor (Terada et al, 2018;Waetzig et al, 2017;Wood et al, 2004;Zhang et al, 2014), but it can also inhibit TrkB and TrkC (Lawn et al, 2015;Wang, Hancock, Dudek, & Bi, 2008); thus, the possible involvement of TrkB or TrkC in tadpole tail regeneration is not excluded. To examine TrkB involvement, we used ANA-12, a selective TrkB receptor antagonist that does not alter TrkA and TrkC function (Cazorla et al, 2011).…”

Atypical Antipsychotic Drug Ziprasidone Protects against Rotenone-Induced Neurotoxicity: An In Vitro Study

“…Western blot analyses were performed as previously described [ 19 ]. The subcellular fractions (cytosolic and nuclear fractions) were separated using a nuclear/cytosolic fractionation kit (Cell Biolabs, San Diego, CA, USA) according to the manufacturer’s instructions.…”

“…PC12 is a cell line derived from the pheochromocytoma of rat adrenal medulla. It has been widely used as a model system for nerve growth factor (NGF)-induced neuronal-like differentiation [ 19 ]. Recently, it has been reported that atypical antipsychotic drugs, namely olanzapine and aripiprazole, reduced oxidative stress through the prevention of ROS generation in PC12 cells [ 20 ].…”

Is Combining an Anticholinergic with a Cholinesterase Inhibitor a Good Strategy for High-Level CNS Cholinesterase Inhibition?

“…The potential role of NGF in Alzheimer’s is being tested by NGF replacement therapy as a strategy for slowing or delaying the progression of Alzheimer’s [47,48]. Conversely, the complementary anti-neurodegenerative effects of cholinesterase inhibition and the beneficial effect of the resulting increased cholinergic tone is increased synthesis and release of NGF and increased survival of cholinergic cell bodies in the basal forebrain [49,50]. Overall, anticholinergics could act to decrease, and cholinesterase inhibitors could act in the opposing direction to increase, acetylcholine-dependent NGF synthesis and release.…”