Protective effects of VMY-2-95 on corticosterone-induced injuries in mice and cellular models

Abstract

Nicotinic α 4 β 2 receptor antagonists have drawn increasing attention in the development of new antidepressants. In this study, we aimed to investigate the protective effect of VMY-2-95, the new selective antagonist of α 4 β 2 nicotinic acetylcholine receptor (nAChR) on corticosterone (CORT) injured mice and cellular models. Fluoxetine was applied as a positive control, and the effects of VMY-2-95 were investigated with three different doses or concentrations (1, 3, 10 mg/kg in mice, and 0.003, 0.03, 0.1 μmol/L in cells). As a result, VMY-2-95 showed significant antidepressant-like effects in the CORT injured mice by improving neuromorphic function, promoting hippocampal nerve proliferation, and regulating the contents of monoamine transmitters. Meanwhile, VMY-2-95 exhibited protective effects on cell viability, cell oxidant, cell apoptosis, and mitochondrial energy metabolism on corticosterone-impaired SH-SY5Y cells. Also, the PKA–CREB–BDNF signaling pathway was up-regulated by VMY-2-95 both in vitro and in vivo , and pathway blockers were also combined with VMY-2-95 to verify the effects furtherly. Therefore, we preliminarily proved that VMY-2-95 had protective effects in depressed mice and SH-SY5Y cells against injuries induced by corticosterone. This work indicated that the application of VMY-2-95 is a potential pharmacological solution for depression. This study also supported the development of α 4 β 2 nAChR antagonists towards neuropsychiatric dysfunctions.

Antidepressant Drug Discovery and Development: Mechanism and Drug Design Based on Small Molecules

“…[212] Moreover, VMY-2-95 exhibited antidepressant activity by significantly decreasing the immobility time in TST and FST, and increasing the sucrose preference percent in SPT in a corticosterone induced mice model. [213] The general of SARs of bearing 1-(alicyclic amine-2ylmethoxy)pyridin-5-yl scaffold were shown in Figure 26. Substituted pyridine ring was a core scaffold to discover novel nicotinic ligands which substituted by isoxazole ring was proved to display desired subtype selectivity profile.…”

“…[ 212 ] Moreover, VMY‐2‐95 exhibited antidepressant activity by significantly decreasing the immobility time in TST and FST, and increasing the sucrose preference percent in SPT in a corticosterone induced mice model. [ 213 ]…”

Essential oil from the roots of Paeonia lactiflora pall. has protective effect against corticosterone-induced depression in mice via modulation of PI3K/Akt signaling pathway

“…All the behavioral tests were performed between 20:30 and 06: 30 and the observers were blinded, meaning the behavioral test participants were unaware of the treatment the mice were receiving. Tail suspension test (TST) and forced swimming test (FST) were conducted 2 days before the end of the experiment, and sucrose preference test (SPT) and open pit test (OFT) were conducted 1 day before the end of the experiment (Yu et al, 2021).…”

“…Depression which characterized by increased negative and depressed mood and decreased positive anhedonia, is one of the most common presenting clinical psychiatric symptoms worldwide (McCarron et al, 2021;Xu et al, 2021). Owing to the increasing pressure from the fast-paced life and work, the prevalence of depression remains high with over than 15% of the people worldwide (Malhi and Mann, 2018;Yu et al, 2021). Depression would bring heavy burdens to individuals and their families in health, economy, work, and interpersonal relationships, etc.…”

“…Depression would bring heavy burdens to individuals and their families in health, economy, work, and interpersonal relationships, etc. Worse still, depression is prone to suicidal tendencies, which attracts considerable attention from the society (Oh et al, 2019;Yu et al, 2021). Although nowadays, some breakthroughs have been achieved in diagnosis of depression and clarification of its underlying pathological mechanisms, the therapeutical effect of depression remains unsatisfactory (Malhi and Mann, 2018).…”