Antidepressant effects of 3‐(3,4‐methylenedioxy‐5‐trifluoromethyl phenyl)‐2E‐propenoic acid isobutyl amide involve TSPO‐mediated mitophagy signalling pathway

Abstract

Piper laetispicum C. DC is one of the Chinese herbal medicines used for alleviating depressive disorders. G11-5 [3-(3, 4-methylenedioxy-5-trifluoromethyl phenyl)-2Epropenoic acid isobutyl amide] is synthesized based on the chemical structure of an active integrant of Piper laetispicum C. DC. The present study assessed the antidepressant effect of G11-5 and investigated the underlying mechanism with learned helplessness (LH) and social defeat stress (SDS) mice model of depression. In the LH model, mice were exposed to 60 inescapable electric shocks once a day for three consecutive days followed by 2-week drug administration and helpless behaviour assessment. In the SDS model, mice were subjected to repeated social defeat by an aggressive CD-1 mouse once a day for consecutive 10 days. Following oral administration for 2 weeks, the mice were subjected to a series of behavioural tests including social interaction test. G11-5 significantly decreased the number of escape failures induced by LH paradigm, meanwhile increased the social interaction ratio and shortened the immobility time in forced swimming test for the SDS-exposed mice, suggesting remarkable antidepressant effect. Moreover, G11-5 ameliorated the changes in mitophagy-related proteins induced by two stress exposures and restored retrograde axonal transport and neurotransmitter release. Our findings suggested that G11-5 exhibited an obvious antidepressant through TSPO-mediated mitophagy pathway.

A 6-week, phase IIb, randomized, double-blind, placebo-controlled trial of Anyu Peibo capsules for the treatment of major depressive disorder in adults

“…DC., exhibited a significant antidepressant effect through the TSPO-mediated mitophagy pathway. 28 Therefore, these studies clearly demonstrate that Piper laetispicum C. Dc. and its extract may have antidepressant effects.…”

Targeting mitophagy for depression amelioration: a novel therapeutic strategy

“…Studies have revealed inhibited mitophagy levels in animal models of depression induced by learned helplessness (LH) and social defeat stress (SDS). These models showed substantial decreases in the expression of key proteins involved in mitophagy such as TSPO, Parkin, VDAC1, and the autophagy initiator protein Beclin-1 (Li et al, 2016;Wei et al, 2020). Similarly, mitophagy suppression was observed in the hippocampus of rats induced with chronic CUMS.…”

“…G11-5 can improve depression-like behavior in LH and SDS mice, and leads to an increased success rate for electric shock escape and greater total distance traveled during OFT movement, as well as reduced FST immobility time. Furthermore, G11-5 regulated mitophagy levels and increasing the expression of TSPO, Parkin, VDAC1, and autophagy promoter Beclin-1 in the brain of LH mice (Wei et al, 2020). Microglia are the resident immune surveillance cells of the central nervous system (von Bernhardi et al, 2016).…”

Identification of mitophagy-related biomarkers and immune infiltration in major depressive disorder

“…Several studies have reported that mitophagy and subsequent mitochondrial dysfunction are significant contributors to the pathophysiology of MDD [ 9 – 11 ]. Mitophagy has also been considered the emerging mechanism of action for some antidepressants [ 12 , 13 ]. Shu et al discovered that the antidepressant fluoxetine protects astrocytes by enhancing astrocytic mitophagy and removing damaged mitochondria in a corticosteroid-treated cell model [ 12 ].…”