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)‐2 E ‐propenoic 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.