Piper laetispicum C.DC is one of Chinese Herbal Medicine used for alleviating depressive disorders. G11-5 [3-(3, 4-Methylenedioxy-5-trifluoromethyl phenyl)-2E-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 model (SDS) mice model of depression. In the LH model, mice were exposed to 60 inescapable electric shock 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 test 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 of 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.

Keywords: Piper laetispicum; depression; learned helplessness; mitochondria; mitophagy; social defeat stress.