LAUSR

&NA; Riparin II (RIP II) is an alkamide isolated from Aniba riparia that has presented antidepressant and anxiolytic effects in acute stress behavioral models. This study aimed to investigate the activity of RIP II in a corticosterone‐induced depression mice model. Corticosterone (20 mg/kg, s.c.) was administered once a day for 21 days. RIP II (50 mg/kg, p.o.) or fluvoxamine (FLU, 50 mg/kg, standard antidepressant, p.o.) was administered after corticosterone (CORT) injection, for the last 7 days of CORT treatment. Mice were exposed to the following behavioral tests: forced swimming, tail suspension, open field, sucrose preference, elevated plus maze and ymaze. After behavioral evaluation, brain areas (prefrontal cortex, hippocampus and striatum) were dissected for neurochemical evaluation: oxidative stress parameters (MDA, nitrite and GSH) and BDNF dosage. Repeated CORT administration caused depressive‐like behavior in mice as indicated by increased despair effects in forced swimming and tail suspension tests and anhedonia in sucrose preference test. In addition, CORT decreased BDNF levels in the mice hippocampus and induced oxidative load in the brain with significative increase in pro‐oxidant markers (lipid peroxidation and nitrite levels) and a decline in anti‐oxidant defense system (reduced glutathione levels), indicating a direct effect of stress hormones in the induction of the brain oxidative stress. On the other hand, RIP II treatment reversed CORT‐induced depressive‐like behavior. Furthermore, this treatment reversed the impairment in BDNF levels and oxidative brain insults caused by CORT. This may demonstrate the mechanisms involved in antidepressant‐like effect of RIP II. These findings further support that RIP II may be implicated as pharmacological intervention targeting depression associated with HPA‐axis dysregulation. HighlightsChronic administration of corticosterone elicits a depressive‐like behavior in mice.Riparin II abolishes the depressive‐like behavior induced by corticosterone.Corticosterone administration decreases BDNF levels in the mice hippocampus.Riparin II reverses the decrease in BDNF levels in the mice hippocampus.Riparin II reverses the oxidative damage caused by corticosterone.