A triazole-derived compound mitigates behavioral, biochemical, and molecular alterations in a chronic stress-induced depression model.

The increase in psychiatric disorders such as depression, largely associated with chronic stress exposure, highlights the need for safer and more effective therapeutic strategies. Compounds containing the triazole ring, such as 1-(2-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethan-1-one (ETAP), have gained attention due to their antidepressant potential. Previous studies demonstrated antidepressant-like effects of ETAP through different pathways. Based on these findings, the present study evaluated its protective effect in C57BL/6 male mice subjected to the chronic unpredictable mild stress (CUMS) model. CUMS exposure induced behavioral alterations associated with a depressive phenotype, including reduced sucrose preference, increased immobility in the forced swim test, and decreased grooming behavior in the splash test. These behavioral impairments were accompanied by increased corticosterone levels, oxidative damage indicated by elevated thiobarbituric acid reactive substances, increased hepatic transaminases and serum urea, and activation of inflammatory markers in the hippocampus and hypothalamus. At the molecular level, chronic stress reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and brain-derived neurotrophic factor (BDNF) in the prefrontal cortex, while intensifying inflammatory signaling in the hippocampus. ETAP administration prevented the development of depressive-like behaviors, preserved behavioral performance, and attenuated biochemical and molecular alterations induced by chronic stress. In addition, ETAP increased Nrf2 and BDNF expression in the prefrontal cortex even in non-stressed animals, suggesting intrinsic neuroprotective properties. Collectively, these findings demonstrate that ETAP exerts a preventive effect against chronic stress-induced behavioral and neurobiological dysfunctions, reinforcing its therapeutic potential as a multitarget antidepressant candidate.