Curcumin Relieves Chronic Unpredictable Mild Stress-Induced Depression-Like Behavior through the PGC-1 alpha/FNDC5/BDNF Pathway

Background and Aim. Increasing evidence suggests that the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha)/fibronectin type III domain-containing 5 (FNDC5)/brain-derived neurotrophic factor (BDNF) pathway might be critical for neuroprotection. Our present study is aimed at investigating the antidepressant-like effects of curcumin (CUR) in a chronic unpredictable mild stress- (CUMS-) induced depression rat model and explore whether the PGC-1 alpha/FNDC5/BDNF pathway is the major driving force behind the therapeutic effects of CUR. Methods. All rats were randomly divided into four groups, namely, control, CUMS, CUMS+CUR, and CUMS+CUR+SR18292 (PGC-1 alpha inhibitor). Behavioral tests were conducted to assess the antidepressant-like effects of CUR. The expressions of PGC-1 alpha, estrogen-related receptor alpha (ERR alpha), FNDC5, and BDNF were determined to investigate the regulatory effects of CUR on the PGC-1 alpha/FNDC5/BDNF pathway. The PGC-1 alpha inhibitor SR18292 was used to explore the role of PGC-1 alpha in the induction of BDNF by CUR. Results. Daily gavage of 100 mg/kg CUR successfully attenuated the abnormal behaviors induced by CUMS and effectively prevented CUMS-induced reduction of PGC-1 alpha, ERR alpha, FNDC5, and BDNF expressions. CUR also enhanced PGC-1 alpha and ERR alpha translocation from cytoplasm to nucleus. Furthermore, we found that CUR supplementation effectively promoted neurocyte proliferation and suppressed neuronal apoptosis induced by CUMS. Of note, the PGC-1 alpha inhibitor SR18292 remarkably reversed the beneficial effects of CUR on depressed rats, indicating an important role of PGC-1 alpha in the antidepressant-like effects of CUR. Conclusion. Collectively, our data evaluating the neuroprotective action of CUR in the CUMS rats highlights the involvement of the PGC-1 alpha/FNDC5/BDNF pathway in the antidepressant-like effects of CUR.