Curcumin Ameliorates Depressive-like Behaviors by Modulating mGluR2/PGC-1α-Mediated Glutamatergic Homeostasis and...

Curcumin (CUR), a natural polyphenolic compound from Curcuma longa L., exhibits anti-inflammatory, anti-oxidative, and antidepressant properties. However, the underlying antidepressant mechanisms of CUR remain unclear. Here, we used corticosterone (CORT) to establish the cellular injury and mouse depressive models to investigate CUR's protective activities. The neuroprotective effects of CUR on cells and antidepressant effects on mice were evaluated through a series of biochemical assays and behavior tests. Furthermore, the metabotropic glutamate receptor 2 (mGluR2) overexpression plasmid and siRNA-mGluR2 were separately transfected into PC12 cells to investigate the role of mGluR2 in CUR's neuroprotection. Additionally, a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) inhibitor was used to confirm the mediating effect of mGluR2 on PGC-1α. Glutamatergic and mitochondrial-related parameters were also measured to validate CUR's protective mechanisms. Results showed that CUR intervention significantly normalized CORT-induced injuries in PC12 and depressive phenotypes in C57BL/6, restoring the mGluR2 and PGC-1α expressions repressed by CORT. mGluR2 knockdown blunted CUR's protection and aggravated CORT's effects, while mGluR2 overexpression alleviated CORT-induced injury, an effect abolished by PGC-1α inhibition, confirming mGluR2's functional role and dependence on the mGluR2/PGC-1α axis. Additionally, CUR normalized CORT-disturbed glutamate, reactive oxygen species (ROS), C-reactive protein (CRP), serotonin (5-HT) levels, mitochondrial membrane potential/morphology, and inhibited microglial activation/NF-κB signaling, confirming its effects in maintaining glutamatergic and mitochondrial homeostasis. In conclusion, CUR alleviated CORT-induced neuroinjury and depressive phenotypes by restoring mGluR2/PGC-1α signaling and maintaining glutamatergic homeostasis and mitochondrial function. Our work provides novel insights into CUR-mediated antidepressant mechanisms and underscores its therapeutic potential in depression.