Protective Effects of Curcuma longa L. on Corticosterone-Induced Neurotoxicity and Anti-Depression-Like Behavior: Involvement of NMDA and 5-HT7A Receptors.

Curcuma longa L. is a traditional medicinal plant known for its therapeutic potential in mental disorders, including depression. Previous studies have reported its antidepressant-like effects in animal models, primarily attributed to curcumin, its major bioactive compound. However, the underlying mechanisms of these effects remain poorly understood. In this study, we investigated the neuroprotective and antidepressant-like effects of C. longa through the N-methyl-D-aspartate (NMDA) receptor-linked corticosterone (CORT)-induced neurotoxicity pathway in primary cultured rat cortical neurons. Among various extraction methods tested, the 80% ethanol extract of C. longa (CL-80) exhibited the highest neuroprotective activity and the highest concentration of curcuminoids, including curcumin. Further fractionation of the CL-80 by polarity revealed that the n-butanol fraction (n-BuOH Fr.) demonstrated the most potent neuroprotective effect, with curcumin identified as the primary active constituent. Additionally, serotonin (5-hydroxytryptamine; 5-HT) receptor screening indicated that both the CL-80 and curcumin selectively modulate the 5-HT_7A receptor. In a restraint stress-induced depression mouse model, CL-80 and curcumin administration significantly mitigated stress-induced behavioral changes, including the prolongation of immobility time and reduction in climbing time during the forced swim test (FST). These findings suggest that C. longa exerts its antidepressant-like effects via modulation of NMDA and 5-HT_7A receptor-mediated pathways, highlighting its potential for development as a novel antidepressant agent.