Antidepressant Effects of p-Coumaric Acid in Mice: Role of NMDA Receptors and Nitric Oxide Pathways

Introduction: Antidepressant medications have various complications. p-Coumaric acid (PCA), a phenolic compound, was investigated for its antidepressant effects and the impacts of N-methyl-D-aspartate acid (NMDA) receptors and nitric oxide (NO). Methods: Ninety-six mice were divided into 12 groups: Group 1 (normal saline), Groups 2–4 (PCA at 10, 50, and 100 mg/kg), Group 5 (NO precursor L-arginine at 750 mg/kg), Group 6 (NO antagonist L-NAME at 10 mg/kg), Group 7 (NMDA receptor agonist at 150 mg/kg), Group 8 (NMDA receptor antagonist ketamine at 3 mg/kg), Groups 9–12 (combinations of PCA with LArg, L-NAME, NMDA agonist, or antagonist). Drugs were administered intraperitoneally 30 minutes before tests, with agonists/antagonists given 15 minutes earlier. Behavioral and biochemical assessments were analyzed using RT-PCR and SPSS16. Results: PCA at 50 mg/kg reduced immobility time, serum and brain malondialdehyde (MDA) and NO levels, and expression of inducible nitric oxide synthase (iNOS), neuronal NO synthase (nNOS), NR2A, and NR2B, while increasing grooming time and total antioxidant capacity (TAC) (p<0.05). NMDA receptor agonist co-administration reversed these effects, while the ineffective CA dose with ketamine partially modulated NMDA receptor expression (p<0.05). Discussion: PCA showed antidepressant-like effects by reducing oxidative stress and modulating NO and NMDA receptor activity, aligning with existing literature. Limitations include shortterm design and limited behavioral tests. Future studies should assess long-term effects and underlying mechanisms. Conclusion: PCA alleviated depression-like behaviors, suggesting a potential role for CA in mood regulation by enhancing antioxidant capacity and lowering MDA levels while regulating NMDA receptor activity and NO levels.