Role of Nitric Oxide in the Antidepressant Effect of an Aqueous Extract of Punica granatum L.: Effects on GSH/GSSG Ratio and Lipoperoxidation in Adult Male Swiss Webster Mice

Depression is a prevalent psychiatric disorder in which oxidative stress and nitric oxide (NO) signaling have been implicated. Natural compounds such as <i>Punica granatum</i> have shown potential antidepressant effects, but their mechanisms remain unclear. This study aimed to evaluate the antidepressant-like effects of an aqueous extract of <i>P. granatum</i> in male Swiss Webster mice and to explore the possible involvement of NO-related system. Acute administration of <i>P. granatum</i> (0.25-2 mg/kg, i.p.) was tested in the forced swim and tail suspension tests. The interaction with NO signaling was examined through co-administration with an NO donor (sodium nitroprusside, SNP) and NOS inhibitors (NG-nitro-L-arginine methyl ester, L-NAME and 7-nitroindazole, 7-NI). Biochemical markers of oxidative stress (lipid peroxidation and GSH/GSSG ratio) were also assessed. <i>P. granatum</i> significantly reduced immobility and increased swimming behavior, consistent with an antidepressant-like effect. SNP, L-NAME, and 7-NI induced pro-depressant effects, which were prevented by <i>P. granatum</i> co-administration. Treatment also attenuated oxidative stress markers in the hippocampus and prefrontal cortex. These findings suggest that the antidepressant-like effects of <i>P. granatum</i> may involve interactions with NO signaling, although this interpretation remains indirect, as specific NO pathway indices were not measured. Acute <i>P. granatum</i> administration exerts antidepressant-like and antioxidant effects in male mice. The results support its potential as a natural candidate for depression treatment, particularly in conditions associated with oxidative imbalance and possible NO dysregulation. Future studies should confirm these mechanisms using direct molecular assessments and include female cohorts.