# 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

## TL;DR

Punica granatum extract shows antidepressant-like effects in mice, possibly through nitric oxide signaling and antioxidant actions.

## Contribution

The study explores the antidepressant mechanism of Punica granatum extract, linking it to nitric oxide signaling and oxidative stress reduction.

## Key findings

- Punica granatum reduced immobility and increased swimming behavior in mice, indicating antidepressant-like effects.
- The extract attenuated oxidative stress markers in the hippocampus and prefrontal cortex.
- Co-administration with NO donor or inhibitors prevented pro-depressant effects, suggesting NO signaling involvement.

## Abstract

Depression is a prevalent psychiatric disorder in which oxidative stress and nitric oxide (NO) signaling have been implicated. Natural compounds such as Punica granatum have shown potential antidepressant effects, but their mechanisms remain unclear. This study aimed to evaluate the antidepressant-like effects of an aqueous extract of P. granatum in male Swiss Webster mice and to explore the possible involvement of NO-related system. Acute administration of P. granatum (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. P. granatum 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 P. granatum co-administration. Treatment also attenuated oxidative stress markers in the hippocampus and prefrontal cortex. These findings suggest that the antidepressant-like effects of P. granatum may involve interactions with NO signaling, although this interpretation remains indirect, as specific NO pathway indices were not measured. Acute P. granatum 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.