Repurposing of rebamipide as a neuroprotective agent to alleviate letrozole-induced depressive-like behaviors in female rats: Targeting SIRT1/FoxO1/wnt/ β-catenin, and related ferroptosis pathways.

Aims: Polycystic ovarian syndrome (PCOS) is a hormonal disorder affecting females worldwide. PCOS is associated with the development of depression, which is exacerbated by oxidative stress, neuro-inflammation, and ferropotosis. Rebamipide (Reba) is a potent antioxidant agent exhibiting cytoprotective effects. Reba notably activates SIRT1, which in turn plays a major role in ameliorating cellular iron deposition, thus preventing ferooptosis-related cell death. This study aimed to elucidate the neuroprotective effects of Reba against letrozole-induced depressive-like behaviour in female rats and further explore the role of SIRT1/FoxO/wnt/β-catenin and related ferroptosis pathways.

Materials And Methods: Forty female Wistar rats were allocated into four groups: control group, a letrozole-treated group (1 mg/kg/day, p.o.), a Reba-treated group (80 mg/kg/day, p.o.) and a group receiving niacinamide (NAM), a selective SIRT1 blocker (100 mg/kg/day, i.p.) in addition to Reba.

Key Findings: Reba restored the normal morphological structure of the hippocampi with significant improvement in the rats' behaviors. Reba up-regulated SIRT1, a key regulator of numerous antioxidant and anti-inflammatory cascades, including Nrf2, SOD, and HO-1. The anti-inflammatory activity of SIRT-1 was revealed by the downregulation of NF-κB-p65, TNF-α, and NLRP3 inflammasome, as well as the upregulation of FoxO/wnt/β-catenin signaling. Furthermore, the anti-ferroptosis effects were demonstrated by the inhibition of total iron and ferrous levels as well as the upregulation of Gpx4 and SLC7A11 genes. Pre-treatment with NAM abolished Reba's neuroprotective effects.

Significance: Reba has a major neuroprotective role via activating SIRT1 and inhibiting related oxidative, neuroinflammatory, and ferroptosis pathways.