Neuroprotective efficacy of methanolic extract of propolis against early life stress-induced oxidative and inflammatory damage: Involvement of the Nrf2-Keap1 signaling pathway.

Background: Early-life stress (ELS) is a major environmental risk factor for neurobehavioral impairments, including cognitive dysfunction, repetitive behaviors, and social deficits. Propolis, a natural bee product with strong antioxidant and anti-inflammatory properties, may counteract oxidative stress-related disorders. This study examined whether methanolic extract of propolis (MEP) mitigates ELS-induced oxidative and inflammatory damage in a maternal separation (MS) rat model, focusing on the Nrf2-Keap1 pathway. Methods: Male Wistar rats (200-220 g) were allocated to Control, Vehicle, Propolis (200 mg/kg), MS, and MS + Propolis (100 or 200 mg/kg) groups. ELS was induced by separating pups from dams for 3 h/day during postnatal days (P) 1-9. MEP was given orally from P21 to P42. Behavioral tests assessed social interaction, cognition, repetitive, and anxiety-like behaviors. Biochemical analyses measured antioxidant enzymes (SOD, CAT, GRx), glutathione, lipid peroxidation (MDA), and expression of Nrf2, Keap1, IL-6, and TNF-α. Results: MEP (100 and 200 mg/kg) improved social interaction (p < 0.05, p < 0.01), reduced repetitive behaviors (p < 0.001), and enhanced cognition (p < 0.05, p < 0.01) and anxiety-like behaviors (p < 0.001) in MS rats. Treatment increased SOD, CAT, and GRx activities (p < 0.01), elevated glutathione (p < 0.001), upregulated Nrf2 (p < 0.001), and reduced MDA (p < 0.001), IL-6, and TNF-α, with stronger effects at 200 mg/kg (p < 0.001). Conclusion: MEP alleviates oxidative and inflammatory responses induced by ELS, likely via Nrf2-Keap1 modulation, supporting its potential as a complementary therapy for stress-related neurobehavioral disorders.