Berberine attenuates methotrexate-induced renal and sciatic nerve toxicity via modulation of the cGAS-STING/NF-κB...

Methotrexate (MTX) is an extensively used chemotherapeutic and anti-inflammatory agent, but its therapeutic application is limited by toxicity affecting multiple organs, primarily the kidneys and sciatic nerve. Berberine (BBR) is known for its potent antioxidant, anti-inflammatory, and cytoprotective properties. This study aims to explore the protective effects of BBR on MTX-induced nephrotoxicity and neurotoxicity.

Twenty-four male Wistar rats (180-200 g) were randomly assigned to four groups (n = 6): Control, BBR (50 mg/kg/day), MTX (single intraperitoneal dose of 20 mg/kg on day 5), and MTX + BBR. Kidney function parameters, oxidative stress markers, histopathological changes, and inflammatory mediators related to the cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) pathway were evaluated in kidney and sciatic nerve tissues.

BBR treatment significantly ameliorated renal impairment, indicated by reduced serum creatinine and urea concentrations, and mitigated histopathological injury in both renal and sciatic nerve tissues. Additionally, BBR attenuated oxidative stress by lowering malondialdehyde (MDA) levels and increasing glutathione (GSH) content and superoxide dismutase (SOD) activity. Significantly, BBR inhibited inflammation by downregulating cGAS mRNA expression and reducing p-STING, interferon regulatory factor-3 (p-IRF3) levels, nuclear factor kappa-B (NF-κB p65), and type-I interferons-α (IFN-α) protein expression. This led to decreased interleukin (IL)-6 and IL-1β and increased IL-10 concentrations.

These results highlight the role of BBR against MTX-induced nephrotoxicity and neurotoxicity. The beneficial effects of BBR are partly mediated by modulation of the cGAS-STING/NF-κB pathway, leading to reduced inflammation and oxidative damage in both kidney and sciatic nerve tissues.