Nerve growth factor acts as a modulator on the p38 MAPK pathway in copper-induced liver damage

Background: Copper (Cu) toxicity induces oxidative and nitrosative stress in hepatocytes, leading to inflammation and Apoptosis. Nerve Growth Factor (NGF), known for its neuroprotective properties, may influence liver tissue via the p38 MAPK pathway; however, its role in Cu-induced hepatotoxicity remains unclear, and hence the aim of this study is to investigate the protective role of exogenous NGF in a Cu-induced liver injury model in mice, with a focus on p38 MAPK pathway.

Methods: Sixty-four adult male BALB/c mice were equally divided into eight groups, with each group receiving intraperitoneal injections 3 times at 24 h intervals of their respective substances at the following doses: 0.9 % NaCl (Control), 10 µg/kg NGF (NGF), 20 mg/kg SB203580 (p38MAPKi), 10 µg/kg NGF + 20 mg/kg SB203580 (NGF+p38MAPKi), 20 mg/kg CuSO₄ (Cu), 20 mg/kg CuSO₄ + 10 µg/kg NGF (Cu+NGF), 20 mg/kg CuSO₄ + 20 mg/kg SB203580 (Cu+p38MAPKi), and 20 mg/kg CuSO₄ + 10 µg/kg NGF + 20 mg/kg SB203580 (Cu+NGF+p38MAPKi). Liver tissues were analyzed using histopathological, immunohistochemical, biochemical, and molecular methods.

Results: CuSO₄ exposure caused severe hepatic damage, evidenced by hydropic degeneration, focal necrosis, and elevated Apoptosis (Caspase 3 and 8). It also increased ALT/AST levels and oxidative/nitrosative stress markers (MDA, TOC, iNOS, nitrotyrosine), while reducing antioxidant markers (GSH, TAC). NGF administration significantly ameliorated these alterations, improved antioxidant status, and reduced pro-inflammatory cytokines (IL-1, IL-6, TNF-α). These effects were abrogated by co-treatment with SB203580, implicating p38 MAPK involvement.

Conclusion: NGF exerts hepatoprotective effects against Cu-induced toxicity by modulating oxidative stress, inflammation, and Apoptosis through the p38 MAPK signaling pathway. These findings underscore NGF's potential as a therapeutic candidate for oxidative liver injuries.

Copper; Hepatotoxicity; Nerve Growth Factor (NGF); P38 MAPK; SB203580.