The Inhibitory Effect of Geraniol on CCL4-induced Hepatorenal Toxicity in Pregnant Mice through the PI3K/AKT Signaling Pathway.

Background: Hepatotoxicity caused by CCL₄ is well known. Geraniol (GNL) has high antioxidant effect that can induces liver regeneration. However, the protective effect of GNL effect on CCL₄-induced hepatorenal toxicity in pregnant mice has not yet been studied.

Objective: To investigate whether GNL could protect against oxidative stress induced by CCL₄ via the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which is regulated by phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), and has been found to have protective effects on renal and hepatic tissues.

Materials and methods: Forty-eight female albino mice weighing 25-30 g were randomly allocated to 4 groups: Group I served as a control; Group II received a toxicity-inducing single dose of 15 μL of CCL₄ on the 4^th day after mating; Group III received 40 mg/kg GNL + CCL₄ (with GNL from the 1^st day of assimilation to delivery); and Group IV received GNL alone from the 1^st day of assimilation to the end of the delivery period. GNL was evaluated for its protective effects on hepatotoxicity in CCL₄-treated pregnant mice. Litter size, weight, survival rate, and resorption were recorded. In addition, H & E staining was done for liver and kidney pathology as well as biochemical markers and oxidative markers malondialdehyde, superoxide dismutase, and catalase were analyzed.

Results: CCL₄ significantly reduced survival rate and increased resorption after exposure. Alanine transaminase and aspartate aminotransferase concentrations in the serum, tissue MDA, blood urea nitrogen, and creatinine were increased after CCL₄ exposure. GNL improved enzyme and antioxidant levels and prevented CCL₄-induced hepatic injury in mice. Caspase-3 cleavage was decreased by GNL, which increased PI3K, phosphorylated AKT, Nrf2, and B-cell lymphoma 2.

Conclusion: GNL demonstrates a protective effect against CCl4-induced hepatorenal toxicity, mediated through the activation of the PI3K/AKT signaling pathway and the upregulation of Nrf2. These findings highlight the potential therapeutic implications of GNL in mitigating oxidative stress and inflammation in liver and kidney tissues.