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

Sabah Ali Alzahrani; Gamal M Bekhet; Rebai Ben Ammar; Basem M Abdallah; Enas Mohamed Ali; Saeed Y Al-Ramadan; Duaa Althumairy; Peramaiyan Rajendran

doi:10.4103/sjmms.sjmms_225_23

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

Saudi J Med Med Sci. 2024 Jan-Mar;12(1):17-26. doi: 10.4103/sjmms.sjmms_225_23. Epub 2024 Jan 15.

Authors

Sabah Ali Alzahrani¹, Gamal M Bekhet^{1

2}, Rebai Ben Ammar^{1

3}, Basem M Abdallah¹, Enas Mohamed Ali^{1

4}, Saeed Y Al-Ramadan⁵, Duaa Althumairy¹, Peramaiyan Rajendran^{1

6}

Affiliations

¹ Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa, Saudi Arabia.
² Department of Zoology, Faculty of Science, Alexandria University Egypt, Alexandria, Egypt.
³ Laboratory of Aromatic and Medicinal Plants, Center of Biotechnology of Borj Cedria, Hammam-Lif, Tunisia.
⁴ Department of Botany and Microbiology, Faculty of Science, Cairo University, Cairo, Egypt.
⁵ Department of Anatomy, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia.
⁶ Department of Biochemistry, Centre of Molecular Medicine and Diagnostics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India.

Abstract

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.

Keywords: Carbon tetrachloride; geraniol; oxidative stress; phosphoinositide 3-kinases/protein kinase B; pregnant.