Hepatoprotective effect of the tyrosine kinase inhibitor nilotinib against cyclosporine‐A induced liver injury in rats through blocking the Bax/Cytochrome C/caspase‐3 apoptotic signaling pathway. Issue 6 (12th March 2021)

• Record Type: Journal Article
• Authors: Serrya, Marwa S.; Nader, Manar A.; Abdelmageed, Marwa E.
• Is Part Of: Journal of biochemical and molecular toxicology. Volume 35:Issue 6(2021)
• Page Start: 1
• Page End: 13
• Publication Date: 2021-03-12
• Subjects: Bax -- caspase‐3 -- Cyclosporine‐A -- cytochrome‐C -- liver injury -- nilotinib -- oxidative stress -- TAC; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Toxicology -- Periodicals; 574
• DOI: 10.1002/jbt.22764
• Languages: English
• ISSNs: 1095-6670

Abstract

Abstract: Cyclosporine‐A (CsA) is a powerful immunosuppressive agent and hepatotoxicity results from CsA treatment. This study aimed to elucidate the effectiveness of tyrosine kinase inhibitor nilotinib against CsA‐induced hepatotoxicity and the underlying molecular mechanisms. Male Sprague‐Dawley rats were allocated into four groups and received drugs for 28 days as follows: Control group: received vehicle, Nilotinib group: received nilotinib (20 mg/kg orally), CsA group: received CsA by subcutaneous injection (20 mg/kg daily), CsA‐nilotinib: received nilotinib and CsA. Serum lactate dehydrogenase (LDH), liver function biomarkers, hepatic levels of oxidative stress biomarkers, nuclear factor erythroid‐2 like‐2 (Nrf2), total antioxidant capacity (TAC), interleukin‐2 (IL‐2), IL‐1β, IL‐6, and cytochrome‐ C were assessed. Additionally, the protein levels and mRNA expression of Bcl2 associated X protein (Bax), caspase‐3, nuclear factor‐κB (NF‐κB), hemoxygenase‐1 (HO‐1) were measured. Moreover, liver tissues were assessed histopathologically using hematoxylin–eosin and Masson trichrome stain. Nilotinib treatment decreased serum LDH, alanine aminotransferase, aspartate aminotransferase, and γ‐glutamyltransferase (γ‐GT), hepatic malondialdehyde, and cytochrome‐ C . It also increased superoxide dismutase, reduced glutathione, glutathione reductase, glutathione peroxidase, glutathione‐ S ‐transferase (GST), TAC, and Nrf2 compared to CsA‐injected rats. In addition, nilotinib decreased NF‐κB, IL‐1β, IL‐6, Bax, and caspase‐3, while elevated IL‐2 and immunoexpression of HO‐1. Additionally, mRNA expression of Bax and caspase‐3 was elevated and that of HO‐1 and inhibitory protein κB‐α was reduced in the nilotinib‐treated group. Moreover, nilotinib significantly attenuated CsA‐induced histopathological alterations. Nilotinib may have a promising role as a hepato‐protective through its antiapoptotic, antioxidant, and anti‐inflammatory effects. Research Highlights: Nilotinib has an ameliorative effect against Cyclosporine‐A‐induced liver injury. Nilotinib decreased serum LDH and ALT, AST, and γ‐GT. Nilotinib increased GSH, SOD, GR, GPx, GST, TAC, Nrf2, and HO‐1 levels Nilotinib decreased hepatic MDA, NF‐κB, IL‐1β, IL‐6, Bax, and caspase‐3 levels. Nilotinib attenuated Cyclosporine‐A‐induced histopathological alterations. Nilotinib raised Bax and caspase‐3 mRNA, lowered HO‐1 and NFκBia mRNA expression.