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

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.

Ameliorative effects of vitamins-loaded flavoured nanophytosomes fortified with star anise volatile oil against CsA-Induced liver and kidney injury in rats: Application in functional ice cream

“…The important antioxidant GSH, which helps keep mitochondria and cell membranes healthy by converting lipid peroxides into harmless byproducts, is similarly decreased by cyclosporine-A administration. Additionally, the antioxidant enzyme activity of GST, SOD, reduced glutathione, glutathione peroxidase, and glutathione reductase are decreased by cyclosporine-A [ 58 ]. To regulate the effects of cyclosporine-A, ROS elimination is therefore regarded as a crucial target.…”

Effects of Yinzhihuang on Alleviating Cyclosporine A-Induced Cholestatic Liver Injury <i>via</i> Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes <i>in Vitro</i> and <i>in Vivo</i>

“…2) However, its usage was limited due to cholestatic liver injury. 3,4) Cholestasis contributed to the intrahepatic retention of cytotoxic bile acids and bilirubin, which eventually could result in liver injury. 5,6) The accumulation of bile acids and bilirubin was related to dysfunction and altered expression of partial hepatic transporters and metabolic enzymes.…”