The protective role of two oxindole derivatives is mediated by modulating NLRP3/caspase-1 and PI3K/AKT pathways in a preclinical animal model of hepatic ischemia reperfusion injury

• Published in: Life sciences (1973) Vol. 352; p. 122872
• Main Authors: Eldafashi, Nardeen, Waaz, Shaimaa, Ali, Taha F.S., Zaki, Marco Y.W., Nazmy, Maiiada Hassan, Fathy, Moustafa
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.09.2024
• Subjects: Animals; Caspase 1 - metabolism; Disease Models, Animal; Hepatic ischemia reperfusion injury; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Diseases - drug therapy; Liver Diseases - metabolism; Liver Diseases - pathology; Liver Diseases - prevention & control; Male; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3/Caspase-1; Oxidative stress; Oxidative Stress - drug effects; Oxindole derivatives; Oxindoles - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; PI3K/AKT; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Wistar; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Signal Transduction - drug effects; TNF-α; NLRP3/Caspase-1; Oxidative stress; Oxindole derivatives; TNF-α; Hepatic ischemia reperfusion injury; PI3K/AKT
• ISSN: 0024-3205; 1879-0631; 1879-0631
• DOI: 10.1016/j.lfs.2024.122872

Aim Hepatic ischemia reperfusion injury (HIRI) is a leading cause of mortality post liver transplantation, hypovolemic shock and trauma. In this study, we tested, on molecular bases, the possible protective role of two different derivatives of 2-oxindole in a preclinical model of HIRI in rats. HIRI was operated in male Wistar albino rats and prophylactic treatment with oxindole-curcumin (Coxi) or oxindole-vanillin (Voxi) was carried out before the operation. The biochemical and histopathological investigations, in addition to the mechanistic characterizations of the effect of the tested drugs were performed. HIRI was assured with elevated liver enzymes and marked changes in histopathological features, inflammatory response and oxidative stress. Pretreatment with Coxi and Voxi improved the hepatic histopathological alterations, reduced the elevated serum liver enzymes level and hepatic Malondialdehyde (MDA) content, increased the hepatic Superoxide Dismutase (SOD) activity and reduced Glutathione (GSH) content, downregulated the expression of TNF-α, IL-6, Nod-Like Receptor p3 (NLRP3), Cleaved caspase1, Cleaved caspase 3 proteins, alongside the expression level of IL-1β, ICAM-1, VCAM-1 and BAX genes, attenuated NF-кB p-P65 Ser536 and Myeloperoxidase (MPO)-positive neutrophils, and activated the PI3K/AKT pathway. Coxi and Voxi have promising hepatoprotective activity against HIRI in rats through ameliorating the biochemical and histopathological alterations, attenuating inflammatory and oxidative stress status by modulating the inflammatory TNF-α/ICAM-1, the pyroptosis NLRP3/Caspase-1, and the antioxidant PI3K/AKT pathways. [Display omitted]