Rupatadine modulates TLR4/MYD88/NF-κB and AKT/PI3K signaling pathways, attenuating sepsis-induced liver injury in mice

One of the manifestations of sepsis-induced multiple organ damage is sepsis-associated liver injury. Acute liver injury (ALI) is a life-threatening acute inflammatory illness which involves acute hepatocytes damage and necrotic cell death. Aims: The aim of this study was to scrutinize the prophylactic impact of rupatadine (RUP) against lipopolysaccharide (LPS)-induced ALI in a mouse model. Main methods: Male Swiss albino mice (18-25 g) were treated with RUP at two different doses (3 and 6 mg/kg) orally for 5 days before single intraperitoneal injection of LPS (3 mg/kg). Liver enzymes were measured in the serum, while oxidative stress and inflammatory mediators were assessed in the hepatic tissue homogenates. Key findings: RUP significantly attenuated liver transaminases in serum and improved histopathological alterations. It also has an antioxidant activity indicated by reduced malondialdehyde (MDA) content and elevated reduced glutathione (GSH) level in hepatic tissues. Furthermore, hepatic expression of toll like receptor 4 (TLR4) and nuclear factor kappa Bp65 (NF-kappa Bp65) were markedly suppressed by RUP pretreatment. Moreover, RUP significantly decreased hepatic levels of myeloid differentiation primary-response protein 88 (MYD88), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and interleukin (IL)-6. Significance: RUP may be considered a novel therapeutic agent in sepsis-related liver injury pending further clinical studies.