Rupatadine Ameliorates Cisplatin‐Induced Hepatotoxicity in Rats: Targeting HMGB1/TLR4/NF‐κB and NLRP3/Caspase‐1 Signaling Pathways

Despite cisplatin (CISP) is broadly employed in cancer therapy, its adverse effects, involving hepatotoxicity, restrict its clinical usage. Thus, this study was designed to explore the prospect of repurposing rupatadine (RUPA), a dual antagonist of histamine and platelet-activating factor (PAF), against CISP-evoked hepatotoxicity in rats. Rats were i.p. injected with CISP (6 mg/kg) for the induction of hepatotoxicity on the 8th day of the study in the presence and absence of RUPA in two dosages (3, 6 mg/kg) orally for 14 days. Different biochemical parameters and histopathological assessments, along with the mechanistic characterizations of the possible protective impact of the RUPA were conducted. Administration of CISP evoked hepatic histopathological modifications and raised serum liver enzyme levels and hepatic MDA content, PAF, and histamine levels, along with diminishing the serum albumin level, hepatic SOD activity, and GSH level. Moreover, CISP remarkably augmented the levels of HMGB1, TLR4, p-NF-κB p65, IL-6, TNF-α, IL-18, IL-1β, NLRP3, and cleaved caspase-1 proteins with an evident decline in the level of IL-10. On the contrary, pretreatment with either RUPA.3 or RUPA.6 dramatically ameliorated these alterations triggered by CISP injection. RUPA counteracts hepatotoxicity evoked by CISP in rats via its anti-oxidative as well as anti-inflammatory properties via repression of hepatic HMGB1/TLR4/NF-κB and thus restricts the activation of NLRP3/caspase-1 signaling cascade.