Abstract

SECUKINUMAB PREVENT CISPLATIN-PROVOKED HEPATOTOXICITY VIA RESTRAINING OF IL-6–MEDIATED INFLAMMATION AND ALTERATION OF P62-RELATED AUTOPHAGY IN RATS

Faiz N. Alenezi, Marwa E. Abdelmageed, Marwa S. Zaghloul, Manar A. Nader*

ABSTRACT

Cisplatin, a successful chemotherapeutic drug broadly used versus many malignancies, clinical use is frequently restrained by severe adverse effects, comprising hepatotoxicity. Inflammatory cytokines, principally interleukin-17A (IL-17A), may contribute to cisplatin-provoked hepatic injury. Secukinumab, a monoclonal antibody against IL-17A, may provide a protecting strategy against hepatotoxicity. Current work directed to examine the possible hepatoprotective effect of secukinumab versus cisplatin- stimulated liver damage in rats. Thirty adults male Wistar rats were randomly allocated into five groups: control, secukinumab control, cisplatin, secukinumab (10 mg/kg) + cisplatin, and secukinumab (20 mg/kg) + cisplatin. A single Cisplatin injection was delivered by I.P. dose (8 mg/kg). After three days, ALT, AST, and LDH were assessed. Histopathological and immunohistochemical for IL-6 and P62 expression were processed on liver specimens. Meaningful uprise in serum ALT, AST, and LDH levels upon Cisplatin administration and noticeable tissue damage evident by histopathology modifications, comprising hepatocellular degeneration, necrosis, and inflammatory infiltration. hepatic IL-6 and P62 expression were also elevated after Cisplatin administration. Pre-management with secukinumab considerably remodeled these biochemical and histological irregularities in a dose-increasing manner, with the superior dose displayed exclusive defense. Secukinumab noticeably diminished IL-6 immunoreactivity and mitigated P62 accumulation. Secukinumab revealed a substantial defensive action versus cisplatin-provoked hepatic injury, possibly via squashing of inflammatory signaling and improvement of autophagic dysfunction. These outcomes highpoint the prospective of IL-17A blocking as a repurposed therapeutic plan for decreasing chemotherapy-related hepatic damage.

Keywords: Cisplatin; Hepatotoxicity; Secukinumab; IL-17A; IL-6; P62; Autophagy.