Lapatinib mitigates acetic acid-induced ulcerative colitis and hepatic damage in rats.

Abstract

Ulcerative colitis (UC) is an inflammatory condition of the colon. In some cases, current treatments produce no response or may not be enough for remission, fostering a need for more effective medications. Tyrosine kinase inhibitors have shown to be effective in some inflammatory diseases. This study aimed to investigate the potential protective effect of lapatinib (LAP), a dual tyrosine kinase inhibitor, against acetic acid (AA)-induced UC in rats. Four groups were formed from twenty-four rats (6 rats each) as control, AA, AA + LAP (50 mg/kg) and AA + LAP (75 mg/kg). LAP (50 or 75 mg/kg/day) was administered orally for 7 days prior to induction of UC. On the 8th day, UC was induced by instillation of AA (4%) intrarectally. The rats were sacrificed 1 day following UC induction, colons and livers were collected for biochemical, histopathological and immunohistochemical examination. LAP markedly alleviated histological damage of both the colon and the liver. LAP effectively reduced the oxidative stress status by diminishing MDA, upregulating GSH and Nrf2 contents and enhancing SOD activity in colonic and hepatic tissues. Mechanistically, LAP significantly suppressed NF-κB p65 and TNF-α, pJAK2, pSTAT3 and the proinflammatory cytokines IL-17 and IL-23. Additionally, it decreased apoptosis by downregulating caspase-3 expression in colonic and hepatic tissues. Conclusion: LAP prevented AA-induced colitis and associated hepatic damage in rats, at least partially, via targeting IL-23/IL-17/JAK2/STAT3 axis., inhibiting NF-κB/TNF-α pathway, enhancement of Nrf2-mediated antioxidant defense, and suppression of caspase-3-dependent apoptosis.