Protective effect of ambroxol on cyclophosphamide-induced intestinal damage: involvement of oxidative stress, inflammation, and Keap-1/Nrf2/HO-1 signaling

Abstract

Cyclophosphamide (CP) is an effective chemotherapeutic agent whose clinical efficacy is often limited by toxicity, including intestinal injury. Oxidative stress and inflammation are central to CP-induced tissue damage and represent a valuable target to attenuate intestinal injury. Ambroxol (ABX), a clinically approved mucolytic agent, has demonstrated antioxidant, anti-inflammatory, and mucoregulatory properties that may confer multi-organ protection. This study investigated the protective effects of ABX against CP-induced intestinal injury in rats, exploring the involvement of oxidative stress, inflammation and Keap-1/Nrf2/HO-1 signaling. Adult male rats received ABX (20 mg/kg/day) orally for seven consecutive days, with CP (100 mg/kg, i.p.) administered on the fifth day. CP induced significant intestinal injury manifested by intestinal mucosal atrophy, decreased length of villi and goblet cell depletion. CP triggered oxidative stress characterized by increased MDA and decreased GSH, SOD, and catalase, upregulated NF-κB, IL-6, and TNF-α, and increased caspase-3 expression in the intestine. ABX attenuated histopathological alterations, mitigated oxidative stress, suppressed NF-κB and cytokines, and downregulated caspase-3. In addition, ABX preserved intestinal goblet cells while modulating the Keap-1/Nrf2/HO-1 pathway in intestinal tissue. These findings demonstrate the protective role of ABX against CP-induced intestinal injury via antioxidant, anti-inflammatory, and mucoprotective mechanisms, supporting its potential repurposing as an adjuvant during CP chemotherapy. The protective mechanism of ABX involves its ability to modulate the Keap-1/Nrf2/HO-1 signaling pathway.