BS29 Ambroxol attenuates cyclophosphamide cardiotoxicity by suppressing NF-κB/NLRP3 inflammasome axis and oxidative stress, and upregulating NRF2/HO-1 signalling

Mahmoud, Ayman M ORCID: https://orcid.org/0000-0003-0279-6500 and Hassanein, Emad HM (2025) BS29 Ambroxol attenuates cyclophosphamide cardiotoxicity by suppressing NF-κB/NLRP3 inflammasome axis and oxidative stress, and upregulating NRF2/HO-1 signalling. In: Heart, A258-A259. Presented at British Cardiovascular Society Annual Conference, 2 June - 4 June 2025, Manchester Central Convention Complex, Manchester, UK.

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Abstract

Background Advances in cancer treatment have significantly improved patient prognosis, but cardiovascular complications of chemotherapies remain a major challenge in patient management. Cyclophosphamide (CP) is an alkylating chemotherapeutic agent used in the treatment of various types of cancers and autoimmune conditions. However, acute cardiotoxicity is an adverse effect that limits its clinical use. Ambroxol is a mucolytic agent with emerging anti-inflammatory and antioxidant properties. This study aimed to investigate whether ambroxol attenuates CP-induced acute cardiotoxicity by mitigating oxidative stress, and modulating NF-κB/NLRP3 inflammasome axis and Keap1/Nrf2/HO-1 signalling in rats. Methods Male Wistar rats received ambroxol via oral gavage for 7 days and a single intraperitoneal injection of CP (100 mg/kg body weight) on day 5. Blood and heart samples were collected for biochemical, histopathological, and immunohistochemical assays. The binding affinity of ambroxol towards NF-κB p65, NLRP3 pyrin domain (PYD), ASC PYD, Keap1, and HO-1 was explored in silico. Results CP administration caused myocardial injury evidenced by elevated serum CK-MB, AST and cardiac troponin I along with histopathological alterations, including congested and dilated blood vessels, hypertrophied muscle with enlarged nuclei, vacuolated cytoplasm, hypereosinophilic myocytes with pyknotic nuclei, and increased collagen deposition. CP increased malondialdehyde (MDA) and decreased enzymatic and non-enzymatic antioxidants in the heart of rats. Ambroxol significantly alleviated CP-induced cardiotoxicity, as evidenced by alleviated serum cardiac markers and prevention of histopathological alterations. Ambroxol suppressed oxidative stress by decreasing MDA and increasing GSH content, and SOD and catalase activities. The protective effect of ambroxol was associated with downregulation of NF-κB, NLRP3, ASC, caspase-1, interleukin-1β, gasdermin, and Keap1, while upregulating Nrf2 and HO-1. In silico molecular docking revealed the binding affinity of ambroxol to NF-κB p65, ASC PYD, NLRP3 PYD, Keap1, and HO-1. Conclusion Ambroxol attenuates CP-induced cardiotoxicity by suppressing oxidative stress and NF-κB/NLRP3 inflammasome axis and enhancing Nrf2/HO-1 signalling. These findings highlight the potential of ambroxol as a therapeutic adjunct to mitigate CP acute cardiotoxicity, offering a promising strategy to improve patient outcomes.