Liraglutide Ameliorates Methotrexate‐Induced Cardiotoxicity in Rats: Modulation of Oxidative Stress, Autophagy, and the TNF‐α/NF‐κB Signaling Inflammatory Pathway

Methotrexate (MTX) is mostly used to treat different types of malignancies, but unfortunately, it also has fatal cytotoxic effects on many organs, including the heart. Liraglutide (LIR) is known to exhibit anti-inflammatory and cardioprotective effects. Therefore, our study aimed to explore the possible cardioameliorative effects of two different dosages of LIR on MTX-induced cardiotoxicity in rats. Four groups of rats were divided into a control group, a group that received a single dose of 20 mg/kg of MTX by intraperitoneal injection (ip) (MTX-alone group), a group that received a subcutaneous (sc) dosage of 0.2 mg/kg/day of LIR for 2 weeks (low-dose LIR group), and a group that received a sc dosage of 0.4 mg/kg/day of LIR for 2 weeks (high-dose LIR group). The latter two groups were given MTX on day 10. After 2 weeks, each group was assessed by an electrocardiography (ECG) and by measuring serum levels of cardiac enzymes and histopathological and caspase-3 immunohistochemical levels in heart tissues. In addition, cardiac tissue was evaluated for oxidative stress and inflammatory and apoptotic markers. When compared with the MTX-alone group, the LIR-treated groups had improved ECG results and significantly decreased levels of the cardiac enzyme malondialdehyde (creatine kinase (CK) and troponin), autophagy markers (including the microtubule-associated proteins 1 A/1B light chain 3B MAP1LC3B and Beclin-1), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β). The LIR-treated groups also had significantly increased superoxide dismutase activity compared with the MTX-alone group. In addition, the LIR-treated groups had much less cardiac tissue destruction and had mitigated the increased caspase-3 immunoexpression that had been produced by MTX. These improvements were greater in the group that received the higher dosage of LIR than in the group that received the lower dosage of LIR. In conclusion, LIR improved MTX-induced cardiotoxicity more significantly at a dosage of 0.4 mg/kg/day, probably through the interruption of oxidative stress and autophagy pathways and the activation alleviation of inflammatory cytokines.