Saxagliptin mitigates doxorubicin-induced cardiotoxicity by modulating NLRP3/caspase-1/IL-1β and TLR-4/NF-κB pathways

Doxorubicin (DOX) is a powerful anthracycline utilized in the management of several malignant disorders, involving both solid and hematological tumors. Despite its effectiveness as cytotoxic agent, its therapeutic use is restricted as cardiac toxicity proportional to the drug dosage. Saxagliptin (SAXA) is a selective and potent member of the dipeptidyl peptidase (DPP)-IV inhibitor family utilized in the management of type two diabetes. It also possesses several biological actions, involving anti-inflammatory and antioxidant properties. This work sought to ascertain the underlying molecular mechanisms and determine the shielding role of SAXA against DOX-induced cardiotoxicity. Thirty-two rats were randomly assigned to four experimental groups, including a normal control group administered the vehicle only, a SAXA group receiving SAXA alone (10 mg/kg), a DOX control group receiving DOX (20 mg/kg) as a single dose, and a SAXA treatment group receiving SAXA plus DOX. Compared to DOX control group, pretreatment with SAXA (10 mg/kg) significantly reduced serum concentrations of CK-MB and CTnI by 37.11 % and 46.32 %, respectively, in addition to a marked improvement in the histopathological features of heart tissues. Moreover, SAXA significantly decreased MDA by 56.05 % and increased GSH and SOD in DOX-intoxicated rats by 493.28 % and 458.32 %, respectively. Additionally, western blot analysis revealed that SAXA pretreatment significantly down-regulated TLR-4 and NLRP3 by 34.9 % and 33.99 %, respectively. Furthermore, ELISA analysis showed that SAXA pretreatment significantly down-regulated NF-κB, caspase-1, and IL-1β by 44.04 %, 78.7 %, and 57.7 %, respectively. The findings of this study suggest that SAXA may exert a cardioprotective effect against DOX-induced toxicity, likely through its antioxidant and anti-inflammatory properties.