Linagliptin attenuates cisplatin-induced cardiotoxicity in rats via modulation of the SIRT1/AMPK/Nrf2 signaling pathway

Abstract

Cisplatin (CP), an effective chemotherapeutic agent, is known to cause cardiotoxicity, limiting its clinical application. This study aimed to investigate the potential cardioprotective effects of linagliptin (LG) against cisplatin-induced cardiac injury and to elucidate its underlying mechanisms. There were four groups of male Wistar rats: control, cisplatin (CP, 8 mg/kg, IP), and two groups with LG treatment (5 mg/kg and 10 mg/kg, orally) and CP. CP significantly increased cardiac injury markers (CK, CK-MB, TNNC1) and oxidative stress (decreased SOD and GSH, increased MDA) compared to controls (p < 0.05). It also elevated inflammatory cytokines (TNF-α, IL-6) and disrupted mitochondrial function (altered ATP level and NADP/NADPH ratios). Furthermore, CP decreased the expression of SIRT1 and Nrf2 and the level of p-AMPK. LG treatment dose-dependently attenuated these changes, with the 10 mg/kg dose showing greater efficacy. Histopathological examination and immunohistochemistry confirmed these biochemical findings, showing improved cardiac structure and increased expression of SIRT1 and Nrf2 with LG treatment. Linagliptin demonstrates potent cardioprotective effects against cisplatin-induced toxicity, primarily through modulation of the SIRT1/AMPK/Nrf2 signaling pathway, thereby resulting in reduced oxidative stress and inflammation. These findings suggest that linagliptin may serve as a potential adjuvant therapy to mitigate cisplatin-induced cardiotoxicity.