Cardioprotective role of vincamine in cyclophosphamide-induced cardiotoxicity through modulation of AMPK/SIRT1, PI3K/Akt, and MAPK pathways

Cyclophosphamide (CP) remains widely used in oncology and immunotherapy; however, its therapeutic value is limited by the onset of myocardial injury. The present study investigated whether vincamine (VIN) protects against CP-associated myocardial injury and whether this effect is accompanied by changes in the AMPK/SIRT1 and PI3K/Akt axes, MAPK, TLR4/NF-κB p65 signaling, as well as NLRP3-related signaling. Adult male Wistar rats were assigned to four experimental groups (n = 6): control animals received distilled water (10 mL/kg), whereas CP-administered rats received one intraperitoneal CP injection (200 mg/kg) on day 7; two VIN-pretreated groups were given VIN pretreatment administered orally at doses of 20 or 40 mg/kg/day across the 10-day protocol, with CP administered on day 7. Cardiac injury indices, redox status, inflammatory and apoptotic mediators, as well as gene and protein expression, were examined using biochemical measurements, histological examination, immunohistochemical staining, qRT-PCR, and Western blotting. CP exposure significantly elevated serum cTn-T, CK-MB, and LDH levels, increased cardiac MDA, MPO, iNOS and inflammatory cytokine levels, namely TNF-α, IL-6, and IL-1β, together with reduced GSH content and Nrf2/HO-1 expression. CP administration reduced AMPK/SIRT1 and PI3K/Akt transcript expression and increased TLR4 and NLRP3 expression, β-actin-normalized phosphorylated MAPK abundance, and NF-κB p65 immunoreactivity. VIN attenuated these alterations in a dose-responsive manner, and its cardioprotective effects were accompanied by improved redox balance, increased AMPK/SIRT1 and PI3K/Akt expression, reduced phosphorylated MAPK abundance, and lower inflammatory and apoptosis-related indices. Overall, these data strengthen the scientific basis for evaluating VIN as a potential cardioprotective intervention against CP-induced myocardial damage.