Repurposing of piracetam to alleviate doxorubicin-induced cardiotoxicity in rats: Targeting TLR2/MyD88/AP-1/NF-κB and VEGF/eNOS signaling pathways

Doxorubicin (DOXO) is a highly efficient antineoplastic agent, but its clinical usefulness faces major cardiotoxic hazards. Thus, current study aimed to investigate the novel potential ameliorative effect of piracetam (PIRA) against DOXO-induced cardiotoxicity in addition to highlight the role of toll-like receptor 2 (TLR2)/myeloid differentiation primary response 88 (MyD88)/activator protein-1 (AP-1)/nuclear factor kappa-B (NF-κB) and vascular endothelial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) signaling cascades. Rats were allocated in a random manner into five equal groups as follows: control (CONT), PIRA.400, DOXO, DOXO + PIRA.400, and DOXO + PIRA.400 + Nω-nitro-L-arginine methylester (L-NAME). Different cardiac enzymes along with oxidative stress, inflammatory and apoptotic biomarkers were detected. Furthermore, examination of the histopathological alterations in the cardiac tissue was evaluated. DOXO administration remarkably elevated the levels of cardiac enzymes, heart/body weight ratio (%), malondialdehyde (MDA), and upregulated active caspase-3, TLR2/MyD88/AP-1/NF-κB signaling cascade but downregulated VEGF/eNOS pathway along with substantial histopathological alterations. However, levels of serum total antioxidant capacity (T-AOC) and tissue reduced glutathione (GSH) significantly diminished with DOXO administration. All biochemical, histological, and molecular changes were considerably alleviated by the PIRA.400 treatment relative to DOXO alone. Interestingly, findings detected reducing the cardioprotective impact of PIRA on concurrent pretreatment with L-NAME, indicating the crucial role of eNOS in modulating this protection. This study revealed that PIRA ameliorated the DOXO-evoked cardiotoxicity via modulation of TLR2/MyD88/AP-1/NF-κB as well as VEGF/eNOS signaling cascades.