DECIPHERING THE NOVEL ROLE OF ERDOSTEINE IN PREVENTION OF MYOCARDIAL ISCHEMIA-REPERFUSION INJURY IN RAT

Abstract

Objective: Myocardial ischemia-reperfusion injury (MIRI) is caused by thrombotic obstruction of the coronary artery subsequently leading to heart failure. Despite the availability of improved prognosis, MIRI is a foremost cause of morbidity and mortality worldwide. In this study, we investigated the therapeutic potential of Erdosteine (a mucoactive antioxidant molecule, with multifaceted pharmacological properties), to attenuate myocardial infarction in rat model of MIRI. Design and method: This study was conducted in adult male Wistar rats (n=40), randomized into five groups: Sham, IR-C (disease control), Erdosteine (80 mg/kg; s.c.) + IR, Telmisartan (10 mg/kg; orally) +IR and Erdosteine (80 mg/kg) perse groups. Erdosteine and telmisartan were administered for 28 days as a pre-treatment. On the 29th day, animals were subjected to LAD coronary artery occlusion for 1 h followed by reperfusion for 45 minutes. The cardioprotective potential was assessed through measurement of hemodynamic parameters, biochemical markers (MDA, GSH, SOD), cardiac injury markers (CK-MB and LDH), inflammatory markers (IL-6, TNF), histopathological evaluation, TUNEL assay and immunohistochemistry analysis (Bax, caspase 3, Bcl2). Further, the underlying mechanism was evaluated using immune-blotting of MAPK, Nrf-2/HO-1, and Akt/p-Akt. The statistics analysis was performed by one-way ANOVA followed by Turkey-Kramer post hoc tests. Results: Erdosteine and telmisartan pretreatment improves hemodynamic parameters by preserving MAP, ±LVdP/dt, and HR as compared to the IR-C group. Pretreatment markedly restored the levels of antioxidants (GSH and SOD) and decreased peroxidation marker (MDA) compared to the IR-C group. Also, the pretreatment significantly prevented the damage following IR injury as compared to the IR-C group when investigated through cardiac injury markers and histopathological evaluation. Erdosteine profoundly reversed the expressions of Bcl2/BAX ratio, in comparison to the IR-C group indicating its anti-apoptotic effect when reconfirmed through TUNEL assay. Erdosteine pretreatment preserved the levels of NF-kB, TNF, and IL-6 following IR challenge. Erdosteine pretreatment restores FABP, Nrf-2, and Hsp27. Conclusions: Erdosteine protects the myocardial cell membrane from peroxidation and inhibits oxidative burst and inflammation through NF-kB pathway activation. Erdosteine attenuates MIRI injury in rats preserving the MAPK and Nrf-2 signaling cascade.