Glycogen synthase kinase 3 inhibition protects the heart from acute ischemia-reperfusion injury via inhibition of inflammation and apoptosis

Glycogen synthase kinase (GSK)-3 beta inhibitors play all anti-inflammatory role in several inflammatory diseases. Recent studies have demonstrated that GSK-3 beta inhibitors protect against myocardial ischemia-reperfusion injury. However, the precise mechanisms remain unclear. We aimed to investigate the roles of inflammation and apoptosis induced by ischemia-reperfusion in the cardioprotection by GSK-3 beta inhibitor 4-benzyl-2-methyl-1, 2, 4-thiadiazolidine-3, 5-dione (TDZD-8). Anaesthetized Sprague-Dawley rats underwent all open-chest procedure involving 30 min of myocardial ischemia and 6 h of reperfusion with or without TDZD-8 given at reperfusion. TDZD-8 reduced myocardial infarct size by nearly 43%, (P < 0.05 vs. myocardial ischemia-reperfusion) and attenuated myeloperoxidase activity (21.80 +/- 1.07 U/100 mg tissue. vs. myocardial ischemia-reperfusion group, P < 0.05). Administration of TDZD-8 significantly suppressed nuclear factor kappa B (NF-kappa B) and p38 MAPK activation (P < 0.05 vs. myocardial ischemia-reperfusion) and the concentrations of the myocardial-derived cytokines tumor necrosis factor-alpha (TNF-alpha, 107.40 +/- 7.34 pg/mg protein vs. myocardial ischemia-reperfusion group, P < 0.05) and interleukin-6 (IL-6, 29.28 +/- 6.3 pg/mg protein vs. myocardial ischemia-reperfusion group, P < 0.05). Treatment with TDZD-8 also inhibited myocardial cell apoptosis compared with the myocardial ischemia-reperfusion group (12 +/- 1%, vs. 22 +/- 2%, P < 0.05). Therefore, blocking this protein kinase activity may be a novel approach to the treatment of this condition. which is characterized by inflammation and apoptosis.