Abstract
MLC901, a traditional Chinese medicine containing a cocktail of active molecules, both reduces cerebral infarction and improves recovery in patients with ischemic stroke. The aim of this study was to evaluate the acute and long-term benefits of MLC901 in ischemic and reperfused mouse hearts. Ex vivo, under physiological conditions, MLC901 did not show any modification in heart rate and contraction amplitude. However, upon an ischemic insult, MLC901 administration during reperfusion, improved coronary flow in perfused hearts. In vivo, MLC901 (4 µg/kg) intravenous injection 5 minutes before reperfusion provided a decrease in both infarct size (49.8%) and apoptosis (49.9%) after 1 hour of reperfusion. Akt and ERK1/2 survival pathways were significantly activated in the myocardium of those mice. In the 4-month clinical follow-up upon an additional continuous per os administration, MLC901 treatment decreased cardiac injury as revealed by a 45%-decrease in cTnI plasmatic concentrations and an improved cardiac performance assessed by echocardiography. A histological analysis revealed a 64%-decreased residual scar fibrosis and a 44%-increased vascular density in the infarct region. This paper demonstrates that MLC901 treatment was able to provide acute and long-term cardioprotective effects in a murine model of myocardial ischemia-reperfusion injury in vivo.
Highlights
Despite an extensive research to target ischemia followed by 1h-reperfusion (IR) injury[2,3,4,5,6,7,8] the only treatment providing efficient cardioprotective effects for AMI patients is early revascularization of the culprit artery
We showed that MLC901 administration does not affect the basic cardiac physiological parameters
A smaller cardioprotective effect was observed for the treatment with 0.4 μg/kg MLC901. This cardioprotective effect was not observed with 40 μg/kg MLC901. (C) Scatter dot blots and means ± SD were plotted for AR/Left ventricles (LV) mass. (D) IR24h animals received MLC901 (4 μg/kg) or physiological saline serum alone (IR). (E) Scatter dot blots and means ± SD were plotted for infarct size. (F) Scatter dot blots and means ± SD were plotted for AR/LV mass
Summary
Despite an extensive research to target IR injury[2,3,4,5,6,7,8] the only treatment providing efficient cardioprotective effects for AMI patients is early revascularization of the culprit artery. Clinical utility has emerged[9,10] This difficulty of discovering new treatments for patients suffering from myocardial ischemia comes from the failure to translate to humans the strategies developed in animal models. Pharmacological data obtained from rodents have demonstrated that, in addition to infarct volume reduction, MLC601 and MLC901 drastically improve recovery of both motor and cognitive functions in focal and global ischemia[16,21]. These beneficial effects have been observed in an in vitro assay of oxygen-glucose deprivation that mimics brain ischemic conditions[25]. Both MLC601 and MLC901 are cocktail of molecules acting on many different targets such as free radical production (inhibition), ATP-sensitive K+ channels (activation)[15,16,25] or HIF1α (Hypoxia-Inducible Factor 1-alpha), EPO (erythropoietin), VEGF (Vascular Endothelial Growth Factor) expression[26]
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