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Acute and long-term cardioprotective effects of the Traditional Chinese Medicine MLC901 against myocardial ischemia-reperfusion injury in mice.

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.

SUBMITTER: Vincent A

PROVIDER: S-EPMC5665902 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Acute and long-term cardioprotective effects of the Traditional Chinese Medicine MLC901 against myocardial ischemia-reperfusion injury in mice.

Vincent Anne A Covinhes Aurélie A Barrère Christian C Gallot Laura L Thoumala Soulit S Piot Christophe C Heurteaux Catherine C Lazdunski Michel M Nargeot Joël J Barrère-Lemaire Stéphanie S

Scientific reports 20171031 1

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 cor ...[more]

PMID: 29089640

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Project description:Lixisenatide is a glucagon-like peptide-1 analog which stimulates insulin secretion and inhibits glucagon secretion and gastric emptying. We investigated cardioprotective effects of lixisenatide in rodent models reflecting the clinical situation.The acute cardiac effects of lixisenatide were investigated in isolated rat hearts subjected to brief ischemia and reperfusion. Effects of chronic treatment with lixisenatide on cardiac function were assessed in a modified rat heart failure model after only transient coronary occlusion followed by long-term reperfusion. Freshly isolated cardiomyocytes were used to investigate cell-type specific mechanisms of lixisenatide action.In the acute setting of ischemia-reperfusion, lixisenatide reduced the infarct-size/area at risk by 36% ratio without changes on coronary flow, left-ventricular pressure and heart rate. Treatment with lixisenatide for 10 weeks, starting after cardiac ischemia and reperfusion, improved left ventricular end-diastolic pressure and relaxation time and prevented lung congestion in comparison to placebo. No anti-fibrotic effect was observed. Gene expression analysis revealed a change in remodeling genes comparable to the ACE inhibitor ramipril. In isolated cardiomyocytes lixisenatide reduced apoptosis and increased fractional shortening. Glucagon-like peptide-1 receptor (GLP1R) mRNA expression could not be detected in rat heart samples or isolated cardiomyocytes. Surprisingly, cardiomyocytes isolated from GLP-1 receptor knockout mice still responded to lixisenatide.In rodent models, lixisenatide reduced in an acute setting infarct-size and improved cardiac function when administered long-term after ischemia-reperfusion injury. GLP-1 receptor independent mechanisms contribute to the described cardioprotective effect of lixisenatide. Based in part on these preclinical findings patients with cardiac dysfunction are currently being recruited for a randomized, double-blind, placebo-controlled, multicenter study with lixisenatide.(ELIXA, ClinicalTrials.gov Identifier: NCT01147250).

Project description:Background and objectiveThe urgent need to identify pathways that can mitigate myocardial ischemia-reperfusion injury (MIRI) has become a central focus in cardiovascular treatment. Chinese herbal medicine (CHM), renowned for its multi-component, multi-channel, and multi-target therapeutic properties, holds significant promise in the management of MIRI. Mitochondria, as pivotal players in MIRI, have been shown to be effectively modulated by CHM through various mechanisms. The objective of this narrative review is to underscore the critical role of mitochondria in MIRI and to provide an up-to-date overview of the latest research advancements in utilizing CHM to treat MIRI by targeting mitochondrial morphology and function.MethodsThe PubMed and the China National Knowledge Infrastructure (CNKI) databases were searched using keywords related to MIRI. Relevant English-language articles published from January 2019 to July 2024 were included in this narrative review.Key content and findingsMitochondria are intimately linked to MIRI. The mechanisms involve the regulation of mitochondrial biogenesis and energy metabolism, the functionality of the mitochondrial respiratory chain, resistance to oxidative stress-induced damage, the maintenance of mitochondrial homeostasis, the modulation of calcium ion homeostasis, the preservation of mitochondrial membrane potential, the opening of adenosine triphosphate (ATP)-sensitive potassium channels, and the effective control over the opening of the mitochondrial permeability transition pore, all of which contribute to the balance between autophagy and apoptosis in cardiomyocytes. Various effective monomers of CHM, extracts of CHM, compounds, and proprietary Chinese medicine have demonstrated promising therapeutic potential in basic research, among them, tonic and blood-activating CHMs account for the largest proportion.ConclusionsThe prospect of CHM targeting mitochondria for the treatment of MIRI is promising, yet it necessitates overcoming challenges such as low bioavailability and inadequate mechanistic research. By integrating traditional Chinese medicine theories with modern scientific technologies, it is imperative to delve deeper into and optimize the pharmacodynamics, pharmacokinetics, and clinical applications of these herbs.

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Acute and long-term cardioprotective effects of the Traditional Chinese Medicine MLC901 against myocardial ischemia-reperfusion injury in mice.

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Acute and long-term cardioprotective effects of the Traditional Chinese Medicine MLC901 against myocardial ischemia-reperfusion injury in mice.

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