Effectiveness of a single versus repeated administration of trimetazidine in the protection against warm ischemia/reperfusion injury of rat liver

Boussaid, Asma Mahfoudh; Selmi, Rabi; Béjaoui, Mohamed; Ayed, Kaouther Hadj; Zaoualí, Mohamed Amine; Abdennebi, Hassen Ben

doi:10.3906/sag-1505-102

Cited by 15 publications

(4 citation statements)

References 19 publications

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“…Although diazoxide significantly decreases liver mitochondrial dysfunction after hepatic IR, the MDA content and myeloperoxidase (MPO) activity are not affected in the liver . A similar drug, trimetazidine, effectively rescue hepatic IR injury in rat model, but repeated administration of this drug confers more protection by significantly enhancing signalling pathways including phosphorylated adenosine monophosphate‐activated protein kinase (AMPK) and eNOS .…”

Section: Pharmacological Pre‐conditioning Before Hepatic Irmentioning

confidence: 99%

Pre‐conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion

Hu¹

2017

J Cellular Molecular Medi

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The liver, the largest organ with multiple synthesis and secretion functions in mammals, consists of hepatocytes and Kupffer, stem, endothelial, stellate and other parenchymal cells. Because of early and extensive contact with the external environment, hepatic ischaemia reperfusion (IR) may result in mitochondrial dysfunction, autophagy and apoptosis of cells and tissues under various pathological conditions. Because the liver requires a high oxygen supply to maintain normal detoxification and synthesis functions, it is extremely susceptible to ischaemia and subsequent reperfusion with blood. Consequently, hepatic IR leads to acute or chronic liver failure and significantly increases the total rate of morbidity and mortality through multiple regulatory mechanisms. An increasing number of studies indicate that mitochondrial structure and function are impaired after hepatic IR, but that the health of liver tissues or liver grafts can be effectively rescued by attenuation of mitochondrial dysfunction. In this review, we mainly focus on the subsequent therapeutic interventions related to the conservation of mitochondrial function involved in mitigating hepatic IR injury and the potential mechanisms of protection. Because mitochondria are abundant in liver tissue, clarification of the regulatory mechanisms between mitochondrial dysfunction and hepatic IR should shed light on clinical therapies for alleviating hepatic IR‐induced injury.

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Section: Pharmacological Pre‐conditioning Before Hepatic Irmentioning

confidence: 99%

Pre‐conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion

Hu¹

2017

J Cellular Molecular Medi

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“…This dosage was proven to be adequate to prevent deleterious effects of ischemia‐reperfusion in previous studies. 22 , 23 For all of the rats, the oxygen concentration was maintained at 100% for 1 hour and then was adjusted to 21% after ROSC (Figure 1 ). The resuscitated rats received intensive care for 5 hours, then catheters and endotracheal tube were removed and incisions were surgically closed.…”

Section: Methodsmentioning

confidence: 99%

Trimetazidine Alleviates Postresuscitation Myocardial Dysfunction and Improves 96‐Hour Survival in a Ventricular Fibrillation Rat Model

Wang

et al. 2022

JAHA

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Background Myocardial dysfunction is a critical cause of post‐cardiac arrest hemodynamic instability and circulatory failure that may lead to early mortality after resuscitation. Trimetazidine is a metabolic agent that has been demonstrated to provide protective effects in myocardial ischemia. However, whether trimetazidine protects against postresuscitation myocardial dysfunction is unknown. Methods and Results Cardiopulmonary resuscitation was initiated after 8 minutes of untreated ventricular fibrillation in Sprague‐Dawley rats. Animals were randomized to 4 groups immediately after resuscitation (n=15/group): (1) normothermia control (NTC); (2) targeted temperature management; (3) trimetazidine‐normothermia; (4) trimetazidine‐targeted temperature management. TMZ was administered at a single dose of 10 mg/kg in rats with trimetazidine. The body temperature was maintained at 34.0°C for 2 hours and then rewarmed to 37.5°C in rats with targeted temperature management. Postresuscitation hemodynamics, 96‐hours survival, and pathological analysis were assessed. Heart tissues and blood samples of additional rats (n=6/group) undergoing the same experimental procedure were collected to measure myocardial injury, inflammation and oxidative stress‐related biomarkers with ELISA‐based quantification assays. Compared with normothermia control, tumor necrosis factor‐α, and cardiac troponin‐I were significantly reduced, whereas the left ventricular ejection fraction and 96‐hours survival rates were significantly improved in the 3 experimental groups. Furthermore, inflammation and oxidative stress‐related biomarkers together with collagen volume fraction were significantly decreased in rats undergoing postresuscitation interventions. Conclusions Trimetazidine significantly alleviates postresuscitation myocardial dysfunction and improves survival by decreasing oxidative stress and inflammation in a ventricular fibrillation rat model. A single dose of trimetazidine administrated immediately after resuscitation can effectively improve cardiac function, whether used alone or combined with targeted temperature management.

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“…The animals in the sham group were randomly divided into the Sham4W, Sham10W, Sham10W + TMZ, and Sham10W + QSYQ groups. The animals in the drug treatment groups were administered QSYQ (0.8 g/kg/d) ( Chen et al, 2015 ) or TMZ (10 mg/kg/d) ( Mahfoudh Boussaid et al, 2016 ; Ma et al, 2019 ) for the next 6 weeks by gavage. The dose of 0.8 g/kg/d is 5 times equivalent to the clinical dose of QSYQ for adults ( Shang et al, 2013 ).…”

Section: Methodsmentioning

confidence: 99%

QiShenYiQi Pill Ameliorates Cardiac Fibrosis After Pressure Overload-Induced Cardiac Hypertrophy by Regulating FHL2 and the Macrophage RP S19/TGF-β1 Signaling Pathway

et al. 2022

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Purpose: Heart failure (HF) is a leading cause of morbidity and mortality worldwide, and it is characterized by cardiac hypertrophy and fibrosis. However, effective treatments are not available to block cardiac fibrosis after cardiac hypertrophy. The QiShenYiQi pill (QSYQ) is an effective treatment for chronic HF. However, the underlying mechanism remains unclear.Methods: In the present study, a pressure overload-induced cardiac hypertrophy model was established in rats by inducing ascending aortic stenosis for 4 weeks. QSYQ was administered for 6 weeks, and its effects on cardiac fibrosis, myocardial apoptosis, RP S19 release, macrophage polarization, TGF-β1 production, and TGF-β1/Smad signaling were analyzed. In vitro studies using H9C2, Raw264.7, and RDF cell models were performed to confirm the in vivo study findings and evaluate the contribution to the observed effects of the main ingredients of QSYQ, namely, astragaloside IV, notoginsenoside R1, 3,4-dihydroxyl-phenyl lactic acid, and Dalbergia odorifera T. C. Chen oil. The role of four-and-a-half LIM domains protein 2 (FHL2) in cardiac fibrosis and QSYQ’s effects were assessed by small interfering RNAs (siRNAs).Results: QSYQ ameliorated cardiac fibrosis after pressure overload-induced cardiac hypertrophy and attenuated cardiomyocyte apoptosis, low FHL2 expression, and TGF-β1 release by the injured myocardium. QSYQ also inhibited the following: release of RP S19 from the injured myocardium, activation of C5a receptors in monocytes, polarization of macrophages, and release of TGF-β1. Moreover, QSYQ downregulated TGF-βR-II expression induced by TGF-β1 in fibroblasts and inhibited Smad protein activation and collagen release and deposition.Conclusion: The results showed that QSYQ inhibited myocardial fibrosis after pressure overload, which was mediated by RP S19-TGF-β1 signaling and decreased FHL2, thus providing support for QSYQ as a promising therapy for blocking myocardial fibrosis.

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Effectiveness of a single versus repeated administration of trimetazidine in the protection against warm ischemia/reperfusion injury of rat liver

Cited by 15 publications

References 19 publications

Pre‐conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion

Pre‐conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion

Trimetazidine Alleviates Postresuscitation Myocardial Dysfunction and Improves 96‐Hour Survival in a Ventricular Fibrillation Rat Model

QiShenYiQi Pill Ameliorates Cardiac Fibrosis After Pressure Overload-Induced Cardiac Hypertrophy by Regulating FHL2 and the Macrophage RP S19/TGF-β1 Signaling Pathway

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