3-(2-4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3h)-quinazolinone and Prediabetic-State

There is an increasing body of evidence to show that impairment in mitochondrial dynamics including excessive fission and insufficient fusion has been observed in the pre-diabetic condition. In pre-diabetic rats with cardiac ischemia-reperfusion (I/R) injury, acute treatment with a mitochondria fission inhibitor (Mdivi-1) and a fusion promoter (M1) showed cardioprotection. However, the potential preventive effects of chronic Mdivi-1 and M1 treatment in a pre-diabetic model of cardiac I/R have never been elucidated.. Male Wistar rats (n = 40) were fed with a high-fat diet (HFD) for 12 weeks to induce prediabetes. Then, all pre-diabetic rats received the following treatments daily via intraperitoneal injection for 2 weeks: (1) HFDV (Vehicle, 0.1% DMSO); (2) HFMdivi1 (Mdivi-1 1.2 mg/kg); (3) HFM1 (M1 2 mg/kg); and (4) HFCom (Mdivi-1 + M1). At the end of treatment protocols, all rats underwent 30 min of coronary artery ligation followed by reperfusion for 120 min.. Chronic Mdivi-1, M1, and the combined treatment showed markedly improved cardiac mitochondrial function and dynamic control, leading to a decrease in cardiac arrhythmias, myocardial cell death, and infarct size (49%, 42%, and 51% reduction for HFMdivi1, HFM1, and HFCom, respectively vs HFDV). All of these treatments improved cardiac function following cardiac I/R injury in pre-diabetic rats.. Chronic inhibition of mitochondrial fission and promotion of fusion exerted cardioprevention in prediabetes with cardiac I/R injury through the relief of cardiac mitochondrial dysfunction and dynamic alterations, and reduction in myocardial infarction, thus improving cardiac function.

Topics: Animals; Apoptosis; Diabetes Mellitus, Experimental; Male; Mitochondria; Mitochondrial Dynamics; Myocardial Reperfusion Injury; Myocytes, Cardiac; Prediabetic State; Rats; Rats, Wistar

An imbalance of brain mitochondrial dynamics, increases in brain inflammation and apoptosis, and increasing cognitive dysfunction, have been reported as being associated with prediabetes and myocardial ischemia-reperfusion (IR) injury. Since inhibiting mitochondrial fission with Mdivi-1 or promoting fusion with M1 had cardioprotective effects in myocardial IR injury and obesity, the neuroprotective roles of Mdivi-1 and M1 when administered at different time points of myocardial IR injury in obese prediabetes have never been determined. Ninety-six male Wistar rats were fed with either a normal (ND: n = 8) or a high-fat diet to induce prediabetes (HFD: n = 88) for 12 weeks. At week 13, all rats were subjected to left anterior descending coronary artery ligation for 30 min, followed by reperfusion for 120 min. HFD rats were randomly divided into 10 groups and assigned into either a pre-ischemic group treated with vehicle (HFV), pre-ischemic, during-ischemic, or onset of reperfusion groups treated with either Mdivi-1 (MDV), M1, or combined (COM). Heart function was examined invasively, with the heart being terminated to investigate myocardial infarction. Brains were collected to determine mitochondrial functions, inflammation, apoptosis, and pathological markers. Mdivi-1, M1, and COM treatment at different periods exerted cardioprotection against myocardial IR injury in HFD-fed rats by reducing infarct size and left ventricular dysfunction. All interventions also improved all brain pathologies against myocardial IR injury in prediabetic rats. These findings suggest that differential temporal modulation of mitochondrial dynamics may be appropriate regimens for preventing heart and brain complications after myocardial IR injury in obese prediabetes.

Topics: Animals; Apoptosis; Brain; Cardiotonic Agents; Inflammation; Male; Mitochondrial Dynamics; Myocardial Reperfusion Injury; Obesity; Prediabetic State; Rats; Rats, Wistar

Mitochondria are extraordinarily dynamic organelles that have a variety of morphologies, the status of which are controlled by the opposing processes of fission and fusion. Our recent study shows that inhibition of excessive mitochondrial fission by Drp1 inhibitor (Mdivi-1) leads to a reduction in infarct size and left ventricular (LV) dysfunction following cardiac ischemia-reperfusion (I/R) injury in high fat-fed induced pre-diabetic rats. In the present study, we investigated the cardioprotective effects of a mitochondrial fusion promoter (M1) and a combined treatment (M1 and Mdivi-1) in pre-diabetic rats. Wistar rats were given a high-fat diet for 12 weeks to induce prediabetes. The rats then subjected to 30 min-coronary occlusions followed by reperfusion for 120 min. These rats were intravenously administered M1 (2 mg/kg) or M1 (2 mg/kg) combined with Mdivi-1 (1.2 mg/kg) prior to ischemia, during ischemia or at the onset of reperfusion. We showed that administration of M1 alone or in combination with Mdivi-1 prior to ischemia, during ischemia or at the onset of reperfusion all significantly attenuated cardiac mitochondrial ROS production, membrane depolarization, swelling and dynamic imbalance, leading to reduced arrhythmias and infarct size, resulting in improved LV function in pre-diabetic rats. In conclusion, the promotion of mitochondrial fusion at any time-points during cardiac I/R injury attenuated cardiac mitochondrial dysfunction and dynamic imbalance, leading to decreased infarct size and improved LV function in pre-diabetic rats.

Topics: Animals; Diabetes Mellitus, Experimental; Diet, High-Fat; Dose-Response Relationship, Drug; Male; Mitochondrial Dynamics; Molecular Structure; Myocardial Reperfusion Injury; Prediabetic State; Quinazolinones; Rats; Rats, Wistar; Structure-Activity Relationship

An increase in the number of fragmented mitochondria contributes to the pathogenesis of ischemia-reperfusion (I/R) injury. Also, mitochondrial fission has shown an increase in obese condition. However, the cardioprotective roles of a mitochondrial fission inhibitor in obesity with cardiac I/R injury are unclear. We hypothesized that a fission inhibitor (Mdivi-1) reduces cardiac dysfunction during I/R injury in pre-diabetic rats. Male Wistar rats (n = 40) were received a high-fat diet for 12 weeks to induce prediabetes. Then, rats underwent a 30-min coronary artery ligation was performed followed by reperfusion for 120 min. These I/R rats were given either: (1) vehicle or Mdivi-1 treatment at 3 time points relative to onset of ischemia: (2) pre-ischemia; (3) during ischemia; and (4) at onset of reperfusion. Cardiac function, myocardial infarct size, mitochondrial function and dynamic balance were determined. Interestingly, Mdivi-1 given at any time points effectively attenuated mitochondrial reactive oxygen species production, depolarization, swelling, and dynamic imbalance, resulting in reduced arrhythmias, myocardial cell death, infarct size and enhanced cardiac performance during I/R injury in pre-diabetic rats. Taken together, inhibition of mitochondrial fission effectively protected the heart against cardiac I/R injury regardless of the time of administration in pre-diabetic rats.

Topics: Animals; Diabetes Mellitus, Experimental; Diet, High-Fat; Electrocardiography; Male; Mitochondrial Dynamics; Myocardial Reperfusion Injury; Prediabetic State; Quinazolinones; Rats; Rats, Wistar; Reactive Oxygen Species