3-(2-4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3h)-quinazolinone and Heart-Arrest

Dynamin-related protein 1 (Drp1) regulates mitochondrial fission, it has been proven that inhibition of Drp1 by mdivi-1 improves survival and attenuates cerebral ischemic injury after cardiac arrest. In this study, we compared the effects of Drp1 inhibition with therapeutic hypothermia on post-resuscitation neurologic injury in a rat model of cardiac arrest. Rats were randomized into 4 groups: mdivi-1 treatment group (n = 39), hypothermic group (n = 38), normothermic group (n = 41), and sham group (n = 12). The rats in the mdivi-1 treatment group were received intravenously 1.2 mg/kg of mdivi-1 at 1 minute after the return of spontaneous circulation (ROSC). In rats in hypothermia group, rapid cooling was initiated at 5 minutes after resuscitation, and the core temperature was maintained to 33 ± 0.5°C for 2 hours. The results showed that both Drp1 inhibition and therapeutic hypothermia increased 3-day survival time (all P <0.05) and improved neurologic function up to 72 hours post cardiac arrest. In addition, both Drp1 inhibition and therapeutic hypothermia decreased cell injury, apoptosis in hippocampal cornu ammonis 1 region and brain mitochondrial dysfunction including adenosine triphosphate production, reactive oxygen species and mitochondrial membrane potential after cardiac arrest. Moreover, therapeutic hypothermia decreased mitochondrial Drp1 expression and mitochondrial fission after cardiac arrest. In conclusion, inhibition of Drp1 has a similar effect to therapeutic hypothermia on neurologic outcome after resuscitation in this cardiac arrest rat model, and the neuroprotective effects of therapeutic hypothermia are associated with inhibition of mitochondrial fission.

Topics: Animals; Disease Models, Animal; Dynamins; Heart Arrest; Hypothermia, Induced; Male; Mitochondrial Dynamics; Neuroprotective Agents; Quinazolinones; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Survival following sudden cardiac arrest is poor despite advances in cardiopulmonary resuscitation and the use of therapeutic hypothermia. Dynamin-related protein 1, a regulator of mitochondrial fission, is an important determinant of reactive oxygen species generation, myocardial necrosis, and left ventricular function following ischemia/reperfusion injury, but its role in cardiac arrest is unknown. We hypothesized that dynamin-related protein 1 inhibition would improve survival, cardiac hemodynamics, and mitochondrial function in an in vivo model of cardiac arrest.. Laboratory investigation.. University laboratory.. Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent an 8-minute KCl-induced cardiac arrest followed by 90 seconds of cardiopulmonary resuscitation. Mice were then blindly randomized to a single IV injection of Mdivi-1 (0.24 mg/kg), a small molecule dynamin-related protein 1 inhibitor or vehicle (dimethyl sulfoxide).. Following resuscitation from cardiac arrest, mitochondrial fission was evidenced by dynamin-related protein 1 translocation to the mitochondrial membrane and a decrease in mitochondrial size. Mitochondrial fission was associated with increased lactate and evidence of oxidative damage. Mdivi-1 administration during cardiopulmonary resuscitation inhibited dynamin-related protein 1 activation, preserved mitochondrial morphology, and decreased oxidative damage. Mdivi-1 also reduced the time to return of spontaneous circulation (116 ± 4 vs 143 ± 7 s; p < 0.001) during cardiopulmonary resuscitation and enhanced myocardial performance post-return of spontaneous circulation. These improvements were associated with significant increases in survival (65% vs 33%) and improved neurological scores up to 72 hours post cardiac arrest.. Post-cardiac arrest inhibition of dynamin-related protein 1 improves time to return of spontaneous circulation and myocardial hemodynamics, resulting in improved survival and neurological outcomes in a murine model of cardiac arrest. Pharmacological targeting of mitochondrial fission may be a promising therapy for cardiac arrest.

Topics: Aconitate Hydratase; Animals; Disease Models, Animal; Dynamins; Female; Heart Arrest; Immunoblotting; Mice; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Mitochondrial Dynamics; Quinazolinones; Random Allocation

Mitochondrial fission is predominantly controlled by the activity of dynamin-related protein1 (Drp1), which has been reported to be involved in mitochondria apoptosis pathways. However, the role of Drp1 in a rat model of cardiac arrest remains unknown. In this study, we found that activation of Drp1 in the mitochondria was increased after cardiac arrest and inhibition of Drp1 by 1.2 mg/kg of mitochondrial division inhibitor-1 (Mdivi-1) administration after the restoration of spontaneous circulation (ROSC) significantly protected against cerebral ischemic injury, shown by the increased 72-h survival rate and improved neurological function. Moreover, the increase of the vital neuron and the reduction of cytochrome c (CytC) release, apoptosis-inducing factor (AIF) translocation and caspase-3 activation in the brain indicate that this protection might result from the suppression of neuron apoptosis. Altogether, these results indicated that Drp1 is activated after cardiac arrest and the inhibition of Drp1 is protective against cerebral ischemic injury in a rat of cardiac arrest model via inhibition of the mitochondrial apoptosis pathway.

Topics: Animals; Apoptosis; Brain; Brain Ischemia; Disease Models, Animal; Dose-Response Relationship, Drug; Dynamins; Heart Arrest; Male; Mitochondria; Neurons; Neuroprotective Agents; Quinazolinones; Random Allocation; Rats, Sprague-Dawley

To investigate the effects of mitochondrial division inhibitor 1 (mdivi-1) in rats after cardiopulmonary resuscitation (CPR) and its mechanism.. Fifty Sprague-Dawley (SD) rats were randomly (random number table) divided into sham group (n = 8), cardiac arrest (CA) model group (n = 14), dimethyl sulfoxide post-treatment control group (DMSO group, n = 14), and mdivi-1 post-treatment group (mdivi-1 group, n = 14). Asphyxial CA was reproduced in animals, and they were resuscitated by CPR. In the mdivi-1 group or DMSO group, the animals were given mdivi-1 (1.2 mg/kg) or DMSO (0.1%) intravenously after restoration of spontaneous circulation ( ROSC ). The neurological functions were assessed using neurological deficit score (NDS) determined at 24, 48 and 72 hours after CPR. The brain tissues were harvested at 72 hours after CPR. The histopathologic changes were assessed by hematoxylin and eosin (HE) staining, and the normal neuron was counted. The neuronal apoptosis was assessed with terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and the expressions of cytochrome C (Cyt-C) protein in mitochondria and cytoplasm from hippocampus were determined by Western Blot.. NDS in all experiment groups was gradually increased after CPR, and they were significantly lower than those of the sham group at 24, 48, and 72 hours (51.5 ± 3.7 vs. 80.0 ± 0.0, 59.3 ± 3.6 vs. 80.0 ± 0.0, 66.7 ± 2.6 vs. 80.0 ± 0.0, all P < 0.05). The number of normal pyramidal neurons in the hippocampal CA1 region was markedly reduced (cells/HP: 4.4 ± 1.1 vs. 23.1 ± 4.0, P < 0.05), the apoptotic index was significantly increased [(86.9 ± 6.9)% vs. (3.4 ± 0.8)%, P < 0.05], the expressions of Cyt-C in mitochondria were significantly decreased (A value: 0.46 ± 0.18 vs. 1.00 ± 0.00, P < 0.05), and the expressions of Cyt-C in cytoplasm were significantly up-regulated (A value: 6.65 ± 0.21 vs. 1.00 ± 0.00, P < 0.05). Compared with the CA group, NDS at 24 hours and 48 hours in mdivi-1 group was slightly increased (55.2 ± 3.3 vs. 51.5 ± 3.7, 64.7 ± 2.4 vs. 59.3 ± 3.6, both P > 0.05), and it was significantly increased at 72 hours (74.5 ± 2.3 vs. 66.7 ± 2.6, P < 0.05), the number of normal pyramidal neurons in the hippocampal CA region was markedly increased (cells/HP: 16.2 ± 2.4 vs. 4.4 ± 1.1, P < 0.05), the apoptotic index was dramatically reduced [(42.3 ± 3.9 )% vs. (86.9 ± 6.9 )%, P < 0.05], the expressions of Cyt-C in mitochondria were significantly increased (A value: 0.83 ± 0.22 vs. 0.46 ± 0.18, P < 0.05), and the expressions of Cyt-C in cytoplasm were significantly decreased (A value: 3.84 ± 0.47 vs. 6.65 ± 0.21, P < 0.05). There was no statistically significant difference in above indexes between CA group and DMSO group.. By inhibiting mitochondrial Cyt-C apoptotic pathway to reduce neuronal apoptosis in rats after CA-CPR, mdivi-1 can improve brain function after CPR.

Topics: Animals; Apoptosis; Asphyxia; Cardiopulmonary Resuscitation; Cytochromes c; Heart Arrest; Mitochondria; Neurons; Quinazolinones; Random Allocation; Rats; Rats, Sprague-Dawley