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.
Abbreviations:
Drp1 (dynamin-related protein 1), ROSC (return of spontaneous circulation), CA (cardiac arrest), CPR (cardiopulmonary resuscitation), IR (ischemia-reperfusion), ACA (asphyxial cardiac arrest), PC (precordial compression), MAP (mean arterial blood pressure), NDS (neurologic deficit score), TUNEL (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay), TEM (transmission electron microscope), VDAC (voltage-dependent anion channel protein), ATP (adenosine triphosphate), ΔΨm (mitochondrial membrane potential), ROS (reactive oxygen species), SD (standard deviation), mdivi (mdivi-1 treatment group), HT (hypothermic group), NT (normothermic group)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Heart disease and stroke statistics—2016 update: a report from the American Heart Association.Circulation. 2016; 133: e38
- Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council.Circulation. 2008; 118: 2452-2483
- Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.N Engl J Med. 2002; 346: 549-556
- Protecting mitochondrial bioenergetic function during resuscitation from cardiac arrest.Crit Care Clin. 2012; 28: 245-270
- Mitochondrial dysfunction in cardiac disease: ischemia–reperfusion, aging, and heart failure.J Mol Cell Cardiol. 2001; 33: 1065-1089
- Mitochondrial dynamics—mitochondrial fission and fusion in human diseases.N Engl J Med. 2013; 369: 2236
- Mitochondrial fusion and fission in cell life and death.Nat Rev Mol Cell Biol. 2010; 11: 872-884
- Mitochondrial fission in apoptosis, neurodegeneration and aging.Curr Opin Cell Biol. 2003; 15: 706-716
- Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury.Circulation. 2010; 121: 2012-2022
- Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission.FASEB J. 2014; 28: 316
- Inhibition of the mitochondrial fission protein dynamin-related protein 1 improves survival in a murine cardiac arrest model.Crit Care Med. 2015; 43: e38-e47
- Intermolecular and interdomain interactions of a dynamin-related GTP-binding protein, Dnm1p/Vps1p-like protein.J Biol Chem. 1999; 274: 2780-2785
- Aberrant mitochondrial fission in neurons induced by protein kinase Cδ under oxidative stress conditions in vivo.Mol Biol Cell. 2011; 22: 256-265
- Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission.J Biol Chem. 2007; 282: 11521-11529
- Chemical inhibition of the mitochondrial division dynamin reveals its role in bax/bak-dependent mitochondrial outer membrane permeabilization.Dev Cell. 2008; 14: 193-204
- Inhibition of Drp1 provides neuroprotection in vitro and in vivo.Cell Death Differ. 2012; 19: 1446-1458
- A selective inhibitor of Drp1, mdivi-1, acts against cerebral ischemia/reperfusion injury via an anti-apoptotic pathway in rats.Neurosci Lett. 2013; 535: 104-109
- Inhibition of Drp1 by Mdivi-1 attenuates cerebral ischemic injury via inhibition of the mitochondria-dependent apoptotic pathway after cardiac arrest.Neuroscience. 2015; 311: 67-74
- Remote ischemic pre- and postconditioning improve postresuscitation myocardial and cerebral function in a rat model of cardiac arrest and resuscitation.Crit Care Med. 2015; 43: 12-18
- Asphyxia, cardiac arrest and resuscitation in rats. I. Short term recovery.Resuscitation. 1984; 12: 97-116
- Exogenous carbon monoxide decreases sepsis-induced acute kidney injury and inhibits NLRP3 inflammasome activation in rats.Int J Mol Sci. 2015; 16: 20595-20608
- Isolation and functional assessment of mitochondria from small amounts of mouse brain tissue.in: Manfredi G. Kawamata H. Neurodegeneration: methods and protocols. Humana Press, Totowa, NJ2011: 311-324
- Bench-to-bedside review: mitochondrial injury, oxidative stress and apoptosis—there is nothing more practical than a good theory.Crit Care. 2008; 12: 206
- Cardiac arrest: resuscitation and reperfusion.Circ Res. 2015; 116: 2041
- Resuscitation after cardiac arrest.J Am Med Assoc. 2002; : 3035-3038
- Dynamin-related protein 1 as a therapeutic target in cardiac arrest.J Mol Med. 2015; 93: 243-252
- Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease.Br J Pharmacol. 2014; 171: 1890-1906
- Mitochondrial fission—a drug target for cytoprotection or cytodestruction?.Pharmacol Res Perspect. 2016; 4
- The putative Drp1 inhibitor mdivi-1 is a reversible mitochondrial complex I inhibitor that modulates reactive oxygen species.Dev Cell. 2017; 40: 583
- The effect of mild induced hypothermia on outcomes of patients after cardiac arrest: a systematic review and meta-analysis of randomised controlled trials.Crit Care. 2015; 19: 417
- Mild hypothermia alone or in combination with anesthetic post-conditioning reduces expression of inflammatory cytokines in the cerebral cortex of pigs after cardiopulmonary resuscitation.Crit Care. 2010; 14: R21
- Mild hypothermia reduces per-ischemic reactive oxygen species production and preserves mitochondrial respiratory complexes.Resuscitation. 2013; 84: 249-255
- Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade.J Cereb Blood Flow Metab. 2002; 22: 21-28
- Neuroprotective mechanisms of hypothermia in brain ischaemia.Nat Rev Neurosci. 2012; 13: 267
- Mechanisms of brain injury after global cerebral ischemia.Neurol Clin. 2006; 24: 1
- Brain damage and temperature: cellular and molecular mechanisms.Adv Neurol. 1996; 71: 177
- Mitochondrial H(+) leak and ROS generation: an odd couple.Free Radic Biol Med. 2005; 38: 12-23
- Early mitochondrial dysfunction in electron transfer activity and reactive oxygen species generation after cardiac arrest.Crit Care Med. 2008; 36: S447-S453
- Oxidative stress and mitochondrial dysfunction in Alzheimer's disease.Biochim Biophys Acta. 2014; 1842: 1240-1247
- The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis.Dev Cell. 2007; 1: 515-525
- Comparison of the durations of mild therapeutic hypothermia on outcome after cardiopulmonary resuscitation in the rat.Circulation. 2012; 125: 123-129
Article info
Publication history
Published online: January 08, 2018
Accepted:
January 2,
2018
Received in revised form:
December 21,
2017
Received:
September 19,
2017
Identification
Copyright
© 2018 Elsevier Inc. All rights reserved.
