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Protective effects of cyclosporine A and hypothermia on neuronal mitochondria in a rat asphyxial cardiac arrest model

Published:March 01, 2016DOI:https://doi.org/10.1016/j.ajem.2016.02.066

      Abstract

      Background

      Cyclosporine A (CsA) was neuroprotective in the settings of traumatic brain injury and stroke. We sought to investigate the protective effects of CsA and hypothermia on neuronal mitochondria after cardiac arrest.

      Methods and Results

      Five groups were included: sham (S), normothermia (N), CsA (C), hypothermia (H), and CsA plus hypothermia (C + H). Cardiac arrest was induced by 10 min of asphyxia. CsA (10 mg/kg) was administered immediately after return of spontaneous circulation in the CsA groups. Temperature of the rats was maintained at 33 ± 0.5 °C after return of spontaneous circulation in the hypothermia groups. Hippocampal mitochondria were measured after 2 h of resuscitation. Mitochondrial transmembrane potential was significantly higher in the C, the H, and the C + H groups than in the N group and was higher in the C + H group than in the C and the H groups. Cytosolic cytochrome c was significantly higher in the N group. Superoxide dismutase activity was significantly lower in the N group than in the other groups and was higher in the C and the C + H groups than in the H group. Malondialdehyde concentration was significantly higher in the N group.

      Conclusions

      CsA or hypothermia used immediately after resuscitation enhanced mitochondrial transmembrane potential, kept cytochrome c from releasing out of the mitochondria, increased superoxide dismutase activity, and decreased malondialdehyde concentration in hippocampus. Moreover, the protective effects of CsA were reinforced by hypothermia. One of the mechanisms that hypothermia protected neuronal mitochondria from damage was inhibiting the opening of mitochondrial permeability transition pore.
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      References

        • Neumar RW
        • Nolan JP
        • Adrie C.
        • Aibiki M.
        • Berg RA
        • Bottiger BW
        • et al.
        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
        • Laver S.
        • Farrow C.
        • Turner D.
        • Nolan J.
        Mode of death after admission to an intensive care unit following cardiac arrest.
        Intensive Care Med. 2004; 30: 2126-2128
        • Lim C.
        • Alexander M.P.
        • LaFleche G.
        • Schnyer D.M.
        • Verfaellie M.
        The neurological and cognitive sequelae of cardiac arrest.
        Neurology. 2004; 63: 1774-1778
        • van Alem A.P.
        • de Vos R.
        • Schmand B.
        • Koster R.W.
        Cognitive impairment in survivors of out-of-hospital cardiac arrest.
        Am Heart J. 2004; 148: 416-421
        • Mazzeo A.T.
        • Beat A.
        • Singh A.
        • Bullock M.R.
        The role of mitochondrial transition pore, and its modulation, in traumatic brain injury and delayed neurodegeneration after TBI.
        Exp Neurol. 2009; 218: 363-370
        • Crompton M.
        The mitochondrial permeability transition pore and its role in cell death.
        Biochem J. 1999; 341: 233-249
        • Halestrap A.P.
        The mitochondrial permeability transition: its molecular mechanism and role in reperfusion injury.
        Biochem Soc Symp. 1999; 66: 181-203
        • Nicolli A.
        • Basso E.
        • Petronilli V.
        • Wenger R.M.
        • Bernardi P.
        Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin A-sensitive channel.
        J Biol Chem. 1996; 271: 2185-2192
        • Lemasters J.J.
        • Qian T.
        • He L.
        • Kim J.S.
        • Elmore S.P.
        • Cascio W.E.
        • et al.
        Role of mitochondrial inner membrane permeabilization in necrotic cell death, apoptosis, and autophagy.
        Antioxid Redox Signal. 2002; 4: 769-781
        • Sullivan P.G.
        • Thompson M.B.
        • Scheff S.W.
        Cyclosporin A attenuates acute mitochondrial dysfunction following traumatic brain injury.
        Exp Neurol. 1999; 160: 226-234
        • Leger P.L.
        • De Paulis D.
        • Branco S.
        • Bonnin P.
        • Couture-Lepetit E.
        • Baud O.
        • et al.
        Evaluation of cyclosporine A in a stroke model in the immature rat brain.
        Exp Neurol. 2011; 230: 58-66
        • Huang C.H.
        • Tsai M.S.
        • Hsu C.Y.
        • Su Y.J.
        • Wang T.D.
        • Chang W.T.
        • et al.
        Post-cardiac arrest myocardial dysfunction is improved with cyclosporine treatment at onset of resuscitation but not in the reperfusion phase.
        Resuscitation. 2011; 82: S41-S47
        • Abella B.S.
        • Rhee J.W.
        • Huang K.N.
        • Vanden Hoek T.L.
        • Becker L.B.
        Induced hypothermia is underused after resuscitation from cardiac arrest: a current practice survey.
        Resuscitation. 2005; 64: 181-186
        • Merchant R.M.
        • Soar J.
        • Skrifvars M.B.
        • Silfvast T.
        • Edelson D.P.
        • Ahmad F.
        • et al.
        Therapeutic hypothermia utilization among physicians after resuscitation from cardiac arrest.
        Crit Care Med. 2006; 34: 1935-1940
        • Hagerdal M.
        • Harp J.
        • Nilsson L.
        • Siesjo B.K.
        The effect of induced hypothermia upon oxygen consumption in the rat brain.
        J Neurochem. 1975; 24: 311-316
        • Horiguchi T.
        • Shimizu K.
        • Ogino M.
        • Suga S.
        • Inamasu J.
        • Kawase T.
        Postischemic hypothermia inhibits the generation of hydroxyl radical following transient forebrain ischemia in rats.
        J Neurotrauma. 2003; 20: 511-520
        • Berger C.
        • Schabitz W.R.
        • Georgiadis D.
        • Steiner T.
        • Aschoff A.
        • Schwab S.
        Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a microdialysis study.
        Stroke. 2002; 33: 519-524
        • Hachimi-Idrissi S.
        • Van Hemelrijck A.
        • Michotte A.
        • Smolders I.
        • Sarre S.
        • Ebinger G.
        • et al.
        Postischemic mild hypothermia reduces neurotransmitter release and astroglial cell proliferation during reperfusion after asphyxial cardiac arrest in rats.
        Brain Res. 2004; 1019: 217-225
        • Xu L.
        • Yenari M.A.
        • Steinberg G.K.
        • Giffard R.G.
        Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade.
        J Cereb Blood Flow Metab. 2002; 22: 21-28
        • Siesjo B.K.
        • Bengtsson F.
        • Grampp W.
        • Theander S.
        Calcium, excitotoxins, and neuronal death in the brain.
        Ann N Y Acad Sci. 1989; 568: 234-251
        • Busto R.
        • Globus M.Y.
        • Dietrich W.D.
        • Martinez E.
        • Valdes I.
        • Ginsberg M.D.
        Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain.
        Stroke. 1989; 20: 904-910
        • Okonkwo D.O.
        • Melon D.E.
        • Pellicane A.J.
        • Mutlu L.K.
        • Rubin D.G.
        • Stone J.R.
        • et al.
        Dose–response of cyclosporin A in attenuating traumatic axonal injury in rat.
        Neuroreport. 2003; 14: 463-466
        • Schinzel A.C.
        • Takeuchi O.
        • Huang Z.
        • Fisher J.K.
        • Zhou Z.
        • Rubens J.
        • et al.
        Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia.
        Proc Natl Acad Sci U S A. 2005; 102: 12005-12010
        • Lemasters J.J.
        • Nieminen A.L.
        • Qian T.
        • Trost L.C.
        • Elmore S.P.
        • Nishimura Y.
        • et al.
        The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy.
        Biochim Biophys Acta. 1998; 1366: 177-196
        • Miura T.
        • Tanno M.
        Mitochondria and GSK-3beta in cardioprotection against ischemia/reperfusion injury.
        Cardiovasc Drugs Ther. 2010; 24: 255-263
        • Adhihetty P.J.
        • Ljubicic V.
        • Menzies K.J.
        • Hood D.A.
        Differential susceptibility of subsarcolemmal and intermyofibrillar mitochondria to apoptotic stimuli.
        Am J Physiol Cell Physiol. 2005; 289: C994-C1001
        • Sims N.R.
        • Muyderman H.
        Mitochondria, oxidative metabolism and cell death in stroke.
        Biochim Biophys Acta. 2010; 1802: 80-91
        • Akao M.
        • O'Rourke B.
        • Kusuoka H.
        • Teshima Y.
        • Jones S.P.
        • Marban E.
        Differential actions of cardioprotective agents on the mitochondrial death pathway.
        Circ Res. 2003; 92: 195-202
        • Halestrap A.P.
        • Connern C.P.
        • Griffiths E.J.
        • Kerr P.M.
        Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury.
        Mol Cell Biochem. 1997; 174: 167-172
        • Argaud L.
        • Gateau-Roesch O.
        • Muntean D.
        • Chalabreysse L.
        • Loufouat J.
        • Robert D.
        • et al.
        Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury.
        J Mol Cell Cardiol. 2005; 38: 367-374
        • Nakagawa T.
        • Shimizu S.
        • Watanabe T.
        • Yamaguchi O.
        • Otsu K.
        • Yamagata H.
        • et al.
        Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death.
        Nature. 2005; 434: 652-658
        • Halestrap A.P.
        • Woodfield K.Y.
        • Connern C.P.
        Oxidative stress, thiol reagents, and membrane potential modulate the mitochondrial permeability transition by affecting nucleotide binding to the adenine nucleotide translocase.
        J Biol Chem. 1997; 272: 3346-3354
        • Woodfield K.
        • Ruck A.
        • Brdiczka D.
        • Halestrap A.P.
        Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition.
        Biochem J. 1998; 336: 287-290
        • Wang X.
        • Carlsson Y.
        • Basso E.
        • Zhu C.
        • Rousset C.I.
        • Rasola A.
        • et al.
        Developmental shift of cyclophilin D contribution to hypoxic–ischemic brain injury.
        J Neurosci Off J Soc Neurosci. 2009; 29: 2588-2596
        • Wang X.
        • Han W.
        • Du X.
        • Zhu C.
        • Carlsson Y.
        • Mallard C.
        • et al.
        Neuroprotective effect of bax-inhibiting peptide on neonatal brain injury.
        Stroke. 2010; 41: 2050-2055
        • Griffiths E.J.
        • Halestrap A.P.
        Further evidence that cyclosporin A protects mitochondria from calcium overload by inhibiting a matrix peptidyl-prolyl cis-trans isomerase. implications for the immunosuppressive and toxic effects of cyclosporin.
        Biochem J. 1991; 274: 611-614
        • Friberg H.
        • Ferrand-Drake M.
        • Bengtsson F.
        • Halestrap A.P.
        • Wieloch T.
        Cyclosporin A, but not FK 506, protects mitochondria and neurons against hypoglycemic damage and implicates the mitochondrial permeability transition in cell death.
        J Neurosci. 1998; 18: 5151-5159
        • Uchino H.
        • Minamikawa-Tachino R.
        • Kristian T.
        • Perkins G.
        • Narazaki M.
        • Siesjo B.K.
        • et al.
        Differential neuroprotection by cyclosporin A and FK506 following ischemia corresponds with differing abilities to inhibit calcineurin and the mitochondrial permeability transition.
        Neurobiol Dis. 2002; 10: 219-233
        • Domanska-Janik K.
        • Buzanska L.
        • Dluzniewska J.
        • Kozlowska H.
        • Sarnowska A.
        • Zablocka B.
        Neuroprotection by cyclosporin A following transient brain ischemia correlates with the inhibition of the early efflux of cytochrome C to cytoplasm.
        Brain Res Mol Brain Res. 2004; 121: 50-59
        • He L.
        • Lemasters J.J.
        Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function?.
        FEBS Lett. 2002; 512: 1-7
        • Griffiths E.J.
        • Halestrap A.P.
        Protection by cyclosporin A of ischemia/reperfusion-induced damage in isolated rat hearts.
        J Mol Cell Cardiol. 1993; 25: 1461-1469
        • Clarke S.J.
        • McStay G.P.
        • Halestrap A.P.
        Sanglifehrin A acts as a potent inhibitor of the mitochondrial permeability transition and reperfusion injury of the heart by binding to cyclophilin-D at a different site from cyclosporin A.
        J Biol Chem. 2002; 277: 34793-34799
        • Basso E.
        • Fante L.
        • Fowlkes J.
        • Petronilli V.
        • Forte M.A.
        • Bernardi P.
        Properties of the permeability transition pore in mitochondria devoid of cyclophilin D.
        J Biol Chem. 2005; 280: 18558-18561
        • Baines C.P.
        • Kaiser R.A.
        • Purcell N.H.
        • Blair N.S.
        • Osinska H.
        • Hambleton M.A.
        • et al.
        Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death.
        Nature. 2005; 434: 658-662
        • Okonkwo D.O.
        • Povlishock J.T.
        An intrathecal bolus of cyclosporin A before injury preserves mitochondrial integrity and attenuates axonal disruption in traumatic brain injury.
        J Cereb Blood Flow Metab. 1999; 19: 443-451
        • Gong P.
        • Hua R.
        • Zhang Y.
        • Zhao H.
        • Tang Z.
        • Mei X.
        • et al.
        Hypothermia-induced neuroprotection is associated with reduced mitochondrial membrane permeability in a swine model of cardiac arrest.
        J Cereb Blood Flow Metab. 2013; 33: 928-934
        • Tissier R.
        • Couvreur N.
        • Ghaleh B.
        • Bruneval P.
        • Lidouren F.
        • Morin D.
        • et al.
        Rapid cooling preserves the ischaemic myocardium against mitochondrial damage and left ventricular dysfunction.
        Cardiovasc Res. 2009; 83: 345-353
        • Kuchena A.
        • Merkel M.J.
        • Hutchens M.P.
        Postcardiac arrest temperature management: infectious risks.
        Curr Opin Crit Care. 2014; 20: 507-515
        • Garcia-Saenz-de-Sicilia M.
        • Mukherjee S.
        The adverse pharmacology of calcineurin inhibitors and their impact on hepatitis C recurrence after liver transplantation: implications for clinical practice.
        Expert Rev Clin Pharmacol. 2012; 5: 587-593
        • Li J.
        • Han B.
        • Ma X.
        • Qi S.
        The effects of propofol on hippocampal caspase-3 and bcl-2 expression following forebrain ischemia–reperfusion in rats.
        Brain Res. 2010; 1356: 11-23
        • Chen J.
        • Nagayama T.
        • Jin K.
        • Stetler R.A.
        • Zhu R.L.
        • Graham S.H.
        • et al.
        Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia.
        J Neurosci. 1998; 18: 4914-4928
        • Ohta H.
        • Adachi T.
        • Hirano K.
        Internalization of human extracellular-superoxide dismutase by bovine aortic endothelial cells.
        Free Radic Biol Med. 1994; 16: 501-507
        • Anaya-Prado R.
        • Toledo-Pereyra L.H.
        • Lentsch A.B.
        • Ward P.A.
        Ischemia/reperfusion injury.
        J Surg Res. 2002; 105: 248-258
        • Halliwell B.
        • Gutteridge J.M.
        • Cross C.E.
        Free radicals, antioxidants, and human disease: where are we now?.
        J Lab Clin Med. 1992; 119: 598-620
        • Chan P.H.
        Role of oxidants in ischemic brain damage.
        Stroke. 1996; 27: 1124-1129
        • Hausenloy D.J.
        • Duchen M.R.
        • Yellon D.M.
        Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia-reperfusion injury.
        Cardiovasc Res. 2003; 60: 617-625