Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury
Tóm tắt
Traumatic injury to the mammalian spinal cord is a highly dynamic process characterized by a complex pattern of pervasive and destructive biochemical and pathophysiological events that limit the potential for functional recovery. Currently, there are no effective therapies for the treatment of spinal cord injury (SCI) and this is due, in part, to the widespread impact of the secondary injury cascades, including edema, ischemia, excitotoxicity, inflammation, oxidative damage, and activation of necrotic and apoptotic cell death signaling events. In addition, many of the signaling pathways associated with these cascades intersect and initiate other secondary injury events. Therefore, it can be argued that therapeutic strategies targeting a specific biochemical cascade may not provide the best approach for promoting functional recovery. A “systems approach” at the subcellular level may provide a better strategy for promoting cell survival and function and, as a consequence, improve functional outcomes following SCI. One such approach is to study the impact of SCI on the biology and function of mitochondria, which serve a major role in cellular bioenergetics, function, and survival. In this review, we will briefly describe the importance and unique properties of mitochondria in the spinal cord, and what is known about the response of mitochondria to SCI. We will also discuss a number of strategies with the potential to promote mitochondrial function following SCI.
Tài liệu tham khảo
Lemasters JJ, Holmuhamedov E. Voltage-dependent anion channel (VDAC) as mitochondrial governator--thinking outside the box. Biochim Biophys Acta 2006;1762:181–190.
Saraste M. Oxidative phosphorylation at the fin de siecle. Science 1999;283:1488–1493.
Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol 2003;552:335–344.
Ackerman SH, Tzagoloff A. Function, structure, and biogenesis of mitochondrial ATP synthase. Prog Nucleic Acid Res Mol Biol 2005;80:95–133.
Oster G, Wang H. Reverse engineering a protein: the mechanochemistry of ATP synthase. Biochim Biophys Acta 2000;1458:482–510.
Ahn YH, Lee G, Kang SK. Molecular insights of the injured lesions of rat spinal cords: Inflammation, apoptosis, and cell survival. Biochem Biophys Res Commun 2006;348:560–570.
Genovese T, Cuzzocrea S. Role of free radicals and poly(ADP-ribose)polymerase-1 in the development of spinal cord injury: new potential therapeutic targets. Curr Med Chem 2008;15:477–487.
Hall ED, Springer JE. Neuroprotection and acute spinal cord injury: a reappraisal. NeuroRx 2004;1:80–100.
Rowland JW, Hawryluk GW, Kwon B, Fehlings MG. Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon. Neurosurg Focus 2008;25:E2.
Young W, Koreh I. Potssium and calcium changes in injured spinal cords. Brain Research 1986;365:42–53.
Demediuk P, Lemke M, Faden A. Spinal cord edema and changes in tissue content of Na+, K+, and Mg2+ after impact trauma in rats. Adv Neurol 1990;52:225–232.
Kwo S, Young W, Decrescito V. Spinal cord sodium, potassium, calcium, and water concentration changes in rats after graded contusion injury. J Neurotrauma 1989;6:13–24.
Sharma H, Winkler T, Stalberg E, Olsson Y, Dey P. Evaluation of traumatic spinal cord edema using evoked potentials recorded from the spinal epidural space. An experimental study in the rat. J Neurol Sci 1991;102:150–162.
LoPachin R, Gaughan C, Lehning E, Kaneko Y, Kelly T, Blight A. Experimental spinal cord injury: spatiotemporal characterization of elemental concentrations and water contents in axons and neuroglia. J Neurophysiol 1999;82:2143–2153.
Chinopoulos C, Adam-Vizi V. Mitochondrial Ca2+ sequestration and precipitation revisited. Febs J 2010;277:3637–3651.
Crompton M. The mitochondrial permeability transition pore and its role in cell death. Biochem J 1999;341:233–249.
Pivovarova NB, Andrews SB. Calcium-dependent mitochondrial function and dysfunction in neurons. Febs J 2010;277:3622–3636.
Starkov AA, Chinopoulos C, Fiskum G. Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury. Cell Calcium 2004;36:257–264.
Kinnally KW, Peixoto PM, Ryu SY, Dejean LM. Is mPTP the gatekeeper for necrosis, apoptosis, or both? Biochim Biophys Acta 2010. doi:10.1016/j.bbamcr.2010.09.13.
Hirsch T, Susin SA, Marzo I, Marchetti P, Zamzami N, Kroemer G. Mitochondrial permeability transition in apoptosis and necrosis [In Process Citation]. Cell Biol Toxicol 1998;14:141–145.
Lemasters JJ, Nieminen AL, Qian T, et al. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta 1998;1366:177–196.
Lemasters JJ, Qian T, Elmore SP, et al. Confocal microscopy of the mitochondrial permeability transition in necrotic cell killing, apoptosis and autophagy. Biofactors 1998;8:283–285.
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 2010;11:700–714.
Crompton M. On the involvement of mitochondrial intermembrane junctional complexes in apoptosis. Curr Med Chem 2003;10:1473–1484.
Crompton M, Barksby E, Johnson N, Capano M. Mitochondrial intermembrane junctional complexes and their involvement in cell death. Biochimie 2002;84:143–152.
Halestrap AP, McStay GP, Clarke SJ. The permeability transition pore complex: another view. Biochimie 2002;84:153–166.
Zorov DB, Juhaszova M, Yaniv Y, Nuss HB, Wang S, Sollott SJ. Regulation and pharmacology of the mitochondrial permeability transition pore. Cardiovasc Res 2009;83:213–225.
Nicholls DG, Ward MW. Mitochondrial membrane potential and neuronal glutamate excitotoxicity: mortality and millivolts. Trends Neurosci 2000;23:166–174.
Szabo I, Bernardi P, Zoratti M. Modulation of the mitochondrial megachannel by divalent cations and protons. J Biol Chem 1992;267:2940–2946.
Szabo I, Zoratti M. The giant channel of the inner mitochondrial membrane is inhibited by cyclosporin A. J Biol Chem 1991;266:3376–3379.
Szabo I, Zoratti M. The mitochondrial megachannel is the permeability transition pore. J Bioenerg Biomembr 1992;24:111–117.
Zoratti M, Szabo I. The mitochondrial permeability transition. Biochim Biophys Acta 1995;1241:139–176.
Sesso A, Marques MM, Monteiro MM, et al. Morphology of mitochondrial permeability transition: morphometric volumetry in apoptotic cells. Anat Rec A Discov Mol Cell Evol Biol 2004;281:1337–1351.
Christofferson DE, Yuan J. Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol 2010;22:263–268.
Duprez L, Wirawan E, Vanden Berghe T, Vandenabeele P. Major cell death pathways at a glance. Microbes Infect 2009;11:1050–1062.
Green DR, Evan GI. A matter of life and death. Cancer Cell 2002;1:19–30.
McEwen ML, Springer JE. The biology of capsases in central nervous system trauma. In: Banik N,Lajtha A, eds. Handbook of Neurochemistry and Molecular Neurobiology: Neural Protein Metabolism and Function, 3 rd ed. New York: Springer, 2007:515–550.
Wang X. The expanding role of mitochondria in apoptosis. Genes Dev 2001;15:2922–2933.
Eguchi Y, Shimizu S, Tsujimoto Y. Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 1997;57:1835–1840.
Formigli L, Papucci L, Tani A, et al. Aponecrosis: morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis. J Cell Physiol 2000;182:41–49.
Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 1997;185:1481–1486.
Nicotera P, Leist M, Ferrando-May E. Intracellular ATP, a switch in the decision between apoptosis and necrosis. Toxicol Lett 1998;102–103:139–142.
Jin Y, McEwen ML, Nottingham SA, et al. The mitochondrial uncoupling agent 2,4-dinitrophenol improves mitochondrial function, attenuates oxidative damage, and increases white matter sparing in the contused spinal cord. J Neurotrauma 2004;21:1396–1404.
McEwen ML, Sullivan PG, Springer JE. Pretreatment with the cyclopsorin derivative, NIM811, improves the function of synaptic mitochondria following spinal cord contusion in rats. J Neurotrauma 2007;24:613–624.
Patel SP, Sullivan PG, Lyttle TS, Rabchevsky AG. Acetyl-L-carnitine ameliorates mitochondrial dysfunction following contusion spinal cord injury. J Neurochem 2010;114:291–301.
Patel SP, Sullivan PG, Pandya JD, Rabchevsky AG. Differential effects of the mitochondrial uncoupling agent, 2,4-dinitrophenol, or the nitroxide antioxidant, Tempol, on synaptic or nonsynaptic mitochondria after spinal cord injury. J Neurosci Res 2009;87:130–140.
Sullivan PG, Krishnamurthy S, Patel SP, Pandya JD, Rabchevsky AG. Temporal characterization of mitochondrial bioenergetics after spinal cord injury. J Neurotrauma 2007;24:991–999.
Maragos WF, Korde AS. Mitochondrial uncoupling as a potential therapeutic target in acute central nervous system injury. J Neurochem 2004;91:257–262.
Sullivan PG, Springer JE, Hall ED, Scheff SW. Mitochondrial uncoupling as a therapeutic target following neuronal injury. J Bioenerg Biomembr 2004;36:353–356.
Xiong Y, Singh IN, Hall ED. Tempol protection of spinal cord mitochondria from peroxynitrite-induced oxidative damage. Free Radic Res 2009;43:604–612.
Calabrese V, Ravagna A, Colombrita C, et al. Acetylcarnitine induces heme oxygenase in rat astrocytes and protects against oxidative stress: involvement of the transcription factor Nrf2. J Neurosci Res 2005;79:509–521.
Clark JB, Nicklas WJ. The metabolism of rat brain mitochondria. Preparation and characterization. J Biol Chem 1970;245:4724–4731.
Nicklas WJ, Clark JB, Williamson JR. Metabolism of rat brain mitochondria. Studies on the potassium ion-stimulated oxidation of pyruvate. Biochem J 1971;123:83–95.
Martin E, Rosenthal RE, Fiskum G. Pyruvate dehydrogenase complex: metabolic link to ischemic brain injury and target of oxidative stress. J Neurosci Res 2005;79:240–247.
Paradies G, Petrosillo G, Gadaleta MN, Ruggiero FM. The effect of aging and acetyl-L-carnitine on the pyruvate transport and oxidation in rat heart mitochondria. FEBS Lett 1999;454:207–209.
Petruzzella V, Baggetto LG, Penin F, et al. In vivo effect of acetyl-L-carnitine on succinate oxidation, adenine nucleotide pool and lipid composition of synaptic and non-synaptic mitochondria from cerebral hemispheres of senescent rats. Arch Gerontol Geriatr 1992;14:131–144.
Anonymous. Acetyl-L-carnitine. Altern Med Rev 1999;4:438–441.
Lewen A, Matz P, Chan PH. Free radical pathways in CNS injury. J Neurotrauma 2000;17:871–890.
Fiskum G. Mitochondrial participation in ischemic and traumatic neural cell death. J Neurotrauma 2000;17:843–855.
Starkov A, Fiskum G, Chinopoulos C, et al. Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 2004;24:7779–7788.
Anderson DK, Waters TR, Means ED. Pretreatment with alpha tocopherol enhances neurologic recovery after experimental spinal cord compression injury. J Neurotrauma 1988;5:61–67.
Al Jadid MS, Robert A, Al-Mubarak S. The efficacy of alpha-tocopherol in functional recovery of spinal cord injured rats: an experimental study. Spinal Cord 2009;47:662–667.
Bozbuga M, Izgi N, Canbolat A. The effects of chronic alpha-tocopherol administration on lipid peroxidation in an experimental model of acute spinal cord injury. Neurosurg Rev 1998;21:36–42.
Sheu SS, Nauduri D, Anders MW. Targeting antioxidants to mitochondria: a new therapeutic direction. Biochim Biophys Acta 2006;1762:256–265.
Miller ER, 3 rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37–46.
Kohno M. Applications of electron spin resonance spectrometry for reactive oxygen species and reactive nitrogen species research. J Clin Biochem Nutr 2010;47:1–11.
Kopani M, Celec P, Danisovic L, Michalka P, Biro C. Oxidative stress and electron spin resonance. Clin Chim Acta 2006;364:61–66.
Farooque M, Olsson Y, Hillered L. Pretreatment with alpha-phenyl-N-tert-butyl-nitrone (PBN) improves energy metabolism after spinal cord injury in rats. J Neurotrauma 1997;14:469–476.
Li GL, Farooque M, Holtz A, Olsson Y. Effects of alpha-phenyl-N-tert-butyl nitrone (PBN) on compression injury of rat spinal cord. Free Radic Res 1997;27:187–196.
Hillard VH, Peng H, Zhang Y, et al. Tempol, a nitroxide antioxidant, improves blocomotor and histological outcomes after spinal cord contusion in rats. J Neurotrauma 2004;21:1405–1414.
Xiong Y, Hall ED. Pharmacological evidence for a role of peroxynitrite in the pathophysiology of spinal cord injury. Exp Neurol 2009;216:105–114.
Grilli M, Pizzi M, Memo M, Spano P. Neuroprotection by aspirin and sodium salicylate through blockade of NF-kappaB activation. Science 1996;274:1383–1385.
Ko HW, Park KY, Kim H, et al. Ca2+−mediated activation of c-Jun N-terminal kinase and nuclear factor kappa B by NMDA in cortical cell cultures. J Neurochem 1998;71:1390–1395.
Noh J, Lee ES, Chung JM. The novel NMDA receptor antagonist, 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid, is a gating modifier in cultured mouse cortical neurons. J Neurochem 2009;109:1261–1271.
Gionchetti P, Guarnieri C, Campieri M, et al. Scavenger effect of sulphasalazine (SASP), 5-aminosalicylic acid (5-ASA), and olsalazine (OAZ). Gut 1990;31:730–731.
Ryu BR, Lee YA, Won SJ, et al. The novel neuroprotective action of sulfasalazine through blockade of NMDA receptors. J Pharmacol Exp Ther 2003;305:48–56.
Springer JE, Rao RR, Lim HR, et al. The functional and neuroprotective actions of Neu2000, a dual-acting pharmacological agent, in the treatment of acute spinal cord injury. J Neurotrauma 2010;27:139–149.
Sullivan PG, Rabchevsky AG, Keller JN, et al. Intrinsic differences in brain and spinal cord mitochondria: Implication for therapeutic interventions. J Comp Neurol 2004;474:524–534.
Kelso GF, Porteous CM, Hughes G, et al. Prevention of mitochondrial oxidative damage using targeted antioxidants. Ann N Y Acad Sci 2002;959:263–274.
Kelso GF, Porteous CM, Coulter CV, et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem 2001;276:4588–4596.
Dhanasekaran A, Kotamraju S, Karunakaran C, et al. Mitochondria superoxide dismutase mimetic inhibits peroxide-induced oxidative damage and apoptosis: role of mitochondrial superoxide. Free Radic Biol Med 2005;39:567–583.
Cassina P, Cassina A, Pehar M, et al. Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J Neurosci 2008;28:4115–4122.
Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA, Bernardi P. Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J Biol Chem 2005;280:18558–18561.
Nakagawa T, Shimizu S, Watanabe T, et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 2005;434:652–658.
Schinzel AC, Takeuchi O, Huang Z, 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.
Baines CP, Kaiser RA, Purcell NH, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 2005;434:658–662.
Brustovetsky N, Brustovetsky T, Jemmerson R, Dubinsky JM. Calcium-induced cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane. J Neurochem 2002;80:207–218.
Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y. Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature 2000;406:855–862.
Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000;102:33–42.
Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 2001;412:95–99.
Petronilli V, Penzo D, Scorrano L, Bernardi P, Di Lisa F. The mitochondrial permeability transition, release of cytochrome c and cell death. Correlation with the duration of pore openings in situ. J Biol Chem 2001;276:12030–12034.
van Loo G, Schotte P, van Gurp M, et al. Endonuclease G: a mitochondrial protein released in apoptosis and involved in caspase-independent DNA degradation. Cell Death Differ 2001;8:1136–1142.
Cande C, Cohen I, Daugas E, et al. Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria. Biochimie 2002;84:215–222.
Argaud L, Gateau-Roesch O, Muntean D, et al. Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J Mol Cell Cardiol 2005;38:367–374.
Friberg H, Ferrand-Drake M, Bengtsson F, Halestrap AP, 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.
Gomez L, Thibault H, Gharib A, et al. Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice. Am J Physiol Heart Circ Physiol 2007;293:H1654-1661.
Li PA, Kristian T, He QP, Siesjo BK. Cyclosporin A enhances survival, ameliorates brain damage, and prevents secondary mitochondrial dysfunction after a 30-minute period of transient cerebral ischemia. Exp Neurol 2000;165:153–163.
Matsumoto S, Friberg H, Ferrand-Drake M, Wieloch T. Blockade of the mitochondrial permeability transition pore diminishes infarct size in the rat after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 1999;19:736–741.
Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 2008;359:473–481.
Scheff SW, Sullivan PG. Cyclosporin A significantly ameliorates cortical damage following experimental traumatic brain injury in rodents. J Neurotrauma 1999;16:783–792.
Sullivan PG, Rabchevsky AG, Hicks RR, Gibson TR, Fletcher-Turner A, Scheff SW. Dose-response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats. Neuroscience 2000;101:289–295.
Sullivan PG, Thompson MB, Scheff SW. Cyclosporin A attenuates acute mitochondrial dysfunction following traumatic brain injury. Exp Neurol 1999;160:226–234.
Uchino H, Minamikawa-Tachino R, Kristian T, 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.
Empey PE, McNamara PJ, Young B, Rosbolt MB, Hatton J. Cyclosporin A disposition following acute traumatic brain injury. J Neurotrauma 2006;23:109–116.
Diaz-Ruiz A, Rios C, Duarte I, et al. Cyclosporin-A inhibits lipid peroxidation after spinal cord injury in rats. Neurosci Lett 1999;266:61–64.
Diaz-Ruiz A, Rios C, Duarte I, et al. Lipid peroxidation inhibition in spinal cord injury: cyclosporin-A vs methylprednisolone. Neuroreport 2000;11:1765–1767.
Ibarra A, Correa D, Willms K, et al. Effects of cyclosporin-A on immune response, tissue protection and motor function of rats subjected to spinal cord injury. Brain Res 2003;979:165–178.
Ibarra A, Guizar-Sahagun G, Correa D, et al. Alteration of cyclosporin-A pharmacokinetics after experimental spinal cord injury. J Neurotrauma 1996;13:267–272.
Ibarra A, Reyes J, Martinez S, et al. Use of cyclosporin-A in experimental spinal cord injury: design of a dosing strategy to maintain therapeutic levels. J Neurotrauma 1996;13:569–572.
Rabchevsky AG, Fugaccia I, Sullivan PG, Scheff SW. Cyclosporin A treatment following spinal cord injury to the rat: behavioral effects and stereological assessment of tissue sparing. J Neurotrauma 2001;18:513–522.
Sullivan PG, Rabchevsky AG, Waldmeier PC, Springer JE. Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death? J Neurosci Res 2005;79:231–239.
Hansson MJ, Mattiasson G, Mansson R, et al. The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria. J Bioenerg Biomembr 2004;36:407–413.
Waldmeier PC, Feldtrauer JJ, Qian T, Lemasters JJ. Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811. Mol Pharmacol 2002;62:22–29.
Waldmeier PC, Zimmermann K, Qian T, Tintelnot-Blomley M, Lemasters JJ. Cyclophilin D as a drug target. Curr Med Chem 2003;10:1485–1506.
Chatterji U, Bobardt M, Selvarajah S, et al. The isomerase active site of cyclophilin A is critical for hepatitis C virus replication. J Biol Chem 2009;284:16998–17005.
Goto K, Watashi K, Murata T, Hishiki T, Hijikata M, Shimotohno K. Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811. Biochem Biophys Res Commun 2006;343:879–884.
Ma S, Boerner JE, TiongYip C, et al. NIM811, a cyclophilin inhibitor, exhibits potent in vitro activity against hepatitis C virus alone or in combination with alpha interferon. Antimicrob Agents Chemother 2006;50:2976–2982.
Coelmont L, Kaptein S, Paeshuyse J, et al. Debio 025, a cyclophilin binding molecule, is highly efficient in clearing hepatitis C virus (HCV) replicon-containing cells when used alone or in combination with specifically targeted antiviral therapy for HCV (STAT-C) inhibitors. Antimicrob Agents Chemother 2009;53:967–976.
Flisiak R, Feinman SV, Jablkowski M, et al. The cyclophilin inhibitor Debio 025 combined with PEG IFNalpha2a significantly reduces viral load in treatment-naive hepatitis C patients. Hepatology 2009;49:1460–1468.
Mathy JE, Ma S, Compton T, Lin K. Combinations of cyclophilin inhibitor NIM811 with hepatitis C Virus NS3-4A Protease or NS5B polymerase inhibitors enhance antiviral activity and suppress the emergence of resistance. Antimicrob Agents Chemother 2008;52:3267–3275.
Raisky O, Gomez L, Chalabreysse L, et al. Mitochondrial permeability transition in cardiomyocyte apoptosis during acute graft rejection. Am J Transplant 2004;4:1071–1078.
Fox DA, Poblenz AT, He L, Harris JB, Medrano CJ. Pharmacological strategies to block rod photoreceptor apoptosis caused by calcium overload: a mechanistic target-site approach to neuroprotection. Eur J Ophthalmol 2003;13(suppl 3:S44-S456.
Popovich PG, Horner PJ, Mullin BB, Stokes BT. A quantitative spatial analysis of the blood-spinal cord barrier. I. Permeability changes after experimental spinal contusion injury. Exp Neurol 1996;142:258–275.
Noble LJ, Wrathall JR. Distribution and time course of protein extravasation in the rat spinal cord after contusive injury. Brain Res 1989;482:57–66.
Ravikumar R, McEwen ML, Springer JE. Post-treatment with the cyclosporin derivative, NIM811, reduced indices of cell death and increased the volume of spared tissue in the acute period following spinal cord contusion. J Neurotrauma 2007;24:1618–1630.
Korde AS, Pettigrew LC, Craddock SD, Pocernich CB, Waldmeier PC, Maragos WF. Protective effects of NIM811 in transient focal cerebral ischemia suggest involvement of the mitochondrial permeability transition. J Neurotrauma 2007;24:895–908.
Hokari M, Kuroda S, Iwasaki Y. Pretreatment with the ciclosporin derivative NIM811 reduces delayed neuronal death in the hippocampus after transient forebrain ischaemia. J Pharm Pharmacol 2010;62:485–490.
Mbye LH, Singh IN, Sullivan PG, Springer JE, Hall ED. Attenuation of acute mitochondrial dysfunction after traumatic brain injury in mice by NIM811, a non-immunosuppressive cyclosporin A analog. Exp Neurol 2008;209:243–253.
Mbye LH, Singh IN, Carrico KM, Saatman KE, Hall ED. Comparative neuroprotective effects of cyclosporin A and NIM811, a nonimmunosuppressive cyclosporin A analog, following traumatic brain injury. J Cereb Blood Flow Metab 2009;29:87–97.