In Vivo/Ex Vivo EPR Investigation of the Brain Redox Status and Blood-Brain Barrier Integrity in the 5xFAD Mouse Model of Alzheimer's Disease

Author(s): Ana Vesković, Đura Nakarada, Aleksandra Pavićević, Bogomir Prokić, Milka Perović, Selma Kanazir, Ana Popović-Bijelić*, Miloš Mojović

Journal Name: Current Alzheimer Research

Volume 18 , Issue 1 , 2021


  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor

Abstract:

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by cognitive decline and total brain atrophy. Despite the substantial scientific effort, the pathological mechanisms underlying neurodegeneration in AD are currently unknown. In most studies, amyloid β peptide has been considered the key pathological change in AD. However, numerous Aβ-targeting treatments have failed in clinical trials. This implies the need to shift the research focus from Aβ to other pathological features of the disease.

Objective: The aim of this study was to examine the interplay between mitochondrial dysfunction, oxidative stress and blood-brain barrier (BBB) disruption in AD pathology, using a novel approach that involves the application of electron paramagnetic resonance (EPR) spectroscopy.

Methods: In vivo and ex vivo EPR spectroscopy using two spin probes (aminoxyl radicals) exhibiting different cell-membrane and BBB permeability were employed to assess BBB integrity and brain tissue redox status in the 5xFAD mouse model of AD. In vivo spin probe reduction decay was analyzed using a two-compartment pharmacokinetic model. Furthermore, 15 K EPR spectroscopy was employed to investigate the brain metal content.

Results: This study has revealed an altered brain redox state, BBB breakdown, as well as ROS-mediated damage to mitochondrial iron-sulfur clusters, and up-regulation of MnSOD in the 5xFAD model.

Conclusion: The EPR spin probes were shown to be excellent in vivo reporters of the 5xFAD neuronal tissue redox state, as well as the BBB integrity, indicating the importance of in vivo EPR spectroscopy application in preclinical studies of neurodegenerative diseases.

Keywords: Alzheimer's disease, blood-brain barrier, EPR, mitochondria, spin probes, 5xFAD.

[1]
Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nat Rev Dis Primers 2015; 1: 15056.
[http://dx.doi.org/10.1038/nrdp.2015.56] [PMID: 27188934]
[2]
DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener 2019; 14(1): 32.
[http://dx.doi.org/10.1186/s13024-019-0333-5] [PMID: 31375134]
[3]
Alzheimer association Alzheimer’s disease facts and figures. Alzheimers Dement 2019; 1-88.
[4]
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. Lancet 2011; 377(9770): 1019-31.
[http://dx.doi.org/10.1016/S0140-6736(10)61349-9] [PMID: 21371747]
[5]
Iqbal K, Liu F, Gong C-X, Grundke-Iqbal I. Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 2010; 7(8): 656-64.
[http://dx.doi.org/10.2174/156720510793611592] [PMID: 20678074]
[6]
Weggen S, Beher D. Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer’s disease. Alzheimers Res Ther 2012; 4(2): 9.
[http://dx.doi.org/10.1186/alzrt107] [PMID: 22494386]
[7]
Chow VW, Mattson MP, Wong PC, Gleichmann M. An overview of APP processing enzymes and products. Neuromolecular Med 2010; 12(1): 1-12.
[http://dx.doi.org/10.1007/s12017-009-8104-z] [PMID: 20232515]
[8]
Sun X, Chen WD, Wang YD. β-Amyloid: The key peptide in the pathogenesis of Alzheimer’s disease. Front Pharmacol 2015; 6: 221.
[http://dx.doi.org/10.3389/fphar.2015.00221] [PMID: 26483691]
[9]
Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer’s disease: An appraisal for the development of therapeutics. Nat Rev Drug Discov 2011; 10(9): 698-712.
[http://dx.doi.org/10.1038/nrd3505] [PMID: 21852788]
[10]
Sanz-Blasco S, Calvo-Rodríguez M, Caballero E, García-Durillo M, Núñez L, Villalobos C. Is it all said for NSAIDs in Alzheimer’s disease? Role of mitochondrial calcium uptake. Curr Alzheimer Res 2018; 15(6): 504-10.
[http://dx.doi.org/10.2174/1567205015666171227154016] [PMID: 29283047]
[11]
Beason-Held LL, Goh JO, An Y, et al. Changes in brain function occur years before the onset of cognitive impairment. J Neurosci 2013; 33(46): 18008-14.
[http://dx.doi.org/10.1523/JNEUROSCI.1402-13.2013] [PMID: 24227712]
[12]
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7(3): 263-9.
[http://dx.doi.org/10.1016/j.jalz.2011.03.005] [PMID: 21514250]
[13]
Sabbagh MN, Lue LF, Fayard D, Shi J. Increasing precision of clinical diagnosis of Alzheimer’s disease using a combined algorithm incorporating clinical and novel biomarker data. Neurol Ther 2017; 6(Suppl. 1): 83-95.
[http://dx.doi.org/10.1007/s40120-017-0069-5] [PMID: 28733959]
[14]
Márquez F, Yassa MA. Neuroimaging biomarkers for Alzheimer’s disease. Mol Neurodegener 2019; 14(1): 21.
[http://dx.doi.org/10.1186/s13024-019-0325-5] [PMID: 31174557]
[15]
Khan TK. An algorithm for preclinical diagnosis of Alzheimer’s disease. Front Neurosci 2018; 12: 275.
[http://dx.doi.org/10.3389/fnins.2018.00275] [PMID: 29760644]
[16]
Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol 2019; 15(2): 73-88.
[http://dx.doi.org/10.1038/s41582-018-0116-6] [PMID: 30610216]
[17]
Perez Ortiz JM, Swerdlow RH. Mitochondrial dysfunction in Alzheimer’s disease: Role in pathogenesis and novel therapeutic opportunities. Br J Pharmacol 2019; 176(18): 3489-507.
[http://dx.doi.org/10.1111/bph.14585] [PMID: 30675901]
[18]
Moreira PI. Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease. Eur Neurol Rev 2010; 5(1): 17-21.
[http://dx.doi.org/10.17925/ENR.2010.05.01.17]
[19]
Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y) 2018; 4: 575-90.
[http://dx.doi.org/10.1016/j.trci.2018.06.014] [PMID: 30406177]
[20]
Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 2018; 14(3): 133-50.
[http://dx.doi.org/10.1038/nrneurol.2017.188] [PMID: 29377008]
[21]
Vakifahmetoglu-Norberg H, Ouchida AT, Norberg E. The role of mitochondria in metabolism and cell death. Biochem Biophys Res Commun 2017; 482(3): 426-31.
[http://dx.doi.org/10.1016/j.bbrc.2016.11.088] [PMID: 28212726]
[22]
Marchi S, Giorgi C, Suski JM, et al. Mitochondria-ros crosstalk in the control of cell death and aging. J Signal Transduct 2012; 2012: 329635.
[http://dx.doi.org/10.1155/2012/329635] [PMID: 22175013]
[23]
Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006; 443(7113): 787-95.
[http://dx.doi.org/10.1038/nature05292] [PMID: 17051205]
[24]
Brand MD, Affourtit C, Esteves TC, et al. Mitochondrial superoxide: Production, biological effects, and activation of uncoupling proteins. Free Radic Biol Med 2004; 37(6): 755-67.
[http://dx.doi.org/10.1016/j.freeradbiomed.2004.05.034] [PMID: 15304252]
[25]
Vásquez-Vivar J, Kalyanaraman B, Kennedy MC. Mitochondrial aconitase is a source of hydroxyl radical. An electron spin resonance investigation. J Biol Chem 2000; 275(19): 14064-9.
[http://dx.doi.org/10.1074/jbc.275.19.14064] [PMID: 10799480]
[26]
Kausar S, Wang F, Cui H. The role of mitochondria in reactive oxygen species generation and its implications for neurodegenerative diseases. Cells 2018; 7(12): 274.
[http://dx.doi.org/10.3390/cells7120274] [PMID: 30563029]
[27]
Cenini G, Lloret A, Cascella R. Oxidative stress in neurodegenerative diseases: From a mitochondrial point of view. Oxid Med Cell Longev 2019; 2019: 2105607.
[http://dx.doi.org/10.1155/2019/2105607] [PMID: 31210837]
[28]
Salim S. Oxidative stress and the central nervous system. J Pharmacol Exp Ther 2017; 360(1): 201-5.
[http://dx.doi.org/10.1124/jpet.116.237503] [PMID: 27754930]
[29]
Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G. Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochim Biophys Acta – Mol Bas Dis 2010; 1802(1): 2-10.
[http://dx.doi.org/10.1016/j.bbadis.2009.10.006]
[30]
Mosconi L. Glucose metabolism in normal aging and Alzheimer’s disease: Methodological and physiological considerations for PET studies. Clin Transl Imaging 2013; 1(4): 217-33.
[http://dx.doi.org/10.1007/s40336-013-0026-y] [PMID: 24409422]
[31]
Wojsiat J, Zoltowska KM, Laskowska-Kaszub K, Wojda U. Oxidant/antioxidant imbalance in Alzheimer’s disease: Therapeutic and diagnostic prospects. Oxid Med Cell Longev 2018; 2018: 6435861.
[http://dx.doi.org/10.1155/2018/6435861] [PMID: 29636850]
[32]
Wee M, Chegini F, Power JHT, Majd S. Tau positive neurons show marked mitochondrial loss and nuclear degradation in Alzheimer’s disease. Curr Alzheimer Res 2018; 15(10): 928-37.
[http://dx.doi.org/10.2174/1567205015666180613115644] [PMID: 29895248]
[33]
Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008; 57(2): 178-201.
[http://dx.doi.org/10.1016/j.neuron.2008.01.003] [PMID: 18215617]
[34]
Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006; 7(1): 41-53.
[http://dx.doi.org/10.1038/nrn1824] [PMID: 16371949]
[35]
Weiss N, Miller F, Cazaubon S, Couraud PO. The blood-brain barrier in brain homeostasis and neurological diseases. Biochim Biophys Acta 2009; 1788(4): 842-57.
[http://dx.doi.org/10.1016/j.bbamem.2008.10.022] [PMID: 19061857]
[36]
Tohidpour A, Morgun AV, Boitsova EB, et al. Neuroinflammation and infection: Molecular mechanisms associated with dysfunction of neurovascular unit. Front Cell Infect Microbiol 2017; 7: 276.
[http://dx.doi.org/10.3389/fcimb.2017.00276] [PMID: 28676848]
[37]
Montagne A, Zhao Z, Zlokovic BV. Alzheimer’s disease: A matter of blood-brain barrier dysfunction? J Exp Med 2017; 214(11): 3151-69.
[http://dx.doi.org/10.1084/jem.20171406] [PMID: 29061693]
[38]
Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and dysfunction of the blood-brain barrier. Cell 2015; 163(5): 1064-78.
[http://dx.doi.org/10.1016/j.cell.2015.10.067] [PMID: 26590417]
[39]
Nelson AR, Sweeney MD, Sagare AP, Zlokovic BV. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer’s disease. Biochim Biophys Acta 2016; 1862(5): 887-900.
[http://dx.doi.org/10.1016/j.bbadis.2015.12.016] [PMID: 26705676]
[40]
Nation DA, Sweeney MD, Montagne A, et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med 2019; 25(2): 270-6.
[http://dx.doi.org/10.1038/s41591-018-0297-y] [PMID: 30643288]
[41]
Carvalho C, Moreira PI. Oxidative stress: A major player in cerebrovascular alterations associated to neurodegenerative events. Front Physiol 2018; 9: 806.
[http://dx.doi.org/10.3389/fphys.2018.00806] [PMID: 30018565]
[42]
Dikalov SI, Polienko YF, Kirilyuk I. Electron paramagnetic resonance measurements of reactive oxygen species by cyclic hydroxylamine spin probes. Antioxid Redox Signal 2018; 28(15): 1433-43.
[http://dx.doi.org/10.1089/ars.2017.7396] [PMID: 29037084]
[43]
Valgimigli L, Pedulli GF, Paolini M. Measurement of oxidative stress by EPR radical-probe technique. Free Radic Biol Med 2001; 31(6): 708-16.
[http://dx.doi.org/10.1016/S0891-5849(01)00490-7] [PMID: 11557308]
[44]
Bačić G, Pavićević A, Peyrot F. In vivo evaluation of different alterations of redox status by studying pharmacokinetics of nitroxides using magnetic resonance techniques. Redox Biol 2016; 8: 226-42.
[http://dx.doi.org/10.1016/j.redox.2015.10.007] [PMID: 26827126]
[45]
Babić N, Peyrot F. Molecular probes for evaluation of oxidative stress by in vivo EPR spectroscopy and imaging: State-of-the-art and limitations. Magnetochemistry 2019; 5(13): 1-21.
[46]
Stamenković S, Pavićević A, Mojović M, et al. In vivo EPR pharmacokinetic evaluation of the redox status and the blood brain barrier permeability in the SOD1G93A ALS rat model. Free Radic Biol Med 2017; 108: 258-69.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.03.034] [PMID: 28366802]
[47]
Popović-Bijelić A, Mojović M, Stamenković S, et al. Iron-sulfur cluster damage by the superoxide radical in neural tissues of the SOD1(G93A) ALS rat model. Free Radic Biol Med 2016; 96: 313-22.
[http://dx.doi.org/10.1016/j.freeradbiomed.2016.04.028] [PMID: 27130034]
[48]
Oakley H, Cole SL, Logan S, et al. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J Neurosci 2006; 26(40): 10129-40.
[http://dx.doi.org/10.1523/JNEUROSCI.1202-06.2006] [PMID: 17021169]
[49]
Jaskova K, Pavlovicova M, Jurkovicova D. Electrophysiological variability in the SH-SY5Y cellular line. Gen Physiol Biophys 2014; 31(4): 375-82.
[http://dx.doi.org/10.4149/gpb_2012_053] [PMID: 23255663]
[50]
Iannone A, Hu HP, Tomasi A, Vannini V, Swartz HM. Metabolism of aqueous soluble nitroxides in hepatocytes: Effects of cell integrity, oxygen, and structure of nitroxides. Biochim Biophys Acta 1989; 991(1): 90-6.
[http://dx.doi.org/10.1016/0304-4165(89)90033-0] [PMID: 2540844]
[51]
Zhelev Z, Gadjeva V, Aoki I, Bakalova R, Saga T. Cell-penetrating nitroxides as molecular sensors for imaging of cancer in vivo, based on tissue redox activity. Mol Biosyst 2012; 8(10): 2733-40.
[http://dx.doi.org/10.1039/c2mb25128k] [PMID: 22832934]
[52]
Hyodo F, Matsumoto K, Matsumoto A, Mitchell JB, Krishna MC. Probing the intracellular redox status of tumors with magnetic resonance imaging and redox-sensitive contrast agents. Cancer Res 2006; 66(20): 9921-8.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0879] [PMID: 17047054]
[53]
Fujii HG, Emoto MC, Sato-akaba H. Brain redox imaging using in vivo electron paramagnetic resonance imaging and nitroxide imaging probes. Magnetochemistry 2019; 5(11): 1-12.
[http://dx.doi.org/10.3390/magnetochemistry5010011]
[54]
Nishino N, Yasui H, Sakurai H. In vivo L-band ESR and quantitative pharmacokinetic analysis of stable spin probes in rats and mice. Free Radic Res 1999; 31(1): 35-51.
[http://dx.doi.org/10.1080/10715769900300581] [PMID: 10489118]
[55]
Storck SE, Meister S, Nahrath J, et al. Endothelial LRP1 transports amyloid-β(1-42) across the blood-brain barrier. J Clin Invest 2016; 126(1): 123-36.
[http://dx.doi.org/10.1172/JCI81108] [PMID: 26619118]
[56]
Park R, Kook SY, Park JC, Mook-Jung I. Aβ1-42 reduces P-glycoprotein in the blood-brain barrier through RAGE-NF-κB signaling. Cell Death Dis 2014; 5(6): 1-11.
[http://dx.doi.org/10.1038/cddis.2014.258]
[57]
Kook SY, Hong HS, Moon M, Ha CM, Chang S, Mook-Jung I. Aβ1-42-RAGE interaction disrupts tight junctions of the blood-brain barrier via Ca2+-calcineurin signaling. J Neurosci 2012; 32(26): 8845-54.
[http://dx.doi.org/10.1523/JNEUROSCI.6102-11.2012] [PMID: 22745485]
[58]
Park JC, Baik SH, Han SH, et al. Annexin A1 restores Aβ1-42 -induced blood-brain barrier disruption through the inhibition of RhoA-ROCK signaling pathway. Aging Cell 2017; 16(1): 149-61.
[http://dx.doi.org/10.1111/acel.12530] [PMID: 27633771]
[59]
Uchida T, Togashi H, Kuroda Y, Haga K, Sadahiro M, Kayama T. In vivo visualization of redox status by high-resolution whole body magnetic resonance imaging using nitroxide radicals. J Clin Biochem Nutr 2018; 63(3): 192-6.
[http://dx.doi.org/10.3164/jcbn.18-18] [PMID: 30487668]
[60]
Kosem N, Naganuma T, Ichikawa K, et al. Whole-body kinetic image of a redox probe in mice using Overhauser-enhanced MRI. Free Radic Biol Med 2012; 53(2): 328-36.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.04.026] [PMID: 22579576]
[61]
Yamato M, Egashira T, Utsumi H. Application of in vivo ESR spectroscopy to measurement of cerebrovascular ROS generation in stroke. Free Radic Biol Med 2003; 35(12): 1619-31.
[http://dx.doi.org/10.1016/j.freeradbiomed.2003.09.013] [PMID: 14680685]
[62]
Sano H, Naruse M, Matsumoto K, Oi T, Utsumi H. A new nitroxyl-probe with high retention in the brain and its application for brain imaging. Free Radic Biol Med 2000; 28(6): 959-69.
[http://dx.doi.org/10.1016/S0891-5849(00)00184-2] [PMID: 10802228]
[63]
Ichikawa K, Sato Y, Kondo H, Utsumi H. An ESR contrast agent is transported to rat liver through organic anion transporter. Free Radic Res 2006; 40(4): 403-8.
[http://dx.doi.org/10.1080/10715760600563542] [PMID: 16517505]
[64]
Samuni A, Goldstein S, Russo A, Mitchell JB, Krishna MC, Neta P. Kinetics and mechanism of hydroxyl radical and OH-adduct radical reactions with nitroxides and with their hydroxylamines. J Am Chem Soc 2002; 124(29): 8719-24.
[http://dx.doi.org/10.1021/ja017587h] [PMID: 12121116]
[65]
Goldstein S, Samuni A. Kinetics and mechanism of peroxyl radical reactions with nitroxides. J Phys Chem A 2007; 111(6): 1066-72.
[http://dx.doi.org/10.1021/jp0655975] [PMID: 17286360]
[66]
Goldstein S, Samuni A, Hideg K, Merenyi G. Structure-activity relationship of cyclic nitroxides as SOD mimics and scavengers of nitrogen dioxide and carbonate radicals. J Phys Chem A 2006; 110(10): 3679-85.
[http://dx.doi.org/10.1021/jp056869r] [PMID: 16526651]
[67]
Bar-On P, Mohsen M, Zhang R, Feigin E, Chevion M, Samuni A. Kinetics of nitroxide reaction with iron(II). J Am Chem Soc 1999; 121(35): 8070-3.
[http://dx.doi.org/10.1021/ja990623g]
[68]
Park L, Anrather J, Zhou P, et al. NADPH-oxidase-derived reactive oxygen species mediate the cerebrovascular dysfunction induced by the amyloid β peptide. J Neurosci 2005; 25(7): 1769-77.
[http://dx.doi.org/10.1523/JNEUROSCI.5207-04.2005] [PMID: 15716413]
[69]
Block ML. NADPH oxidase as a therapeutic target in Alzheimer’s disease. BMC Neurosci 2008; 9(Suppl. 2): S8.
[http://dx.doi.org/10.1186/1471-2202-9-S2-S8] [PMID: 19090996]
[70]
Sumi N, Nishioku T, Takata F, et al. Lipopolysaccharide-activated microglia induce dysfunction of the blood-brain barrier in rat microvascular endothelial cells co-cultured with microglia. Cell Mol Neurobiol 2010; 30(2): 247-53.
[http://dx.doi.org/10.1007/s10571-009-9446-7] [PMID: 19728078]
[71]
Cullen KM, Kócsi Z, Stone J. Pericapillary haem-rich deposits: evidence for microhaemorrhages in aging human cerebral cortex. J Cereb Blood Flow Metab 2005; 25(12): 1656-67.
[http://dx.doi.org/10.1038/sj.jcbfm.9600155] [PMID: 15917745]
[72]
Zenaro E, Pietronigro E, Della Bianca V, et al. Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med 2015; 21(8): 880-6.
[http://dx.doi.org/10.1038/nm.3913] [PMID: 26214837]
[73]
Zenaro E, Piacentino G, Constantin G. The blood-brain barrier in Alzheimer’s disease. Neurobiol Dis 2017; 107: 41-56.
[http://dx.doi.org/10.1016/j.nbd.2016.07.007] [PMID: 27425887]
[74]
Lull ME, Levesque S, Surace MJ, Block ML. Chronic apocynin treatment attenuates beta amyloid plaque size and microglial number in hAPP(751)(SL) mice. PLoS One 2011; 6(5): e20153.
[http://dx.doi.org/10.1371/journal.pone.0020153] [PMID: 21655287]
[75]
Bobko AA, Eubank TD, Voorhees JL, et al. In vivo monitoring of pH, redox status, and glutathione using L-band EPR for assessment of therapeutic effectiveness in solid tumors. Magn Reson Med 2012; 67(6): 1827-36.
[http://dx.doi.org/10.1002/mrm.23196] [PMID: 22113626]
[76]
Doussière J, Gaillard J, Vignais PV. Electron transfer across the O2- generating flavocytochrome b of neutrophils. Evidence for a transition from a low-spin state to a high-spin state of the heme iron component. Biochemistry 1996; 35(41): 13400-10.
[http://dx.doi.org/10.1021/bi960916b] [PMID: 8873608]
[77]
Chandran K, Aggarwal D, Migrino RQ, et al. Doxorubicin inactivates myocardial cytochrome c oxidase in rats: Cardioprotection by Mito-Q. Biophys J 2009; 96(4): 1388-98.
[http://dx.doi.org/10.1016/j.bpj.2008.10.042] [PMID: 19217856]
[78]
Zoppellaro G, Teschner T, Harbitz E, et al. Low-temperature EPR and Mössbauer spectroscopy of two cytochromes with His-Met axial coordination exhibiting HALS signals. ChemPhysChem 2006; 7(6): 1258-67.
[http://dx.doi.org/10.1002/cphc.200500693] [PMID: 16688708]
[79]
Meinhardt SW, Kula T, Yagi T, Lillich T, Ohnishi T. EPR characterization of the iron-sulfur clusters in the NADH: Ubiquinone oxidoreductase segment of the respiratory chain in Paracoccus denitrificans. J Biol Chem 1987; 262(19): 9147-53.
[http://dx.doi.org/10.1016/S0021-9258(18)48060-X] [PMID: 3036849]
[80]
Antholine WE, Vasquez-Vivar J, Quirk BJ, et al. Treatment of cells and tissues with chromate maximizes mitochondrial 2Fe2S EPR signals. Int J Mol Sci 2019; 20(5): E1143.
[http://dx.doi.org/10.3390/ijms20051143] [PMID: 30845710]
[81]
De Leo ME, Borrello S, Passantino M, et al. Oxidative stress and overexpression of manganese superoxide dismutase in patients with Alzheimer’s disease. Neurosci Lett 1998; 250(3): 173-6.
[http://dx.doi.org/10.1016/S0304-3940(98)00469-8] [PMID: 9708860]
[82]
Sompol P, Ittarat W, Tangpong J, et al. A neuronal model of Alzheimer’s disease: An insight into the mechanisms of oxidative stress-mediated mitochondrial injury. Neuroscience 2008; 153(1): 120-30.
[http://dx.doi.org/10.1016/j.neuroscience.2008.01.044] [PMID: 18353561]
[83]
Flynn JM, Melov S. SOD2 in mitochondrial dysfunction and neurodegeneration. Free Radic Biol Med 2013; 62: 4-12.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.05.027] [PMID: 23727323]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 18
ISSUE: 1
Year: 2021
Published on: 24 March, 2021
Page: [25 - 34]
Pages: 10
DOI: 10.2174/1567205018666210324121156
Price: $65

Article Metrics

PDF: 39
HTML: 3