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Ischemic Injury to White Matter: An Age-Dependent Process

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Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke

Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

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Abstract

Stroke is the fifth leading cause of death in the United States with aging being one of the most significant risk factor. Axonal injury and dysfunction are responsible for most of the disability observed after stroke. Since white matter (WM) is injured in most strokes and approach aimed at protecting gray matter has failed, we have changed our approach to investigate the impact of ischemic injury on WM as a function of age. This leads to the identification of ischemic WM injury mechanisms, which showed characteristic differences compared to those observed in gray matter. In addition, we observed that WM ischemic injury mechanisms changed as a function of age, rendering aging white matter more susceptible to ischemic injury. Aging WM show an enhanced excitotoxic and oxidative mechanisms of ischemic injury, which is mainly, caused by WM reorganization of its glutamate homeostasis and mitochondrial dynamics with aging. Overall, our research suggests that for the development successful of future stroke therapies, we must tailor our approach to protect both gray matter and white matter as a function of age.

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Abbreviations

AMPA/KA:

AMPA/kainate

CKA:

7-Chlorokynurenic acid

CNS:

Central nervous system

GS:

Glutamate synthetase

KB-R:

2-[2-[4(4-Nitrobenzyloxy)phenyl]ethyl]isothiourea mesylate

MON:

Mouse optic nerve

NCX:

Na+–Ca2+ exchanger

NMDAR:

NMDA-type receptors

OGD:

Oxygen glucose deprivation

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

WM:

White matter

References

  1. AHA. Every 40 seconds a stroke occurs in the United States. http://newsroom.heart.org/news/every-40-seconds-a-stroke-occurs-in-the-united-states (2013).

  2. Baltan S. Ischemic injury to white matter: an age-dependent process. Neuroscientist. 2009;15(2):126–33.

    Article  CAS  PubMed  Google Scholar 

  3. Baltan S, Besancon EF, Mbow B, Ye Z, Hamner MA, Ransom BR. White matter vulnerability to ischemic injury increases with age because of enhanced excitotoxicity. J Neurosci. 2008;28(6):1479–89.

    Article  CAS  PubMed  Google Scholar 

  4. Baltan S. Histone deacetylase inhibitors preserve function in aging axons. J Neurochem. 2012;123 Suppl 2:108–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rosenzweig S, Carmichael ST. Age-dependent exacerbation of white matter stroke outcomes: a role for oxidative damage and inflammatory mediators. Stroke. 2013;44(9):2579–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tekkok SB, Brown AM, Ransom BR. Axon function persists during anoxia in mammalian white matter. J Cereb Blood Flow Metab. 2003;23(11):1340–7.

    Article  PubMed  Google Scholar 

  7. Baltan S. Surviving anoxia: a tale of two white matter tracts. Crit Rev Neurobiol. 2006;18(1–2):95–103.

    Article  CAS  PubMed  Google Scholar 

  8. Wrathall JR, Choiniere D, Teng YD. Dose-dependent reduction of tissue loss and functional impairment after spinal cord trauma with the AMPA/kainate antagonist NBQX. J Neurosci. 1994;14(11 Pt 1):6598–607.

    CAS  PubMed  Google Scholar 

  9. Agrawal SK, Fehlings MG. Role of NMDA and non-NMDA ionotropic glutamate receptors in traumatic spinal cord axonal injury. J Neurosci. 1997;17(3):1055–63.

    CAS  PubMed  Google Scholar 

  10. Fern R, Ransom BR. Ischemic injury of optic nerve axons: the nuts and bolts. Clin Neurosci. 1997;4(5):246–50.

    CAS  PubMed  Google Scholar 

  11. McDonald JW, Althomsons SP, Hyrc KL, Choi DW, Goldberg MP. Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity. Nat Med. 1998;4(3):291–7.

    Article  CAS  PubMed  Google Scholar 

  12. Sanchez-Gomez MV, Matute C. AMPA and kainate receptors each mediate excitotoxicity in oligodendroglial cultures. Neurobiol Dis. 1999;6(6):475–85.

    Article  CAS  PubMed  Google Scholar 

  13. Follett PL, Rosenberg PA, Volpe JJ, Jensen FE. NBQX attenuates excitotoxic injury in developing white matter. J Neurosci. 2000;20(24):9235–41.

    CAS  PubMed  Google Scholar 

  14. Tekkok SB, Goldberg MP. Ampa/kainate receptor activation mediates hypoxic oligodendrocyte death and axonal injury in cerebral white matter. J Neurosci. 2001;21(12):4237–48.

    CAS  PubMed  Google Scholar 

  15. Stys PK. White matter injury mechanisms. Curr Mol Med. 2004;4(2):113–30.

    Article  CAS  PubMed  Google Scholar 

  16. Tekkok SB, Ye Z, Ransom BR. Excitotoxic mechanisms of ischemic injury in myelinated white matter. J Cereb Blood Flow Metab. 2007;27(9):1540–52.

    Article  PubMed  Google Scholar 

  17. Fields RD. White matter in learning, cognition and psychiatric disorders. Trends Neurosci. 2008;31(7):361–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Baltan S. Age-dependent mechanisms of white matter injury after stroke. In: Baltan S, Carmichael ST, Matute C, Xi G, Zhang JH, editors. White matter injury in stroke and CNS disease. New York: Springer; 2014. p. 373–403.

    Chapter  Google Scholar 

  19. Stys PK, Ransom BR, Waxman SG. Effects of polyvalent cations and dihydropyridine calcium channel blockers on recovery of CNS white matter from anoxia. Neurosci Lett. 1990;115(2–3):293–9.

    Article  CAS  PubMed  Google Scholar 

  20. Fern R, Ransom BR, Waxman SG. Voltage-gated calcium channels in CNS white matter: role in anoxic injury. J Neurophysiol. 1995;74(1):369–77.

    CAS  PubMed  Google Scholar 

  21. Wolf JA, Stys PK, Lusardi T, Meaney D, Smith DH. Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels. J Neurosci. 2001;21(6):1923–30.

    CAS  PubMed  Google Scholar 

  22. Ouardouz M, Nikolaeva MA, Coderre E, Zamponi GW, McRory JE, Trapp BD, et al. Depolarization-induced Ca2+ release in ischemic spinal cord white matter involves L-type Ca2+ channel activation of ryanodine receptors. Neuron. 2003;40(1):53–63.

    Article  CAS  PubMed  Google Scholar 

  23. Underhill SM, Goldberg MP. Hypoxic injury of isolated axons is independent of ionotropic glutamate receptors. Neurobiol Dis. 2007;25(2):284–90.

    Article  CAS  PubMed  Google Scholar 

  24. Matute C, Sanchez-Gomez MV, Martinez-Millan L, Miledi R. Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes. Proc Natl Acad Sci U S A. 1997;94(16):8830–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li S, Mealing GA, Morley P, Stys PK. Novel injury mechanism in anoxia and trauma of spinal cord white matter: glutamate release via reverse Na+-dependent glutamate transport. J Neurosci. 1999;19(14):RC16.

    CAS  PubMed  Google Scholar 

  26. Fern R, Moller T. Rapid ischemic cell death in immature oligodendrocytes: a fatal glutamate release feedback loop. J Neurosci. 2000;20(1):34–42.

    CAS  PubMed  Google Scholar 

  27. Alberdi E, Sanchez-Gomez MV, Marino A, Matute C. Ca(2+) influx through AMPA or kainate receptors alone is sufficient to initiate excitotoxicity in cultured oligodendrocytes. Neurobiol Dis. 2002;9(2):234–43.

    Article  CAS  PubMed  Google Scholar 

  28. Rosenberg PA, Li Y, Ali S, Altiok N, Back SA, Volpe JJ. Intracellular redox state determines whether nitric oxide is toxic or protective to rat oligodendrocytes in culture. J Neurochem. 1999;73(2):476–84.

    Article  CAS  PubMed  Google Scholar 

  29. Oka A, Belliveau MJ, Rosenberg PA, Volpe JJ. Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention. J Neurosci. 1993;13(4):1441–53.

    CAS  PubMed  Google Scholar 

  30. Slemmer JE, Shacka JJ, Sweeney MI, Weber JT. Antioxidants and free radical scavengers for the treatment of stroke, traumatic brain injury and aging. Curr Med Chem. 2008;15(4):404–14.

    Article  CAS  PubMed  Google Scholar 

  31. Matute C, Alberdi E, Domercq M, Perez-Cerda F, Perez-Samartin A, Sanchez-Gomez MV. The link between excitotoxic oligodendroglial death and demyelinating diseases. Trends Neurosci. 2001;24(4):224–30.

    Article  CAS  PubMed  Google Scholar 

  32. Ouardouz M, Malek S, Coderre E, Stys PK. Complex interplay between glutamate receptors and intracellular Ca2+ stores during ischaemia in rat spinal cord white matter. J Physiol. 2006;577(Pt 1):191–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cavallotti C, Pacella E, Pescosolido N, Tranquilli-Leali FM, Feher J. Age-related changes in the human optic nerve. Can J Ophthalmol. 2002;37(7):389–94.

    Article  PubMed  Google Scholar 

  34. Cavallotti C, Cavallotti D, Pescosolido N, Pacella E. Age-related changes in rat optic nerve: morphological studies. Anat Histol Embryol. 2003;32(1):12–6.

    Article  CAS  PubMed  Google Scholar 

  35. Brown AM, Tekkok SB, Ransom BR. Hypoglycemia and white matter: pathophysiology of axon injury and role of glycogen. Diabetes Nutr Metab. 2002;15(5):290–3. discussion 3–4.

    CAS  PubMed  Google Scholar 

  36. Baltan S, Murphy SP, Danilov CA, Bachleda A, Morrison RS. Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity. J Neurosci. 2011;31(11):3990–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Baltan S, Inman DM, Danilov CA, Morrison RS, Calkins DJ, Horner PJ. Metabolic vulnerability disposes retinal ganglion cell axons to dysfunction in a model of glaucomatous degeneration. J Neurosci. 2010;30(16):5644–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tymianski M, Charlton MP, Carlen PL, Tator CH. Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons. J Neurosci. 1993;13(5):2085–104.

    CAS  PubMed  Google Scholar 

  39. Rothman SM. The neurotoxicity of excitatory amino acids is produced by passive chloride influx. J Neurosci. 1985;5(6):1483–9.

    CAS  PubMed  Google Scholar 

  40. Szatkowski M, Barbour B, Attwell D. Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature. 1990;348(6300):443–6.

    Article  CAS  PubMed  Google Scholar 

  41. Karadottir R, Cavelier P, Bergersen LH, Attwell D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature. 2005;438(7071):1162–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Micu I, Jiang Q, Coderre E, Ridsdale A, Zhang L, Woulfe J, et al. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature. 2006;439(7079):988–92.

    CAS  PubMed  Google Scholar 

  43. Salter MG, Fern R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature. 2005;438(7071):1167–71.

    Article  CAS  PubMed  Google Scholar 

  44. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996;16(3):675–86.

    Article  CAS  PubMed  Google Scholar 

  45. Hazell AS, Rao KV, Danbolt NC, Pow DV, Butterworth RF. Selective down-regulation of the astrocyte glutamate transporters GLT-1 and GLAST within the medial thalamus in experimental Wernicke’s encephalopathy. J Neurochem. 2001;78(3):560–8.

    Article  CAS  PubMed  Google Scholar 

  46. Nicholls DG, Johnson-Cadwell L, Vesce S, Jekabsons M, Yadava N. Bioenergetics of mitochondria in cultured neurons and their role in glutamate excitotoxicity. J Neurosci Res. 2007;85(15):3206–12.

    Article  CAS  PubMed  Google Scholar 

  47. Albin RL, Greenamyre JT. Alternative excitotoxic hypotheses. Neurology. 1992;42(4):733–8.

    Article  CAS  PubMed  Google Scholar 

  48. Jacquard C, Trioulier Y, Cosker F, Escartin C, Bizat N, Hantraye P, et al. Brain mitochondrial defects amplify intracellular [Ca2+] rise and neurodegeneration but not Ca2+ entry during NMDA receptor activation. FASEB J. 2006;20(7):1021–3.

    Article  CAS  PubMed  Google Scholar 

  49. Silva-Adaya D, Perez-De La Cruz V, Herrera-Mundo MN, Mendoza-Macedo K, Villeda-Hernandez J, Binienda Z, et al. Excitotoxic damage, disrupted energy metabolism, and oxidative stress in the rat brain: antioxidant and neuroprotective effects of L-carnitine. J Neurochem. 2008;105(3):677–89.

    Article  CAS  PubMed  Google Scholar 

  50. Hollenbeck PJ, Saxton WM. The axonal transport of mitochondria. J Cell Sci. 2005;118(Pt 23):5411–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hollenbeck PJ. Mitochondria and neurotransmission: evacuating the synapse. Neuron. 2005;47(3):331–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Karbowski M, Arnoult D, Chen H, Chan DC, Smith CL, Youle RJ. Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis. J Cell Biol. 2004;164(4):493–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mozdy AD, Shaw JM. A fuzzy mitochondrial fusion apparatus comes into focus. Nat Rev Mol Cell Biol. 2003;4(6):468–78.

    Article  CAS  PubMed  Google Scholar 

  54. Scott SV, Cassidy-Stone A, Meeusen SL, Nunnari J. Staying in aerobic shape: how the structural integrity of mitochondria and mitochondrial DNA is maintained. Curr Opin Cell Biol. 2003;15(4):482–8.

    Article  CAS  PubMed  Google Scholar 

  55. Chen H, McCaffery JM, Chan DC. Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell. 2007;130(3):548–62.

    Article  CAS  PubMed  Google Scholar 

  56. Chang DT, Reynolds IJ. Mitochondrial trafficking and morphology in healthy and injured neurons. Prog Neurobiol. 2006;80(5):241–68.

    Article  CAS  PubMed  Google Scholar 

  57. Karbowski M, Youle RJ. Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ. 2003;10(8):870–80.

    Article  CAS  PubMed  Google Scholar 

  58. Parihar MS, Brewer GJ. Simultaneous age-related depolarization of mitochondrial membrane potential and increased mitochondrial reactive oxygen species production correlate with age-related glutamate excitotoxicity in rat hippocampal neurons. J Neurosci Res. 2007;85(5):1018–32.

    Article  CAS  PubMed  Google Scholar 

  59. Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J, Hoppel CL. Mitochondrial dysfunction in cardiac disease: ischemia—reperfusion, aging, and heart failure. J Mol Cell Cardiol. 2001;33(6):1065–89.

    Article  CAS  PubMed  Google Scholar 

  60. Selzner M, Selzner N, Jochum W, Graf R, Clavien PA. Increased ischemic injury in old mouse liver: an ATP-dependent mechanism. Liver Transpl. 2007;13(3):382–90.

    Article  PubMed  Google Scholar 

  61. Toescu EC. Normal brain ageing: models and mechanisms. Philos Trans R Soc Lond B Biol Sci. 2005;360(1464):2347–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Erecinska M, Silver IA. Ions and energy in mammalian brain. Prog Neurobiol. 1994;43(1):37–71.

    Article  CAS  PubMed  Google Scholar 

  63. Scavone C, Munhoz CD, Kawamoto EM, Glezer I, de Sa Lima L, Marcourakis T, et al. Age-related changes in cyclic GMP and PKG-stimulated cerebellar Na,K-ATPase activity. Neurobiol Aging. 2005;26(6):907–16.

    Article  CAS  PubMed  Google Scholar 

  64. Bristow EA, Griffiths PG, Andrews RM, Johnson MA, Turnbull DM. The distribution of mitochondrial activity in relation to optic nerve structure. Arch Ophthalmol. 2002;120(6):791–6.

    Article  PubMed  Google Scholar 

  65. Rintoul GL, Filiano AJ, Brocard JB, Kress GJ, Reynolds IJ. Glutamate decreases mitochondrial size and movement in primary forebrain neurons. J Neurosci. 2003;23(21):7881–8.

    CAS  PubMed  Google Scholar 

  66. Barsoum MJ, Yuan H, Gerencser AA, Liot G, Kushnareva Y, Graber S, et al. Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J. 2006;25(16):3900–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Misgeld T, Kerschensteiner M, Bareyre FM, Burgess RW, Lichtman JW. Imaging axonal transport of mitochondria in vivo. Nat Methods. 2007;4(7):559–61.

    Article  CAS  PubMed  Google Scholar 

  68. Baud O, Li J, Zhang Y, Neve RL, Volpe JJ, Rosenberg PA. Nitric oxide-induced cell death in developing oligodendrocytes is associated with mitochondrial dysfunction and apoptosis-inducing factor translocation. Eur J Neurosci. 2004;20(7):1713–26.

    Article  PubMed  Google Scholar 

  69. Merrill JE, Murphy SP, Mitrovic B, Mackenzie-Graham A, Dopp JC, Ding M, et al. Inducible nitric oxide synthase and nitric oxide production by oligodendrocytes. J Neurosci Res. 1997;48(4):372–84.

    Article  CAS  PubMed  Google Scholar 

  70. Yao S, Pandey P, Ljunggren-Rose A, Sriram S. LPS mediated injury to oligodendrocytes is mediated by the activation of nNOS: relevance to human demyelinating disease. Nitric Oxide. 2009;22(3):197–204.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue (NB21), Cleveland, OH, 44195, USA

    Sylvain Brunet B.Sc., Ph.D. & Selva Baltan M.D., Ph.D.

  2. Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue (NB30), Cleveland, OH, 44195, USA

    Sylvain Brunet B.Sc., Ph.D., Chinthasagar Bastian M.B.B.S., Ph.D. & Selva Baltan M.D., Ph.D.

Authors
  1. Sylvain Brunet B.Sc., Ph.D.
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  2. Chinthasagar Bastian M.B.B.S., Ph.D.
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  3. Selva Baltan M.D., Ph.D.
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Corresponding author

Correspondence to Selva Baltan M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Jun Chen

  2. Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    John H. Zhang

  3. Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, California, USA

    Xiaoming Hu

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Brunet, S., Bastian, C., Baltan, S. (2016). Ischemic Injury to White Matter: An Age-Dependent Process. In: Chen, J., Zhang, J., Hu, X. (eds) Non-Neuronal Mechanisms of Brain Damage and Repair After Stroke. Springer Series in Translational Stroke Research. Springer, Cham. https://doi.org/10.1007/978-3-319-32337-4_16

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  • DOI: https://doi.org/10.1007/978-3-319-32337-4_16

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