Anoxic Injury of Central Myelinated Axons: Nonsynaptic Ionic Mechanisms

  • B. R. Ransom
  • S. G. Waxman
  • P. K. Stys


The pathophysiology of stroke and central nervous system (CNS) trauma can now be effectively studied at a molecular level. This research is concerned with understanding how cells in the brain, devoid of oxygen and/or metabolic substrates, are injured and ultimately destroyed. The reasonable presumption is that knowledge about the fundamental mechanisms of cell injury will yield clinically applicable insights relevant to how the brain may be protected during periods of disrupted perfusion or metabolism. This work can be subdivided into the study of how each of the major cellular compartments in the brain, i.e., neuronal cell bodies and dendrites, axons and glial cells, are injured by anoxia/ischemia. While great progress has been made in analyzing the mechanisms of neuronal injury in gray matter (GM) areas such as cortex, much less is known about how anoxia/ischemia damages glial cells and axons. We have been interested in the pathophysiology of CNS axonal injury and have developed a reliable model system for studying the basic mechanisms of injury to CNS-myelinated axons caused by anoxia (Stys et al. 1990a; Ransom et al. 1993). The nonsynaptic ionic mechanisms which are critical in the development of irreversible anoxic injury in white matter (WM) are the focus of this review.


Gray Matter Optic Nerve Axonal Injury Compound Action Potential Cereb Blood Flow 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Ames A III, Li Y, Heher EC, Kimble CR (1992) Energy metabolism of rabbit retina as related to function: High cost of Na+ transport. J Neurosci 12: 840–853Google Scholar
  2. Benveniste H, Drejer J, Shousboe A, Diemer NH (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43: 1369–1374PubMedCrossRefGoogle Scholar
  3. Blaustein MP (1988) Calcium transport and buffering in neurons. TINS 11: 438–443PubMedGoogle Scholar
  4. Chesler M (1990) The regulation and modulation of pH in the nervous system. Prog Neurobiol 34: 401–427PubMedCrossRefGoogle Scholar
  5. Choi DW (1988a) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:62–634CrossRefGoogle Scholar
  6. Choi DW (1988b) Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci 11: 465–469PubMedCrossRefGoogle Scholar
  7. Connors BW, Ransom BR, Kunis DM, Gutnick MJ (1982) Activity-dependent K+ accumulation in the developing rat optic nerve. Science 216: 1341–1343PubMedCrossRefGoogle Scholar
  8. Davis P, Ransom BR (1987) Anoxia and CNS white matter: in vitro studies using the rat optic nerve. Soc Neurosci Abstr 13: 1634Google Scholar
  9. Fisher CM (1979) Capsular infarcts: the underlying vascular lesions. Arch Neurol 36: 65–73PubMedGoogle Scholar
  10. Foster RE, Connors BW, Waxman SG (1982) Rat optic nerve: electrophysiological, pharmacological and anatomical studies during development. Dev Brain Res 3: 371–386CrossRefGoogle Scholar
  11. Goldman SA, Pulsinelli WA, Clarke WY, Kraig RP, Plum F (1989) The effects of extracellular acidosis on neurons and glia in vitro. J Cereb Blood Flow Metab 9: 471–477PubMedCrossRefGoogle Scholar
  12. Hansen AJ (1985) Effect of anoxia on ion distribution in the brain. Physiol Rev 65: 101–148PubMedGoogle Scholar
  13. Hossmann KA, Sato K (1970) Recovery of neuronal function after prolonged cerebral ischemia. Science 168: 375–376PubMedCrossRefGoogle Scholar
  14. Kass IS, Lipton P (1982) Mechanisms involved in irreversible anoxic damage to the in vitro rat hippocampal slice. J Physiol (Lond) 332: 459–472Google Scholar
  15. Kimelberg HK, Ransom BR (1986) Physiological and pathological aspects of astrocytic swelling. In: Fedoroff S, Vernadakis A (eds) Astrocytes, vol 3. Academic, Orlando, pp 129–166Google Scholar
  16. Kraig RP, Pulsinelli WA, Plum F (1985) Hydrogen ion buffering during complete brain ischemia. Brain Res 342: 281–190PubMedCrossRefGoogle Scholar
  17. Kraig RP, Petito CK, Plum F, Pulsinelli WA (1987) Hydrogen ions kill brain at concentrations reached in ischemia. J Cereb Blood Flow Metab 7: 379–386PubMedCrossRefGoogle Scholar
  18. Lagnado L, Cervetto L, McNaughton PA (1988) Ion transport by the Na-Ca exchanger in isolated rod outer segments. Proc Natl Acad Sci USA 85: 4548–4552PubMedCrossRefGoogle Scholar
  19. Orrenius S, McConkey DJ, Jones DP, Nicotera P (1988) Ca2+-activated mechanisms in toxicity and programmed cell death. ISI Atlas of Science: Pharmacology 2: 319–324Google Scholar
  20. Paulson OB, Newman EA (1987) Does the release of potassium from astrocyte endfeet regulate cerebral blood flow? Science 237: 896–898PubMedCrossRefGoogle Scholar
  21. Plum F (1983) What causes infarction in ischemic brain? Neurology 33: 222–233PubMedGoogle Scholar
  22. Pulsinelli WA, Waldman S, Rawlinson D, Plum F (1982) Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat. Neurology 32: 1239–1246PubMedGoogle Scholar
  23. Ransom BR, Philbin DM (1992) Anoxia-induced extracellular ionic changes in CNS white matter: the roles of glial cells. Can J Physiol Pharmacol 70: 181–189CrossRefGoogle Scholar
  24. Ransom BR, Yamate CL, Connors BW (1985) Activity-dependent shrinkage of extracellular space in rat optic nerve: a developmental study. J Neurosci 5: 532–535PubMedGoogle Scholar
  25. Ransom BR, Carlini WG, Connors BW (1986) Brain extracellular space: developmental studies in rat optic nerve. Ann NY Acad Sci 481: 87–105PubMedCrossRefGoogle Scholar
  26. Ransom BR, Stys PK, Waxman SG (1990a) The pathophysiology of anoxic injury in CNS white matter. Stroke 21: [Suppl III] 52–57CrossRefGoogle Scholar
  27. Ransom BR, Waxman SG, Davis PK (1990b) Anoxic injury of CNS white matter: protective effect of ketamine. Neurology 40: 1399–1403PubMedGoogle Scholar
  28. Ransom BR, Walz W, Davis PK, Carlini WG (1992) Anoxia-induced changes in extracellular K+ and pH in mammalian central white matter. J Cereb Blood Flow Metab 12: 593–602PubMedCrossRefGoogle Scholar
  29. Ransom BR, Stys PK, Waxman SG (1993) Anoxic injury of central myelinated axons: ionic mechanisms and pharmacology. In: Waxman S (ed) Molecular and cellular approaches to the treatment of neurological disease. Raven, New York, pp 121–151Google Scholar
  30. Schanne FA, Kane AB, Young EE, Farber JL (1979) Calcium–dependence of toxic cell death: a final common pathway. Science 206: 700–702PubMedCrossRefGoogle Scholar
  31. Schlaepfer WW (1977) Structural alterations of peripheral nerve induced by the calcium ionophore A23817. Brain Res 136: 1–9PubMedCrossRefGoogle Scholar
  32. Schwartz EA, Tachibana M (1990) Electrophysiology of glutamate and sodium cotransport in a glial cell of the salamander retina. J Physiol (Lond) 426: 43–80Google Scholar
  33. Siesjö BK (1981) Cell damage in the brain: a speculative synthesis. J Cereb Blood Flow Metab 1: 155–185PubMedCrossRefGoogle Scholar
  34. Siesjö BK, Wieloch T (1985) Brain injury: neurochemical aspects. In: Becker D, Povlishock JT (eds) Central nervous system trauma status report. NIH, NINCDS, Bethesda, pp 513–532Google Scholar
  35. Somjen GG, Aitken PG, Balestrino M, Herreras O, Kawasaki K (1990) Spreading depressionlike depolarization and selective vulnerability of neurons: a brief review. Stroke 21:111– 179—III–183Google Scholar
  36. Stafstrom CE, Schwindt PC, Chubb MC, Crill WE (1985) Properties of persistent sodium conductance and calcium conductance of layer V neurons from cat sensorimotor cortex. J Neurophys 53: 153–170Google Scholar
  37. Stys PK, Ransom BR, Waxman SG, Davis PK (1990a) The role of extracellular calcium in anoxic injury of mammalian white matter. Proc Natl Acad Sci USA 87: 4212–4216PubMedCrossRefGoogle Scholar
  38. Stys PK, Ransom BR, Waxman SG (1990b) Effects of polyvalent cations and dihydropyridine calcium channel blockers on recovery of CNS white matter from anoxia. Neurosci Lett 115: 293–299PubMedCrossRefGoogle Scholar
  39. Stys PK, Ransom BR, Waxman SG (1991a) Compound action potential of nerve recorded by suction electrode: a theoretical and experimental analysis. Brain Res 546: 18–32PubMedCrossRefGoogle Scholar
  40. Stys PK, Waxman SG, Ransom BR (1991b) Na+-Ca2+ exchanger mediates Ca2+ influx during anoxia in mammalian CNS white matter. Ann Neurol 30: 375–380PubMedCrossRefGoogle Scholar
  41. Stys PK, Waxman SG, Ransom BR (1992) Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na+-Ca2+ exchanger. J Neurosci 12: 430–439PubMedGoogle Scholar
  42. Tang CM, Dichter M, Morad M (1990) Modulation of the N-methyl-D-aspartate channel by extracellular H+. Proc Natl Acad Sci USA 87: 6445–6449PubMedCrossRefGoogle Scholar
  43. Taylor MD, Mellert TK, Parmentier JL, Eddy LJ (1985) Pharmacological protection of reoxygenation damage to in vitro brain slice tissue. Brain Res 347: 268–273PubMedCrossRefGoogle Scholar
  44. Waxman SG, Ritchie JM (1985) Organization of ion channels in the myelinated nerve fiber. Science 228: 1502–1507PubMedCrossRefGoogle Scholar
  45. Waxman SG, Ransom BR, Stys PK (1991) Non–synaptic mechanisms of Ca2+-mediated injury in CNS white matter. TINS 14: 461–468PubMedGoogle Scholar
  46. Waxman SG, Black JA, Stys PK, Ransom BR (1992) Ultrastructural concomitants of anoxic injury and early post-anoxic recovery in rat optic nerve. Brain Res 574: 105–119PubMedCrossRefGoogle Scholar
  47. Waxman SG, Black JA, Ransom BR, Stys PK (1993) Protection of the axonal cytoskeleton in anoxic optic nerve by decreased extracellular calcium. Brain Res (in press)Google Scholar
  48. Young W (1985) Blood flow, metabolic and neurophysiological mechanisms in spinal cord injury. In: Becker D, Povlishock JT (eds) Central nervous system trauma status report. NIH, NINCDS, Bethesda, pp 463–473Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • B. R. Ransom
    • 1
    • 2
  • S. G. Waxman
    • 1
    • 2
  • P. K. Stys
    • 1
    • 2
  1. 1.Department of NeurologyYale University School of MedicineNew HavenUSA
  2. 2.Neuroscience Research CenterVA HospitalWest HavenUSA

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