Acta Neuropathologica

, Volume 55, Issue 3, pp 205–220 | Cite as

The role of postischemic recirculation in the development of ischemic neuronal injury following complete cerebral ischemia

  • L. W. Jenkins
  • J. T. Povlishock
  • W. Lewelt
  • J. D. Miller
  • D. P. Becker
Original Works


The neuronal response to complete cerebral ischemia (CCI) of 5–15 min duration was evaluated at the light and electron microscopic level subsequent to postischemic recirculation periods of up to 60 min. Following postischemic reperfusion, the homogeneous neuronal changes characteristic of permanent CCI were modified into a heterogeneous pattern of selectively vulnerable neuronal responses. Four basic types of neuronal injury were represented within this heterogeneous neuronal population. The Type I neuronal response was most numerous and consisted of chromatin clumping, nucleolar condensation and a breakdown of polysomes. This response may represent a reversal of some of the neuronal changes observed after permanent CCI. In addition to the above changes, Type II neurons contained swollen mitochondria and Golgi saccules which appeared as microvacuoles under the light microscope. Type III neurons displayed varying degrees of neuronal shrinkage and numerous swollen mitochondria. Type IV neurons were markedly shrunken and electron-dense with few identifiable subcellular structures. The distribution of Type I neurons was random but the other neuronal responses occurred in “selectively vulnerable” brain regions. The number of Type II, III, and IV neurons increased with extended insult durations but were unaffected by the length of recirculation. Ten minutes of CCI represented the threshold for a significant increase in the number of severely altered neurons. These findings suggest that considerable neuronal injury may be present after 10–15 min of CCI, and the lack of a recirculation period following CCI appears to afford the brain parenchyma an extensive degree of structural protection.

Key words

Postischemic recirculation Complete cerebral ischemia Ischemic neuronal injury Electron microscopy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ames A III, Wright RL, Kowada M, Thurston JM, Majno G (1968) Cerebral ischemia. II. The no-reflow phenomenon. Am J Pathol 52:437–453Google Scholar
  2. 2.
    Arsenio-Nunes ML, Hossmann K-A, Farkas Bargeton E (1973) Ultrastructural and histochemical investigation of the cerebral cortex of cat during and after complete ischemia. Acta Neuropathol (Berl) 26:329–344Google Scholar
  3. 3.
    Bleyaert AL, Nemoto EM, Safar P (1978) Thiopental amelioration of brain damage after global ischemia in monkeys. Anesthesiology 49:390–398Google Scholar
  4. 4.
    Bourke RS, Kimelberg HK, Nelson LR, Barron KD, Auen EL, Popp AJ, Waldman JB (1980) Biology of glial swelling in experimental brain edema. In: Cervos-Navarro J, Ferszt R (eds) Brain edema. Adv Neurol 28:99–109Google Scholar
  5. 5.
    Brierley JB, Meldrum BS, Brown AW (1973) The threshold and neuropathology of cerebral “anoxic-ischemic” cell change. Arch Neurol 29:367–374Google Scholar
  6. 6.
    Brierley JB, Ljunggren B, Siesjo BK (1974) Neuropathological alterations in rat brain after complete ischaemia due to raised intracranial pressure. In: Lundberg N, Ponten U, Brock M (eds) Intracranial pressure II. Springer, Berlin Heidelberg New York, pp 166–171Google Scholar
  7. 7.
    Brierly JB (1976) Cerebral hypoxia. In: Blackwood W, Corsellis JAN (eds) Greenfield's neuropathology. Arnold, London, pp 43–85Google Scholar
  8. 8.
    Cammermeyer J (1978) Is the solitary dark neuron a manifestation of postmortem trauma to the brain inadequately fixed by perfusion? Histochemistry 56:97–115Google Scholar
  9. 9.
    Chiang J, Kowada M, Ames A, Wright R, Majno G (1968) Cerebral ischemia III. Vascular changes. Am J Pathol 52:455–476Google Scholar
  10. 10.
    Dampney RAL, Kumada M, Reis DJ (1979) Central neural mechanisms of the cerebral ischemic response: I. Characterization, effect of brainstem and cranial nerve transections, and simulation by electrical stimulation of restricted regions of medulla oblongata in rabbit. Circ Res 44:48–62Google Scholar
  11. 11.
    Demopoulos HB (1973) The basis of free radical pathology. Fed Proc 32:1859–1861Google Scholar
  12. 12.
    Demopoulos HB (1973) Control of free radicals in biologic systems. Fed Proc 32:1903–1908Google Scholar
  13. 13.
    Ellis EF, Wei EP, Kontos HA (1979) Vasodilation of cat cerebral arterioles by prostaglandins D2, E2, G2 and I2. Am J Physiol 237:381–385Google Scholar
  14. 14.
    Flamm ES, Demopoulos HB, Seligman ML, Poser RG, Ransohoff J (1978) Free radicals in cerebral ischemia. Stroke 9:445–447Google Scholar
  15. 15.
    Fischer EG, (1973) Impaired perfusion following cerebrovascular stasis: A review. Arch Neurol 29:361–366Google Scholar
  16. 16.
    Fischer EG, Ames A III, Hedley-Whyle ET, O'Gorman S (1977) Reassessment of cerebral capillary changes in acute global ischemia and their relationship to the “no-reflow phenomenon”. Stroke 8:36–39Google Scholar
  17. 17.
    Fischer EG, Ames A III, Lorenzo AV (1979) Cerebral blood flow immediately following brief circulatory stasis. Stroke 10:423–427Google Scholar
  18. 18.
    Frank JS, Beydler S, Kreman M, Rau EE (1980) Structure of the freeze-fractured sarcolemma in the normal and anoxic rabbit myocardium. Circ Res 47:131–143Google Scholar
  19. 19.
    Fridovich I (1979) Hypoxia and oxygen toxicity. In: Fahn S, Davis JN, Rowland LP (eds) Cerebral hypoxia and its consequences. Adv Neurol 26:255–266Google Scholar
  20. 20.
    Furlow TW, Hallenbeck JM (1978) Indomethacin prevents impaired perfusion of the dog's brain after global ischemia. Stroke 9:591–594Google Scholar
  21. 21.
    Garcia JH, Lossinsky AS, Kauffman FC, Conger KA (1978) Neuronal ischemic injury: Light microscopy, ultrastructure, and biochemistry. Acta Neuropathol (Berl) 43:85–95Google Scholar
  22. 22.
    Gaudet RJ, Levine L (1979) Transient cerebral ischemia and brain prostaglandins. Biochem Biophys Res Commun 86:893–901Google Scholar
  23. 23.
    Gauder RJ, Alan I, Levine L (1980) Accumulation of arachidonic acid metabolites in gerbil brain during reperfusion after bilateral carotid artery occlusion. J Neurochem 35:653–658Google Scholar
  24. 24.
    Ginsberg MD, Myers RE (1972) The topography of impaired microvascular perfusion in the primate brain following total circulatory arrest. Neurology 27:998–1011Google Scholar
  25. 25.
    Ginsberg MD, Graham DI, Welsh FA, Budd WW (1979) Diffuse cerebral ischemia in the cat: III. Neuropathological sequelae of severe ischemia. Ann Neurol5:350–358Google Scholar
  26. 26.
    Hallenbeck JM, Furlow TW (1978) Influence of several plasma fractions on post-ischemic microvascular reperfusion in the central nervous system. Stroke 9:375–382Google Scholar
  27. 27.
    Hallenbeck JM, Furlow TW, Ruel TA, Greenbaum LJ (1979) Extracorporeal glass-wool filtration of whole blood enhances post-ischemic recovery of the cortical sensory evoked response. Stroke 10:158–164Google Scholar
  28. 28.
    Horton RW, Meldrum BS, Pedley TA, McWilliam JR (1980) Regional cerebral blood flow in the rat during prolonged seizure activity. Brain Res 192:399–412Google Scholar
  29. 29.
    Hossmann K-A, Sato K (1970) The effect of ischemia on sensorimotor cortex of cat: Electrophysiological, biochemical, and electron-microscopical observations. Z Neurol 198:33–45Google Scholar
  30. 30.
    Hossmann K-A, Lechtape Gruter H, Hossmann V (1973) The role of the cerebral blood flow for the recovery of the brain after prolonged ischemia. Z Neurol 204:281–299Google Scholar
  31. 31.
    Hossmann K-A, Kleihues P (1973) Reversibility of ischemic brain damage. Arch Neurol 29:375–384Google Scholar
  32. 32.
    Hossmann K-A, Hossmann V (1977) Coagulopathy following experimental cerebral ischemia. Stroke 8:249–254Google Scholar
  33. 33.
    Hossmann K-A, Hossmann V, Takagi S (1978) Microsphere analysis of local cerebral and extracerebral blood flow after complete ischemia of the cat brain for one hour. J Neurol 248:275–285Google Scholar
  34. 34.
    Jenkins LW,Povlishock JT, Becker DP, Miller JD, Sullivan HG (1979) Complete cerebral ischemia: An ultrastructural study. Acta Neuropathol (Berl) 48:113–125Google Scholar
  35. 35.
    Kalimo H, Garia JH, Kamijyo Y, Tanaka J, Trump BF (1977) The ultrastructure of “brain death”. II. Electron microscopy of feline cortex after complete ischemia. Virchows Arch B [Cell Pathol] 25:207–220Google Scholar
  36. 36.
    Kalimo H, Paljarvi L, Vapalahti M (1979) The early ultrastructural alterations in the rabbit cerebral and cerebellar cortex after compression ischaemia. Neuropathol Appl Neurobiol 5:211–223Google Scholar
  37. 37.
    Kalimo H, Agardh C-D, Olsson Y, Siesjo BK (1980) Hypoglycemic brain injury. II. Electron microscopic findings in rat cerebral cortical neurons during profound insulin-induced hypoglycemia and in the recovery period following glucose administration. Acta Neuropathol (Berl) 50:43–52Google Scholar
  38. 38.
    Kinter D, Costello DJ, Levin AB, Gilboe DD (1980) Brain metabolism after 30 minutes of hypoxic or anoxic perfusion or ischemia. Am J Physiol 239:E501-E509Google Scholar
  39. 39.
    Klatzo I (1975) Pathophysiologic aspects of cerebral ischemia. In: Tower DB (ed) The basic neurosciences. The nervous system, vol 1, pp 313–322Google Scholar
  40. 40.
    Kofke WA, Nemoto EM, Hossmann K-A, Taylor F, Kessler PD, Stezoski SW (1979) Brain blood flow and metabolism after global ischemia and post-insult thiopental therapy in monkeys. Stroke 10:554–560Google Scholar
  41. 41.
    Kogure K, Morooka H, Busto R, SCheinberg P (1979) Involvement of lipid peroxidation in postischemic brain damage. Neurology 29:546Google Scholar
  42. 42.
    Kogure K, Busto R, Schwartzman RJ, Scheinberg P (1980) The dissociation of cerebral blood flow, metabolism, and function in the early stages of developing cerebral infarction. Ann Neurol 8:278–290Google Scholar
  43. 43.
    Kontos HA, Wei EP, Povlishock JT, Dietrich WD, Ellis EF, Magiera CG (1980) Cerebral arteriolar damage by arachidonic acid and prostaglandin G2. Science 209:1242–1245Google Scholar
  44. 44.
    Leniger-Follert E, Hossmann K-A (1977) Microflow and cortical oxygen pressure during and after prolonged cerebral ischemia. Brain Res 124:158–161Google Scholar
  45. 45.
    Levy DE, Brierley JB, Plum F (1975) Ischaemic brain damage in the gerbil in the absence of “no-reflow”. J Neurol Neurosurg Psychiat 38:1197–1205Google Scholar
  46. 46.
    Levy DE, Brierley JB (1979) Delayed pentobarbital administration limits ischemic brain damage in gerbils. Ann Neurol 5:59–64Google Scholar
  47. 47.
    Levy DE, Van Uitert RL, Pike CL (1979) Delayed postischemic hypoperfusion: A potentially damaging consequence of stroke. Neurology 29:1245–1252Google Scholar
  48. 48.
    Majewska MD, Strosznajder J, Lazarewicz J (1978) Effect of ischemic anoxia and barbiturate anesthesia on free radical oxidation of mitochondrial phospholipids. Brain Res 158:423–434Google Scholar
  49. 49.
    Marshall LF, Graham DI, Durity F, Lounsbury R, Welsh F, Langfitt TW (1975) Experimental cerebral oligemia and ischemia produced by intracranial hypertension. Part 2: Brain morphology. J Neurosurg 43:318–322Google Scholar
  50. 50.
    Michenfelder JD, Milde JH, Sundt TM (1976) Cerebral protection by barbiturate anesthesia. Arch Neurol 33:345–350Google Scholar
  51. 51.
    Miller CL, Lampard DG, Alexander K, Brown WA (1980) Local cerebral blood flow following transient cerebral ischemia. I. Onset of impaired reperfusion within the first hour following global ischemia. Stroke 11:534–541Google Scholar
  52. 52.
    Nemoto EM, Snyder JV, Carroll RG, Morita H (1975) Global ischemia in dogs: Cerebrovascular CO2 reactivity and autoregulation. Stroke 6:425–431Google Scholar
  53. 53.
    Nemoto EM, Erdmann W, Strong E, Rao GR, Moossy J (1979) Regional brain pO2 after global ischemia in monkeys: Evidence for regional differences in critical perfusion pressures. Stroke 10:44–52Google Scholar
  54. 54.
    Nordstrom CH, Rehncrona S, Siesjo BK (1977) Restitution of cerebral energy state as well as of glycolytic metabolites, citric acid cycle intermediates and associated amino acids after 30 minutes of complete ischemia in rats anesthetized with nitrous oxide or phenobarbital. J Neurochem 30:479–486Google Scholar
  55. 55.
    Olsson Y, Hossmann K-A (1971) The effect of intravascular saline perfusion on the sequelae of transient cerebral ischemia: Light and electron-microscopical observations. Acta Neuropathol (Berl) 17:68–79Google Scholar
  56. 56.
    Rehncrona S, Mela L, Siesjo BK (1979) Recovery of brain mitochondrial function in the rat after complete and incomplete cerebral ischemia. Stroke 10:437–446Google Scholar
  57. 57.
    Safar P, Stezoski W, Nemoto EM (1976) Amelioration of brain damage after 12 minutes cardiac arrest in dogs. Arch Neurol 33:91–95Google Scholar
  58. 58.
    Siesjo BK (1978) Ischemia. In: Brain energy metabolism. Wiley, Chichester New York Brisbane Toronto, pp 453–526Google Scholar
  59. 59.
    Siesjo BK, Abdul-Rahman A (1979) Delayed hypoperfusion in the cerebral cortex of the rat in the recovery period following severe hypoglycemia. Acta Physiol Scand 106:375–376Google Scholar
  60. 60.
    Siesjo BK, Abdul-Rahman A (1979) A metabolic basis for the selective vulnerability of neurons in status epilepticus. Acta Physiol Scand 106:377–378Google Scholar
  61. 61.
    Spagnuolo C, Sautebin L, Galli G, Ralagni G, Galli C, Mazzari S, Finesso M (1980) PGF, thromboxane B2 and HETE levels in gerbil brain cortex after ligation of common carotid arteries and decapitation. Prostaglandins 18:53–61Google Scholar
  62. 62.
    Steen PA, Milde JH, Michenfelder JD (1979) No barbiturate protection in a dog model of complete cerebral ischemia. Ann Neurol 5:343–349Google Scholar
  63. 63.
    Takagi S, Cocito L, Hossmann K-A (1977) Blood recirculation and pharmacological responsiveness of the cerebral vasculature following prolonged ischemia of cat brain. Stroke 8:707–712Google Scholar
  64. 64.
    Trump BF, Croker BP, Mergner WJ (1971) The role of energy metabolism, ion and water shifts in the pathogenesis of cell injury. In: Richter GW (ed) Cell membranes, biological and pathological aspects. Williams and Wilkins, Baltimore, pp 88–128Google Scholar
  65. 65.
    Trump BF, Berezesky IK, Collan Y, Kahng MW, Mergner WJ (1976) Recent studies on the pathophysiology of ischemic cell injury. Beitr Pathol 158:363–388Google Scholar
  66. 66.
    Waggener JD, Beggs JL (1977) Parenchymal effects of hypoxic ischemia. In: Thompson RA, Green JR (eds) Stroke. Adv Neurol 16:21–30Google Scholar
  67. 67.
    Yoshida S, Inoh S, Asano T, Sano K, Kubota M, Shimazaki H, Ueta N (1980) Effect of transient ischemia on free fatty acids and phospholipids in the gerbil brain. J Neurosurg 53:323–331Google Scholar

Copyright information

© Springer-Verlag 1981

Authors and Affiliations

  • L. W. Jenkins
    • 1
    • 2
  • J. T. Povlishock
    • 2
  • W. Lewelt
    • 1
  • J. D. Miller
    • 1
  • D. P. Becker
    • 1
  1. 1.Dept of Neurological SurgeryMCV Station, Medical College of Virginia, Virginia Commonwealth UniversityRichmondUSA
  2. 2.Dept of AnatomyMCV Station, Medical College of Virginia, Virginia Commonwealth UniversityRichmondUSA

Personalised recommendations