Brain Edema XIII pp 239-243

Restitution of ischemic injuries in penumbra of cerebral cortex after temporary ischemia

  • U. Ito
  • E. Kawakami
  • J. Nagasao
  • T. Kuroiwa
  • I. Nakano
  • K. Oyanagi
Part of the Acta Neurochirurgica Supplementum book series (NEUROCHIRURGICA, volume 96)


We investigated, at both light and ultrastructural levels, the fate of swollen astrocytes and remodeling of neurites connected to disseminated, dying neurons in the ischemic neocortical penumbra. Specimens from left cerebral cortex were cut coronally at the infundibulum and observed by light and electron microscopy. We measured synapses and spines, and the thickness of neuritic trunks in the neuropil on electron microscopy photos. We also determined percent volume of axon terminals and spines by Weibel’s point-counting method. Astrocytic swelling gradually subsided from day 4 after the ischemic insult, with increases in cytoplasmic glial fibrils and GFAP-positive astrocytes. Disseminated dying electron-dense neurons were fragmented by invading astrocytic cell processes and accumulated as granular pieces. The number of synapses and spines and total percent volume of axon terminals and spines decreased with an increasing sparsity of synaptic vesicles until day 4. One to 12 weeks after the ischemic insult, these values increased to or exceeded control values, and sprouting and increased synaptic vesicles were seen. Axons that had been attached to the dying neurons appeared to have shifted their connections to the spines and the neurites of the surviving neurons, increasing their thickness. Astrocytic restitution and neuronal remodeling processes started at 4 days continuing until 12 weeks after ischemic insult.


Maturation phenomenon cerebral ischemia neuronal remodeling 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Crepel V, Epsztein J, Ben-Ari Y (2003) Ischemia induces short-and long-term remodeling of synaptic activity in the hippocampus. J Cell Mol Med 7: 401–407PubMedGoogle Scholar
  2. 2.
    Frost SB, Barbay S, Friel KM, Plautz EJ, Nudo RJ (2003) Reorganization of remote cortical regions after ischemic brain injury: a potential substrate for stroke recovery. J Neurophysiol 89: 3205–3214PubMedCrossRefGoogle Scholar
  3. 3.
    Graham DI, Lantos PL (2002) Greenfield’s neuropathology illustrated. Oxford University Press, London, pp 230–280Google Scholar
  4. 4.
    Hakamata Y, Hanyu S, Kuroiwa T, Ito U (1997) Brain edema associated with progressive selective neuronal death or impending infarction in the cerebral cortex. Acta Neurochir [Suppl] 70: 20–22Google Scholar
  5. 5.
    Hanyu S, Ito U, Hakamata Y, Nakano I (1997) Topographical analysis of cortical neuronal loss associated with disseminated selective neuronal necrosis and infarction after repeated ischemia. Brain Res 767: 154–157PubMedCrossRefGoogle Scholar
  6. 6.
    Ito U, Spatz M, Walker JT Jr, Klatzo I (1975) Experimental cerebral ischemia in mongolian gerbils. I. Light microscopic observations. Acta Neuropathol Berl 32: 209–223PubMedCrossRefGoogle Scholar
  7. 7.
    Ito U, Hanyu S, Hakamata Y, Nakamura M, Arima K (1997) Ultrastructure of astrocytes associated with selective neuronal death of cerebral cortex after repeated ischemia. Acta Neurochir [Suppl] 70: 46–49Google Scholar
  8. 8.
    Ito U, Hanyu S, Hakamata Y, Arima K, Oyanagi K, Kuroiwa T, Nakano I (1999) Temporal profile of cortical injury following ischemic insult just-below and at the threshold level for induction of infarction — light and electron microscopic study. In: Ito U, Fieschi C, Orzi F, Kuroiwa T, Klatzo I (eds) Maturation phenomenon in cerebral ischemia III. Springer, Berlin New York, pp 227–235Google Scholar
  9. 9.
    Ito U, Kuroiwa T, Hanyu S, Hakamata Y, Nakano I, Oyanagi K (2000) Ultrastructural behavior of astrocytes to singly dying cortical neurons. In: Krieglstein J, Klumpp S (eds) Pharmacology of cerebral ischemia. Medpharm Science Publications, Stuttgart, pp 285–291Google Scholar
  10. 10.
    Ito U, Kuroiwa T, Hakamata Y, Kawakami E, Nakano I, Oyana K (2002) How are ischemically dying eosinophilic neurons scavenged in the penumbra? An ultrastructural study. In: Krieglstein J, Klumpp S (eds) Pharmacology of cerebral ischemia. Medpharm Science Publication, Stuttgart, pp 261–265Google Scholar
  11. 11.
    Ito U, Kuroiwa T, Hanyu S, Hakamata Y, Kawakami E, Nakano I, Oyanagi K (2003) Temporal profile of experimental ischemic edema after threshold amount of insult to induce infarction — ultrastructure, gravimetry and Evans’ blue extravasation. Acta Neurochir [Suppl] 86: 131–135Google Scholar
  12. 12.
    Ito U, Kuroiwa T, Hanyu S, Hakamata Y, Kawakami E, Nakano I, Oyanagi K (2003) Ultrastructural temporal profile of the dying neuron and surrounding astrocytes in the ischemic penumbra: apoptosis or necrosis? In: Buchan AM, Ito U, Colbourne F, Kuroiwa T, Klatzo I (eds) Maturation phenomenon in cerebral ischemia V. Springer, Berlin Heidelberg, pp 189–196Google Scholar
  13. 13.
    Jourdain P, Nikonenko I, Alberi S, Muller D (2002) Remodeling of hippocampal synaptic networks by a brief anoxiahypoglycemia. J Neurosci 22: 3108–3116PubMedGoogle Scholar
  14. 14.
    Kalmar B, Kittel A, Lemmens R, Kornyei Z, Madarasz E (2001) Cultured astrocytes react to LPS with increased cyclooxygenase activity and phagocytosis. Neurochem Int 38: 453–461PubMedCrossRefGoogle Scholar
  15. 15.
    Kirino T, Tamura A, Sano K (1984) Delayed neuronal death in the rat hippocampus following transient forebrain ischemia. Acta Neuropathol Berl 64: 139–147PubMedCrossRefGoogle Scholar
  16. 16.
    Lemkey-Johnston N, Butler V, Reynolds WA (1976) Glial changes in the progress of a chemical lesion. An electron microscopic study. J Comp Neurol 167: 481–501PubMedCrossRefGoogle Scholar
  17. 17.
    Nudo RJ, Larson D, Plautz EJ, Friel KM, Barbay S, Frost SB (2003) A squirrel monkey model of poststroke motor recovery. ILAR J 44: 161–174PubMedGoogle Scholar
  18. 18.
    Ohno K, Ito U, Inaba Y (1984) Regional cerebral blood flow and stroke index after left carotid artery ligation in the conscious gerbil. Brain Res 297: 151–157PubMedCrossRefGoogle Scholar
  19. 19.
    Rosenblum WI (1997) Histopathologic clues to the pathways of neuronal death following ischemia/hypoxia. J Neurotrauma 14: 313–326PubMedCrossRefGoogle Scholar
  20. 20.
    Stroemer RP, Kent TA, Hulsebosch CE (1995) Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke 26: 2135–2144PubMedGoogle Scholar
  21. 21.
    von Lubitz DK, Diemer NH (1983) Cerebral ischemia in the rat: ultrastructural and morphometric analysis of synapses in stratum radiatum of the hippocampal CA-1 region. Acta Neuropathol (Berl) 61: 52–60CrossRefGoogle Scholar
  22. 22.
    Weibel ER (1963) Morphometry of the human lung. Springer, Berlin, pp 19–20Google Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • U. Ito
    • 2
    • 4
    • 1
  • E. Kawakami
    • 2
  • J. Nagasao
    • 2
  • T. Kuroiwa
    • 3
  • I. Nakano
    • 4
  • K. Oyanagi
    • 2
  1. 1.TokyoJapan
  2. 2.Department of NeuropathologyTokyo Metropolitan Institute for NeuroscienceTokyoJapan
  3. 3.Department of Neuropathology, Medical Research InstituteTokyo Medical and Dental UniversityTokyoJapan
  4. 4.Department of NeurologyJichi Medical SchoolTochigiJapan

Personalised recommendations