Neuroprotection in Acute Ischemic Stroke: Lessons for Early Treatment in Multiple Sclerosis

  • J. De Keyser
  • G. Ramsaransing
  • E. Zeinstra
  • N. Wilczak
Part of the Topics in Neuroscience book series (TOPNEURO)


A target for treatment of acute ischemic stroke is the penumbra, a territory of critically reduced blood flow between the core zone of an evolving infarction and the still sufficiently perfused brain. Unless there is early reperfusion of the ischemic area, neurons in the penumbra are destined to die in the ensuing hours to days, due to a cascade of biochemical events, the so-called ischemic cascade [1, 2]. Key steps in this cascade are uncontrolled depolarizations of neurons, build-up of extracellular glutamate, intracellular calcium overload, formation of nitric oxide and free radicals, and inflammation. Some forms of cell death in the ischemic penumbra also involve apoptosis [1, 2]. Studies in patients using positron emission tomography, combined perfusion and diffusion magnetic resonance imaging (MRI), and MR spectroscopy indicate that the penumbra in humans may remain viable for several (up to 48) hours after stroke onset [3-6].


Multiple Sclerosis Acute Ischemic Stroke Guillain Barre Syndrome Ischemic Penumbra Neuroprotective Drug 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397PubMedCrossRefGoogle Scholar
  2. 2.
    De Keyser J, Sulter G, Luiten PG (1999) Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing? Trends Neurosci 22:535–540PubMedCrossRefGoogle Scholar
  3. 3.
    Heis WD et al (1992) Progressive derangement of periinfarct viable tissue in ischemic stroke. J Cerebr Blood Flow Metab 12:193–203CrossRefGoogle Scholar
  4. 4.
    Marchai G et al (1996) Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke: a correlative PET-CT study with voxel-based data analysis. Stroke 27:599–606CrossRefGoogle Scholar
  5. 5.
    Schwamm LH, Koroshetz WJ, Gregory Sorensen A et al (1998) Time course of lesion development in patients with acute stroke: serial diffusion-and hemodynamicweighted magnetic resonance imaging. Stroke 29:2268–2276PubMedCrossRefGoogle Scholar
  6. 6.
    Saunders DE, Howe FA, van den Boogaert A, McLean MA, Griffiths JR, Brown MM (1995) Continuing ischemic damage after acute middle cerebral artery infarction in humans demonstrated by short-echo proton spectroscopy. Stroke 26:1007–1023PubMedCrossRefGoogle Scholar
  7. 7.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285PubMedCrossRefGoogle Scholar
  8. 8.
    Trapp BD, Ransohoff R, Rudick R (1999) Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 12:295–302PubMedCrossRefGoogle Scholar
  9. 9.
    Arnold DL (1999) Magnetic resoñance spectroscopy: imaging axonal damage in MS. J Neuroimmunol 98:2–6PubMedCrossRefGoogle Scholar
  10. 10.
    Andrews T, Zhang P, Bhat NR (1998) TNF alpha potentiates IFN gamma-induced cell death in oligodendrocyte progenitors. J Neurosci Res 54:574–583PubMedCrossRefGoogle Scholar
  11. 11.
    Pitt D, Raine CS, Werner P (2000) Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 6:67–70PubMedCrossRefGoogle Scholar
  12. 12.
    Groom A, Zhu B, Smith T, Turski L (2000) Autoimmune encephalomyelitis ameliorated by AMPA antagonists. Nat Med 6:62–66PubMedCrossRefGoogle Scholar
  13. 13.
    Smith KJ, Kapoor R, Felts PA (1999) Demyelination: the role of reactive oxygen and nitrogen species. Brain Pathol 9:69–92PubMedCrossRefGoogle Scholar
  14. 14.
    Giovannoni G, Heales SJ, Land JM, Thompson AJ (1998) The potential role of nitric oxide in multiple sclerosis. Mult Scier 4:212–216Google Scholar
  15. 15.
    LeVine SM, Wetzel DL (1998) Chemical analysis of multiple sclerosis lesions by FT-IR microspectroscopy. Free Radic Biol Med 25:33–41PubMedCrossRefGoogle Scholar
  16. 16.
    Kuhlmann T, Lucchinetti C, Zettl UK, Bitsch A, Lassmann H, Bruck W (1999) Bd-2 expressing oligodendrocytes in multiple sclerosis lesions. Glia 28:34–39PubMedCrossRefGoogle Scholar
  17. 17.
    Bamford J, Sandercock P, Dennis M, Burn J, Warlow C (1991) Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 337:1521–1526PubMedCrossRefGoogle Scholar
  18. 18.
    Marchal G et al (1993) PET imaging of cerebral perfusion and oxygen consumption in acute ischaemic stroke: relation to outcome. Lancet 341:925–927PubMedCrossRefGoogle Scholar
  19. 19.
    Mohr JP et al (1994) Meta-analysis of oral nimodipine trials in acute ischaemic stroke. Cerebrovasc Dis 4:197–203CrossRefGoogle Scholar
  20. 20.
    De Deyn P, De Reuck J, Deberdt W, Vlietinck R, Orgogozo JM (1997) Treatment of acute ischemic stroke with piracetam. Members of the Piracetam in Acute Stroke Study (PASS) Group. Stroke 28:2347–2352PubMedCrossRefGoogle Scholar
  21. 21.
    Yamaguchi T et al (1998) Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical Trial. Stroke 29:12–17PubMedCrossRefGoogle Scholar
  22. 22.
    Wahlgren NG, MacMahon DG, De Keyser J, Indredavik B, Ryman T (1994) Intravenous Nimodipine West European Stroke Trial (INWEST) of nimodipine in the treatment of acute stroke. Cerebrovasc Dis 4:204–210CrossRefGoogle Scholar
  23. 23.
    Enlimomab Acute Stroke Trial Investigators (1997) The Enlimomab Acute Stroke Trial: final results. Cerebrovasc Dis 7 [Suppl 4]:18Google Scholar
  24. 24.
    Clark WM, Warach SJ, Pettigrew LC, Gammans RE, Sabounjian LA (1997) A randomized dose-response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Neurology 49:671–678PubMedCrossRefGoogle Scholar
  25. 25.
    Wahlgren NG et al (1999) Chlomethiazole Acute Stroke Study (CLASS): results of a randomised, controlled trial of chlomethiazole versus placebo in 1360 acute stroke patients. Stroke 30:21–28PubMedCrossRefGoogle Scholar
  26. 26.
    Bullock R, Zauner A, Woodward J, Young HF (1995) Massive persistent release of excitatory amino acids following human occlusive stroke. Stroke 20:2187–2189CrossRefGoogle Scholar
  27. 27.
    Stroke Unit Trialists’ Collaboration (1997) Collaborative systematic review of the randomised trials of organised inpatient (Stroke unit) care after stroke. BMJ 314:1151–1159CrossRefGoogle Scholar
  28. 28.
    Sulter G, De Keyser J (1999) From stroke unit care to stroke care unit. J Neurol Sci 162:1–5PubMedCrossRefGoogle Scholar
  29. 29.
    Memezawa H, Zhao Q, Smith ML, Siesjo BK (1995) Hyperthermia nullifies the ameliorating effect of dizocilpine maleate (MK-801) in focal cerebral ischemia. Brain Res 670:48–52PubMedCrossRefGoogle Scholar
  30. 30.
    Schlaug G et al (1999) The ischemic penumbra: operationally defined by diffusion and perfusion MRI. Neurology 53:1528–1537PubMedCrossRefGoogle Scholar
  31. 31.
    Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L (1999) Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology 53:1698–1704PubMedCrossRefGoogle Scholar
  32. 32.
    Gonen O et al (2000) Total brain N-acetylaspartate. A new measure of disease load in MS. Neurology 54:15–19PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2004

Authors and Affiliations

  • J. De Keyser
  • G. Ramsaransing
  • E. Zeinstra
  • N. Wilczak

There are no affiliations available

Personalised recommendations