Combination Therapy with Cytoprotective Agents

  • K. Minematsu
Conference paper


Acute ischemic stroke patients often recover spontaneously from the initial deficits [1]. Dramatic improvement following an initial major hemispheric syndrome within minutes to hours after stroke onset, termed as a spectacular shrinking deficit by Mohr and co-workers [2], indicates a migratory embolus in the internal carotid artery territories [3,4]. Many clinical studies have suggested that treatment with thrombolytic agents can promote reopening of the occluded cerebral arteries and may result in better neurological recovery in acute ischemic stroke patients if the treatment is initiated very early after the stroke onset [5–8]. There is, however, a limited time window for successful reperfusion [9–13]. Late reperfusion may cause pronounced brain swelling, hemorrhagic transformation, and a worse outcome than does permanent vascular occlusion [14,15]. Furthermore, thrombolytic agents are likely to increase the risk of hemorrhagic transformation and other hemorrhagic complications [16–19]. Reperfusion, particularly induced by thrombolytic agents, may be a double-edged sword for and against the ischemic brain [20]. Physicians will be likely to hesitate in giving a thombolytic agent to an individual stroke patient, particularly when the patient does not visit the hospital immediately after stroke onset, even if clinical trials going on around the world finally confirm the beneficial effects of thrombolytic therapy.


Middle Cerebral Artery Occlusion Acute Ischemic Stroke Thrombolytic Therapy Focal Cerebral Ischemia NMDA Antagonist 
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.
    Biller J, Love BB, Marsch EE III, Jones MP, Knepper LE, Jiang D, Adams HP Jr. Gordon DL (1990) Spontaneous improvement after acute ischemic stroke. A pilot study. Stroke 21: 1008–1012PubMedCrossRefGoogle Scholar
  2. 2.
    Mohr JP, Barnett HJM (1986) Classification of ischemic stroke. In: Barnett HJM, Stein BM, Mohr JP, Yatsu FM (eds) Stroke: pathophysiology, diagnosis and management. Churchill Livingstone, New York, pp 281–291Google Scholar
  3. 3.
    Minematsu K, Yamaguchi T, Omae T (1992) Spectacular shrinking deficit: rapid recovery from a major hemispheric syndrome by migration of an embolus. Neurology 42: 157–162PubMedGoogle Scholar
  4. 4.
    Minematsu K (1993) Spectacular shrinking deficits in acute ischemic stroke. In: del Zoppo GJ, Mori E, Hacke W (eds) Thrombolytic therapy in acute ischemic stroke II. Springer, Berlin, pp 138–144CrossRefGoogle Scholar
  5. 5.
    del Zoppo GJ, Ferbert A, Otis S, Bruckmann H, Hacke W, Zyroff J, Harker LA, Zeumer H (1988) Local intra-arterial fibrinolytic therapy in acute ischemic stroke. A pilot study. Stroke 19: 307–313PubMedCrossRefGoogle Scholar
  6. 6.
    Mori E, Tabuchi M, Yoshida T, Yamadori A (1988) Intracarotid urokinase with thromboembolic occlusion of the middle cerebral artery. Stroke 19: 802–812PubMedCrossRefGoogle Scholar
  7. 7.
    Mori E, Yoneda Y, Tabuchi M, Yoshida T, Ohkawa S, Ohsumi Y, Kitano K, Tsutsumi A, Yamadori A (1992) Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Neurology 42: 976–982PubMedGoogle Scholar
  8. 8.
    Yamaguchi T, Hayakawa T, Kikuchi H, for the Japanese Thrombolysis Study Group (1993) Intravenous tissue plasminogen activator ameliorates the outcome of hyperacute embolic stroke. Cerebrovasc Dis 3: 269–272CrossRefGoogle Scholar
  9. 9.
    Jones TH, Morawets RB, Crowell RM, Marcoux FW, FitzGibbon SJ, DeGirolami U, Ojemann RG (1981) Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 27: 773–782Google Scholar
  10. 10.
    Heiss WD, Rosner G (1983) Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol 14: 294–301PubMedCrossRefGoogle Scholar
  11. 11.
    Kaplan B, Brint S, Tanabe J, Jacewicz M, Wang X-J, Pulsinelli W (1991) Temporal thresholds for neocortical infarction in rats subjected to reversible focal cerebral ischemia. Stroke 22: 1032–1039PubMedCrossRefGoogle Scholar
  12. 12.
    Memezawa H, Smith M-L, Siesjö BK (1992) Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke 23: 552–559PubMedCrossRefGoogle Scholar
  13. 13.
    Minematsu K, Li L, Sotak Ch, Davis MA, Fisher M (1992) Reversible focal ischemic injury demonstrated by diffusion-weighted magnetic resonance imaging in rats. Stroke 23: 1304–1311PubMedCrossRefGoogle Scholar
  14. 14.
    Nishigaya K, Yoshida Y, Sasuga M, Nukui H, Ooneda G (1991) Effect of recirculation on exacerbation of ischemic vascular lesions in rat brain. Stroke 22: 635–642PubMedCrossRefGoogle Scholar
  15. 15.
    Koudstaal PJ, Stibbe J, Vermeulen M (1988) Fatal ischaemic brain oedema after early thrombolysis with tissue plasminogen activator in acute stroke. Br Med J 297: 1571–1574CrossRefGoogle Scholar
  16. 16.
    Hanaway J, Track R, Fletcher AP, Landau WM (1976) Intracranial bleeding associated with urokinase therapy for acute ischemic hemispheral stroke. Stroke 7: 143–147PubMedCrossRefGoogle Scholar
  17. 17.
    Okada Y, Yamaguchi T, Minematsu K, Miyashita T, Sawada T, Sadoshima S, Fujishima M, Omae T (1989) Hemorrhagic transformation in cerebral embolism. Stroke 20: 598–603PubMedCrossRefGoogle Scholar
  18. 18.
    Wijdicks EFM, Jack CR Jr (1993) Intracerebral hemorrhage after fibrinolytic therapy for acute myocardial infarction. Stroke 24: 554–557PubMedCrossRefGoogle Scholar
  19. 19.
    Longstreth WT Jr, Litwin PE, Weaver WD, the MITI Project Group (1993) Myocardial infarction, thrombolytic therapy, and stroke. A community-based study. Stroke 24: 587–590PubMedCrossRefGoogle Scholar
  20. 20.
    Siesjö BK (1992) Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. J Neurosurg 77: 169–184PubMedCrossRefGoogle Scholar
  21. 21.
    Steinberg GK, Saleh J, Kunis D, DeLaPaz R, Rami Zarnegar S (1989) Protective effect of N-methyl-D-aspartate antagonists after focal cerebral ischemia in rabbits. Stroke 20: 1247–1252PubMedCrossRefGoogle Scholar
  22. 22.
    Zivin JA, Mazzarella V (1991) Tissue plasminogen activator plus glutamate antagonist improves outcome after embolic stroke. Arch Neurol 48: 1235–1238PubMedCrossRefGoogle Scholar
  23. 23.
    Dersi L, Grenberg JH, Hamar J, Sladky J, Karp A, Reivich M (1992) Acute improvement in histological outcome by MK-801 following focal cerebral ischemia and reperfusion in the cat independent of blood flow changes. J Cereb Blood Flow Metab 12: 390–399CrossRefGoogle Scholar
  24. 24.
    Buchan AM, Slivka A, Xue D (1992) The effect of the NMDA receptor antagonist MK-801 on cerebral blood flow and infarct volume in experimental focal stroke. Brain Res 574: 171–177PubMedCrossRefGoogle Scholar
  25. 25.
    Sereghy T, Overgaard K, Boysen G (1993) Neuroprotection by excitatory amino acid augments the benefit of thrombolysis in embolic stroke in rats. Stroke 24: 1702–1708PubMedCrossRefGoogle Scholar
  26. 26.
    Moseley ME, Cohen Y, Mintorovitch J, Chileuitt L, Shimizu H, Kucharczyk J, Wendland MF, Weinstein PR (1990) Early detection of regional cerebral ischemia in cats: comparison of diffusion-and T2-weighted MRI and spectroscopy. Magn Reson Med 14: 330–346PubMedCrossRefGoogle Scholar
  27. 27.
    Mintorovitch J, Moseley ME, Chileuitt L, Shimizu H, Choen Y, Weinstein PR (1991) Comparison of diffusion-and T2-weighted MRI for the early detection of cerebral ischemia and reperfusion in rats. Magn Reson Med 18: 39–50PubMedCrossRefGoogle Scholar
  28. 28.
    Minematsu K, Li L, Fisher M, Sotak CH, Davis MA, Fiandaca MS (1992) Diffusion-weighted magnetic resonance imaging: rapid and quantitative detection of focal brain ischemia. Neurology 42: 235–240PubMedGoogle Scholar
  29. 29.
    Warach S, Chien D, Li W, Ronthal M, Edelman RR (1992) Fast magnetic resonance diffusion-weighted imaging of acute human stroke. Neurology 42: 1717–1723PubMedGoogle Scholar
  30. 30.
    Zea Longa E, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20: 84–91CrossRefGoogle Scholar
  31. 31.
    Selman WR, Crumrine RC, Ricci AJ, LaManna JC, Ratcheson RA, Lust WD (1990) Impairment of metabolic recovery with increasing periods of middle cerebral artery occlusion in rats. Stroke 21: 467–471PubMedCrossRefGoogle Scholar
  32. 32.
    Welsh FA, Marcy VR, Sims RE (1991) NADH fluorescence and regional energy metabolites during focal ischemia and reperfusion of rat brain. J Cereb Blood Flow Metab 11: 459–465PubMedCrossRefGoogle Scholar
  33. 33.
    Memezawa H, Smith ML, Siesjö BK (1992) Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke 23: 552–559PubMedCrossRefGoogle Scholar
  34. 34.
    Minematsu K, Fisher M, Li L, Davis MA, Knapp AG, Cotter RE, McBurney RN, Sotak CH (1993) Effects of a novel NMDA antagonist on experimental stroke rapidly and quantitatively assessed by diffusion-weighted MRI. Neurology 43: 397–403PubMedGoogle Scholar
  35. 35.
    Olney JW, Labruyere J, Price M (1989) Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244: 1360–1362PubMedCrossRefGoogle Scholar
  36. 36.
    Keok W, Colpaert FC (1990) Selective blockade of N-methyl-D-aspartate (NMDA) -induced convulsions by NMDA antagonists and putative glycine antagonist: relationship with pencyclidine-like behavior effects. J Pharmacol Exp Ther 252: 349–357Google Scholar
  37. 37.
    Minematsu K, Fisher M, Li L, Sotak CH (1993) Diffusion and perfusion magnetic resonance imaging studies to evaluate a noncompetitive N-methyl-n-aspartate antagonist and reperfusion in experimental stroke in rats. Stroke 24: 2074–2081PubMedCrossRefGoogle Scholar
  38. 38.
    Koizumi J, Yoshida Y, Nishigaya K, Kanai H. Ooneda G (1989) Experimental studies of ischemic brain edema: effect of recirculation of the blood flow after ischemia on postischemic brain edema (in Japanese with English abstract). Jpn J Stroke 11: 11–17CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 1995

Authors and Affiliations

  • K. Minematsu
    • 1
  1. 1.Cerebrovascular LaboratoryNational Cardiovascular CenterSuita, Osaka, 565Japan

Personalised recommendations