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Neuroprotection and the Ischemic Cascade

Published online by Cambridge University Press:  07 November 2014

Robert A. Felberg ,
W. Scott Burgin  and
James C. Grotta
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Abstract

Brain ischemia is a process of delayed neuronal cell death, not an instantaneous event. The concept of neuroprotection is based on this principle. Diminished cerebral blood flow initiates a series of events (the “ischemic cascade”) that lead to cell destruction. This ischemic cascade is akin to a spreading epidemic starting from a hypothesized core of ischemia and radiating outward. If intervention occurs early, the process may be halted.

Interventions have been directed toward salvaging the ischemic penumbra. Hypothermia decreases the size of the ischemic insult in both anecdotal clinical and laboratory reports. In addition, a wide variety of agents have been shown to reduce infant volume in animal models. Pharmacologic interventions that involve thrombolysis, calcium channel blockade, and cell membrane receptor antagonism have been studied and have been found to be beneficial in animal cortical stroke models. Human trials of neuroprotective therapies have been disappointing. Other than thrombolytics, no agents, have shown an unequivocal benefit. The future of neuroprotection will require a logical extension of what has been learned in the laboratory and previous human trials. A sensible approach to the use of multiple-agent cocktails used in combination with thrombolytics is likely to offer the highest chance for benefit.

Type
Feature Articles
Information
CNS Spectrums , Volume 5 , Issue 3: Neurologic and Psychiatric Sequelae of Stroke , March 2000 , pp. 52 - 58
Copyright
Copyright © Cambridge University Press 2000

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References

REFERENCES

1.Pulsinelli, WA, Brierly, JB, Plum, F. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol. 1982;11:491–498.CrossRefGoogle Scholar
2.Kirino, T, Tamura, A, Sano, K. Delayed neuronal death in the rat hippocampus following transient forebrain ischemia. Acta Neuropathol (Berl). 1984;64:139–147.CrossRefGoogle ScholarPubMed
3.Petito, CK, Pulsinelli, WA. Delayed neuronal recovery and neuronal death in rat hippocampus following severe cerebral ischemia: possible relationship to abnormalities in neuronal processes. J Cereb Blood Flow Metab. 1984;4:194–205.CrossRefGoogle ScholarPubMed
4.Petito, CK, Pulsinelli, WA. Sequential development of reversible and irreversible neuronal damage following cerebral ischemia. J Neuropathol Exp Neurol. 1984;43:141–153.Google Scholar
5.Petito, CK, Feldman, E, Pulsinelli, WA, Plum, F. Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology. 1987;37:1281–1286.Google Scholar
6.Symon, L, Branston, NM, Strong, AJ, et al.The concepts of threshold ischaemia in relation to brain structure and function. J Clin Pathol. 1997;30(suppl 11):149–154.Google Scholar
7.Astrup, J, Symon, L, Siesjö, BK. Thresholds in cerebral ischemia: the ischemic penumbra. Stroke. 1981;12:723–725.Google Scholar
8.Memezawa, H, Smith, M, Siesjö, BK. Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke. 1992;23:552–559.Google Scholar
9.Siesjö, BK. Pathophysiology and treatment of focal cerebral ischemia, II: mechanisms of damage and treatment. J Neurosurg. 1992;77:337–354.Google Scholar
10.Choi, DW, Rothman, SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci. 1990;13:171–182.CrossRefGoogle ScholarPubMed
11.Cheung, JY, Bonventre, JV, Malis, Cd, Leaf, A. Calcium and ischemic injury. N Engl J Med. 1986;314:1670–1676.Google Scholar
12.Rubin, E, Farber, JL. Cell injury. In: Rubin, E, Farber, JL, eds. Pathology. Philadelphia, Pa: J.B. Lippencott Company; 1988:4–33.Google Scholar
13.Auer, RN. Histopathology of cerebral ischemia. In: Ginsburg, MD, Bogousslavsky, J, eds. Cerebrovascular Disease: Pathophysiology, Diagnosis, and Management. Maiden, Mass: Blackwell Science; 1998:90–101.Google Scholar
14.Garcia, JH. Mechanisms of cell death in ischemia. In: Caplan, LR, ed. Brain Ischemia: Bask Concepts and Clinical Relevance. London, UK: Springer-Verlag; 1995:7–18.Google Scholar
15.Ginsberg, MD. Neuroprotection in brain ischemia, I: an update. The Neuroscientist. 1995;1:95–103.Google Scholar
16.The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–1587.CrossRefGoogle Scholar
17.Yang, G, Betz, L. Reperfusion-induced injury to the blood brain barrier after middle cerebral artery occlusion in rats. Stroke. 1994;25:1658–1664.CrossRefGoogle Scholar
18.Grotta, JC, Chiu, D. Pharmacologic modification of acute cerebral ischemia. In: Barnett, HJM, Mohr, JP, Stein, BM, Yatsu, FM, eds. Stroke: Pathophysiology, Diagnosis, and Management. 3rd ed. Philadelphia, Pa: Churchill Livingstone; 1998:1079–1088.Google Scholar
19.Horikawa, Y, Naruse, S, Hirakawa, K, et al.In vivo studies of energy metabolism in experimental cerebral ischemia using topical magnetic resonance: changes in 31P-nuclear magnetic resonance spectra compared with electroencephalograms and regional cerebral blood flow. J Cereb Blood Flow Metab. 1985;235–240.Google Scholar
20.Ricci, PE Jr. Proton MR spectroscopy in ischemic stroke and other vascular disorders. Neuroimaging Clin N Am. 1998;8:881–900.Google Scholar
21.Kohno, K, Hoehn-Berlage, M, Mies, G, Bach, T, Hossmann, KA. Relationship between diffusion weighted MR images, cerebral blood flow, and energy state in experimental brain infarction. Magn Reson Imaging. 1995;13:73–80.Google Scholar
22.von Kummer, R. Ischemic stroke and tissue hypodensity on computed tomography. Stroke. 1999;30:1974.Google Scholar
23.Butcher, SP, Bullock, R, Graham, DI, et al.Correlation between amino acid release and neuropathological outcome in rat brain following middle cerebral artery occlusion. Stroke. 1990;21:1727–1733.Google Scholar
24.Benveniste, H, Drejer, J, Schousboe, A, et al.Elevation of extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem. 1984;43:1369–1374.CrossRefGoogle ScholarPubMed
25.Pellegrini-Giampietro, DE, Zukin, RS, Bennett, MVL, Cho, S, Pulsinelli, WA. Switching glutamate receptor subunit gene in CA1 subfield of hippocampus following global ischemia in rats. Proc Natl Acad Sci USA. 1992;89:10499–10503.Google Scholar
26.Greenamyre, JT. The role of glutamate in neurotransmission in neurological disease. Arch Neurol. 1986;43:1058–1063.Google Scholar
27.MacDermott, AB, Mayer, ML, Westbrook, GL. NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurons. Nature. 1986;321:529–522.Google Scholar
28.Rothman, SM. Excitotoxins: possible mechanisms of action. Ann NY Acad Sci. 1992;648:132–139.CrossRefGoogle ScholarPubMed
29.Lipton, SA, Rosenberg, PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 1994;330:613–622.Google ScholarPubMed
30.Rothman, SM, Olney, JW. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol. 1986;19:105–111.Google Scholar
31.Schoepp, DD, Conn, PJ. Metabotropic glutamate receptors in brain function and pathology. Trends Pharmocol Sci. 1993;14:13–20.Google Scholar
32.Choi, DW. Methods for antagonizing glutamate neurotoxicity. Cerebrovasc Brain Metab Rev. 1990;2:105–147.Google ScholarPubMed
33.Siesjo, BK, Agardh, C, Bengtsson, F. Free radicals and brain damage. Cerebrovasc Brain Metab Rev. 1989;1:165–211.Google ScholarPubMed
34.Siesjo, BK, Bengtsson, F. Calcium fluxes, calcium antagonists, and calcium related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis. J Cereb Blood Flow Metab. 1989;9:127–140.Google Scholar
35.Lee, K, Frank, S, Vanderklish, P, Arai, A, Lynch, G. Inhibition of proteolysis protects hippocampal neurons from ischemia. Proc Natl Acad Sci USA. 1991;88:7233–7237.CrossRefGoogle ScholarPubMed
36.Roberts-Lewis, JM, Savage, MJ, Marcy, VR, Pinsker, LR, Siman, R. Immunolocalization of calpain I-mediated spectrin degradation to vulnerable neurons in the ischemic gerbil brain. J Neurosci. 1994;14:3934–3944.Google Scholar
37.Hong, S-C, Goto, Y, Lanzino, G, Soleau, S, Kassell, NF, Lee, KS. Neuroprotection with a calpain inhibitor in a model of focal cerebral ischemia. Stroke. 1994;24:663–669.Google Scholar
38.Traystman, RJ, Kirsch, JR, Koehler, RC. Oxygen radical mechanisms of brain injury following ischemia and reperfusion. J Appl Physiol. 1991;71:1185–1195.Google Scholar
39.Rice-Evans, CA, Diplock, AT. Current status of antioxidant therapy. Free Radic Biol Med. 1993;15:77–96.Google Scholar
40.Wise, RJS, Bernardi, S, Frackowski, RSJ, et al.Serial observations on the pathophysiology of acute stroke: the transition from ischaemia to infarction as reflected in regional oxygen extraction. Brain. 1983;106:197–222.Google Scholar
41.Heiss, W-D, Huber, M, Fink, GR, et al.Progressive derangement of periinfarct viable tissue in acute ischemic stroke. J Cereb Blood Flow Metab. 1992;12:193–203.Google Scholar
42.Baird, AE, Benefield, A, Schlaug, G, et al.Enlargement of human cerebral ischemic lesion volumes measured by diffusion-weighted magnetic resonance imaging. Ann Neurol. 1997;41:581–589.Google Scholar
43.Hakim, AM, Evans, AC, Berger, L, et al.The effect of nimodipine on the evolution of human cerebral infarction studied by PET. J Cereb Blood Flow Metab. 1989;9:523–534.Google Scholar
44.Shinohara, M, Dollinger, B, Brown, G, et al.Cerebral glucose utilization: local changes during and after recovery from spreading cortical depression. Science. 1979;203:188–190.Google Scholar
45.Kocher, M. Metabolic and hemodynamic activation of postischemic rat brain by cortical spreading depression. J Cereb Blood Flow Metab. 1990;10:564–571.CrossRefGoogle ScholarPubMed
46.Mies, G, Iijama, T, Hossman, K-A. Correlation between periinfarct DC shifts and ischemic neuronal damage in the rat. Neuroreport. 1993;4:709–711.CrossRefGoogle Scholar
47.The Hemodilution in Stroke Study Group. Hypervolemic hemodilution treatment of acute stroke: results of a randomized multicenter trial using pentastarch. Stroke. 1989;20:317–323.Google Scholar
48.Feuerstein, GZ, Wang, X, Barone, FC. Inflammatory mediators and brain injury: the role of cytokines and chemokines in stroke and CNS diseases. In: Ginsburg, MD, Bogousslavsky, J, eds. Cerebrovascular Disease: Pathophysiology, Diagnosis, and Management. Maiden, Mass: Blackwell Science; 1998:507–531.Google Scholar
49.Gage, FH. Stem cells of the central nervous system. Curr Opin Neurobiol. 1998;8:671–676.Google Scholar
50.Kirschner, P, Henshaw, R, Weise, J, et al.Basic fibroblast growth factor protects against excitotoxicity and chemical hypoxia in both neonatal and adult rats. J Cereb Blood Flow Metab. 1995;15:619–623.Google Scholar
51.Aronowski, J, Ostrow, P, Samways, E, Strong, R, Zivin, J, Grotta, J. Graded bioassay for demonstration of brain rescue from experimental acute ischemia in rats. Stroke. 1994;25:2235–2240.CrossRefGoogle ScholarPubMed
52.Ginsberg, MD. Neuroprotection in brain ischemia, II: an update. The Neuroscientist. 1995;1:164–175.Google Scholar
53.Clifton, G, Allen, S, Barrodale, P, et al.A phase II study of moderate hypothermia in severe brain injury. J Neurotrauma. 1993;10:263–271.Google Scholar
54.Bernard, SA, Jones, BM, Horne, MK. Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Ann Emerg Med. 1997;30:146–153.Google Scholar
55.Felberg, RA, Hickenbottom, SJ, Burgin, WS, Kim, Y, Persse, DE, Grotta, JC. Moderate induced hypothermia following cardiac arrest: a safety and feasibility trial (abstract). Stroke. 2000;1:284.Google Scholar
56.Schwab, S, Schwarz, S, Spranger, M, Keller, E, Bertram, M, Hacke, W. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke. 1998;29:2461–2466.Google Scholar
57.del Zoppo, GJ, Higashida, RT, Furlan, AJ, Pessin, MS, Rowley, HA, Gent, M. PROACT: a phase II randomized trial of recombinant prourokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke. 1998;29:4–11.Google Scholar
58.Atkinson, RP. Ancrod in the treatment of acute ischemic stroke: a review of clinical data. Cerebrovasc Dis. 1998;8(suppl 1):23–28.CrossRefGoogle ScholarPubMed
59.Grotta, JC. Acute stroke therapy at the millennium: consummating the marriage between the laboratory and bedside: the Feinberg lecture. Stroke. 1999;30:1722–1728.Google Scholar
60.Hacke, W, Kaste, M, Fieschi, et al.Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischemic stroke (ECASS II): Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352:1245–1251.Google Scholar
61.Tettenhorn, D, Dycka, J. Prevention and treatment of delayed ischemic dysfunction in patients with aneurysmal subarachnoid hemorrhage. Stroke. 1990;21(suppl 4):85–89.Google Scholar
62.Mohr, J, Orgogozo, J, Harrison, M, et al.Meta-analysis of oral nimodipine trials in acute ischemic stroke. Cerebrovasc Dis. 1994;4:197–201.CrossRefGoogle Scholar
63.Grotta, J. The current status of neuronal protective therapy: why have all the neuronal protective drugs worked in animals but none so far in stroke patients? Cerebrovasc Dis. 1994;4:115–120.Google Scholar
64.Arrowsmith, JE, Harrison, MJ, Newman, SP, Stygall, J, Timberlake, N, Pugsley, WB. Neuroprotection of the brain during cardiopulmonary bypass: a randomized trial of remacemide during coronary artery bypass in 171 patients. Stroke. 1998;29:2357–2362.CrossRefGoogle ScholarPubMed
65.Uematsu, D, Araki, N, Greenberg, JH, Sladky, J, Reivich, M. Combined therapy with MK-801 and nimodipine for protection of ischemic brain damage. Neurology. 1991;41:88–94.Google Scholar
66.Globus, MY-T, Dietrich, WD, Busto, R, Valdes, I, Ginsburg, MD. The combined treatment with a dopamine D-1 antagonist (SCH-23390) and NMDA receptor blocker (MK-801) dramatically protects against ischemia-induced hippocampal damage. J Cereb Blood Flow Metab. 1989;9(suppl 1):S5.Google Scholar
67.Zivin, JA. Therapy of embolic stroke with tissue plasminogen activator plus a glutamate antagonist. Neurology. 1989;39(suppl 1):372.Google Scholar
68.Sereghy, T, Overgaard, K, Boysen, G. Neuroprotection by excitatory amino acid antagonist augments the benefit of thrombolysis in embolic stroke in rats. Stroke. 1993;24:1702–1708.Google Scholar
69.Frazee, JG, Jordan, SE, Dion, JE, et al.Ischemic brain rescue by transvenous perfusion in baboons with venous sinus occlusion. Stroke. 1990;21:87–93.CrossRefGoogle ScholarPubMed
70.Spilker, J, Kongable, G, Barch, C, et al.Using the NIH Stroke Scale to assess stroke patients: the NINDS rt-PA Stroke Study Group. J Neurosci Nurs. 1997;29:384–392.Google Scholar
71.Kreiger, DW, Demchuk, AM, Kasner, SE, Jauss, M, Hanston, L. Early clinical and radiological predictors of fatal brain swelling in ischemic stroke. Stroke. 1999;30:287–292.Google Scholar
72.de Haan, R, Limburg, M, Bossuyt, P, van der Meulen, J, Aaronson, N. The clinical meaning of Rankin “handicap” grades after stroke. Stroke. 1995;26:2027–2030.Google Scholar
73.Wolfe, CD, Taub, NA, Woodrow, EJ, Burney, PG. Assessment of scales of disability and handicap for stroke patients. Stroke. 1991;22:1242–1244.CrossRefGoogle ScholarPubMed
74.Sulter, G, Steen, C, De Keyser, J. Use of Barthel index and modified Rankin scale in acute stroke trials. Stroke. 1999;30:1538–1541.Google Scholar