In developed countries, ischemic stroke is one of the leading causes of death and neurological impairment. The two most important therapeutic approaches in patients with acute cerebral ischemia consist of improving cerebral blood flow and blocking the biochemical and metabolic changes at the ischemic cascade level. The significant advances made in the past decade in the knowledge of the physiopathological mechanisms of cerebral ischemia, and the development of new drugs have given rise to true expectations regarding treatment and the rejection of nihilist attitudes. In the past 15 years, based on the excellent results obtained in experimental models of ischemia, many clinical trials have been conducted with different neuroprotective drugs. The results obtained in most studies have been negative, or the studies were terminated early owing to side effects. However, some drugs (citicoline, clomethiazole, piracetam and ebselen) have shown a certain degree of clinical efficacy, limited to subgroups of patients, and with a narrow therapeutic window, longer-lasting in the case of citicoline. The design of new clinical trials with neuroprotective drugs requires adequate preclinical assessment and the use of the new magnetic resonance techniques for the selection of patients and the assessment of the efficacy of treatment. The new trends in neuroprotection in focal cerebral ischemia and the results of the clinical trials published to date are reviewed.

Keywords:
Neuroprotection, Cerebral ischemia, Ischemic stroke
1.
Bonita R: Epidemiology of stroke. Lancet 1992;339:342–344.
2.
The European Ad Hoc Consensus Group: Neuroprotection as initial therapy in acute stroke. Third Report of an Ad Hoc Consensus Group Meeting. Cerebrovasc Dis 1998;8:59–72.
3.
Smith AL, Hoff JT, Nielsen SL, Larson CP: Barbiturate protection in acute focal cerebral ischemia. Stroke 1974;5:1–7.
4.
Pulsinelli W: Pathophysiology of acute ischemic stroke. Lancet 1992;339:533–536.
5.
Allain H, Decombe R, Saiag B, Bentué-Ferrer D, Guez D: Mechanistic basis for the development of anti-ischemic drugs. Cerebrovasc Dis 1991;1(suppl 1):83–92.
6.
Dávalos A, Castillo J, Martínez-Vila E: Delay in neurological attention and stroke outcome. Stroke 1995;26:2233–2237.
7.
Meyer FB, Anderson RE, Sundt TM, Yaksh TL: Intracellular brain pH, indicator tissue perfusion, electroencephalography, and histology in severe and moderate focal cortical ischemia in the rabbit. J Cereb Blood Flow Metab 1986;6:71–78.
8.
García JH: The evolution of brain infarcts. A review. J Neuropathol Exp Neurol 1992;51:387–393.
9.
Ginsberg MD: Neuroprotection in brain ischemia: An update (part I). Neuroscientist 1995;1:95–103.
10.
Pulsinelli WA: The therapeutic window in ischemic brain injury. Curr Opin Neurol 1995;8:3–5.
11.
Astrup J, Siesjo BK, Symon L: Treshold in cerebral ischemia. The ischemic penumbra. Stroke 1981;12:723–727.
12.
Jones TH, Morawetz RB, Crowell RM, Marcoux FW, Fitzggibon SK, DeGirolami U, et al: Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 1981;29:657–665.
13.
Hass WK: The cerebral ischemic cascade. Neurol Clin 1983;1:345–353.
14.
Marchal G, Beaudouin V, Rioux P, de la Sayette V, Le Doze F, Viader F, Derlon JM, Baron JC: Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke. A correlative PET-CT study with voxel-based data analysis. Stroke 1996;27:599–606.
15.
Baron JC, Von Kummer R, Del Zoppo GJ: Treatment of acute ischemic stroke. Challenging the concept of a rigid and universal time window. Stroke 1995;26:2219–2221.
16.
Ginsberg MD: Neuroprotection in brain ischemia: An update (part II). Neuroscientist 1995;1:164–175.
17.
Devuyst G, Bogousslavsky J: Clinical trial update: Neuroprotection against acute ischemic stroke. Curr Opin Neurol 1999;12:73–79.
18.
Meldrum BS: Cytoprotective therapies in stroke. Curr Opin Neurol 1995;8:15–23
19.
Wahlgren NG: Cytoprotective therapy for acute ischemic stroke; in Fisher M (ed): Stroke Therapy. Boston, Butterworth-Heinemann, 1995, pp 315–350.
20.
Fisher M: An overview of cytoprotective therapy for acute ischemic stroke; in Moskowitz MA, Caplan LR (eds): Cerebrovascular Diseases. Boston, Butterworth-Heinemann, 1995, pp 391–401.
21.
Goldszmidt A, Wityk RJ: Recent advances in stroke therapy. Curr Opin Neurol 1998;11:57–64.
22.
Onal MZ, Fisher M: Acute ischemic stroke therapy. A clinical overview. Eur Neurol 1997;38:141–154.
23.
Fisher M, Bogousslavsky J: Further evolution toward effective therapy for acute ischemic stroke. JAMA 1998;279:1298–1303.
24.
The European Ad Hoc Consensus Group: Neuroprotection as initial therapy in acute stroke. Third Report of an Ad Hoc Consensus Group Meeting. Cerebrovasc Dis 1998;8:59–72.
25.
Hickenbottom SL, Grotta J: Neuroprotective therapy. Semin Neurol 1998;18:485–492.
26.
De Keyser J, Sulter G, Luiten PG: Clinical trials with neuroprotective drugs in acute ischemic stroke: Are we doing the right thing? Trends Neurosci 1999;22:535–540.
27.
Martínez-Vila E, Irimia-Sieira P, Gállego-Culleré J: Situación actual de la neuroprotección en el ictus. Rev Neurol 1999;29:526–536.
28.
The American Nimodipine Study Group: Clinical trial of nimodipine in acute ischemic stroke. Stroke 1992;23:3–9.
29.
Hennerici M, Kramer G, North PM, Schmitz H, Tettenborn D: Nimodipine in the treatment of acute MCA ischemic stroke. Cerebrovasc Dis 1994;4:189–193.
30.
Mohr JP, Orgogozo JM, Harrison MJG, Hennerici M, Wahlgren NG, Gelmers JH, Martinez-Vila E, Dycka J, Tettenborn D: Meta-analysis of oral nimodipine trials in acute ischemic stroke. Cerebrovasc Dis 1994;4:197–203.
31.
Horn J, Limburg M, Vermeulen M: VENUS – very early nimodipine use in stroke: Final results from a randomised, placebo-controlled trial. Cerebrovasc Dis 1999;9 (suppl 1):127.
32.
Wahlgren NG, MacMahon DG, De Keyser J, Indredavik B, Ryman T: Intravenous nimodipine West European Stroke Trial (INWEST) of nimodipine in the treatment of acute ischemic stroke. Cerebrovasc Dis 1994;4:204–210.
33.
Bridgers S, Koch G, Munera C, Karwon M, Kurtz N: Intravenous nimodipine in acute stroke: Interim analysis of randomized trial. Stroke 1991;22:29.
34.
Rosenbaum DM, Zabramski J, Frey J, Yatsu F, Marler J, Spetzler R, Grotta J: Early tratment of ischemic stroke with a calcium antagonist. Stroke 1991;22:437–441.
35.
Lataste X, Maurer W, Whitehead J, the Asclepios Study Group: Application of sequential methods to clinical trial in stroke: The Asclepios Study. 2nd World Congress of Stroke, 1992, S16.
36.
Oczkowski WJ, Hachinski VC, Bogousslavsky J, Barnett HJM, Carruthers SG: A double-blind, randomized trial of PY 108-086 in acute ischemic cerebral infarction. Stroke 1989;20:604–608.
37.
Franke CL, Palm R, Dalby M, Schoonderwaldt HC, Hantson L, Eriksson B, Lang-Jenssen L, Smakman J: Flunarizine in stroke treatment (FIST): A double-blind, placebo-controlled trial in Scandinavia and the Netherlands. Acta Neurol Scand 1996;93:56–60.
38.
Horn J, Limburg M: Calcium antagonists for acute ischemic stroke. Cochrane Database Syst Rev 2000;2:CD001928.
39.
Albers GW, Goldberg MP, Choi DW: N-methyl-D-aspartate antagonists: Ready for clinical trial in brain ischemia? Ann Neurol 1989;25:398–403.
40.
Muir KW, Lees KR: Clinical experience with excitatory amino acid antagonist drugs. Stroke 1995;26:503–513.
41.
Muir KW, Lees KR, Hamilton SJC: A randomised double blind, placebo controlled ascending dose tolerance study of 619C89 in acute stroke (abstract). Proceedings of the 2nd International Conference on Neuroprotective Agents. Lake George, July 1994.
42.
Grotta J, for the US and Canadian Lubeluzole Ischemic Stroke Study Group: Lubeluzole treatment of acute ischemic stroke. Stroke 1997;28:2338–2346.
43.
Diener HC, for the European and Australian Lubeluzole Ischemic Stroke Study Group: Multinational randomised controlled trial of lubeluzole in acute ischemic stroke. Cerebrovasc Dis 1998;8:172–181.
44.
Lees KR: Does neuroprotection improve stroke outcome? Lancet 1998;351:1447–1448.
45.
Pulsinelli WA, Mann ME, Welch KMA, Zivin JA, Biller J, Maisel J, Rubin JJ, Verro P, Grahan GD, Pierce M, Kugler AR, Mohberg N, Knapp LE, Poole RM: Fosphenytoin in acute ischemic stroke: Efficacy results. Neurology 1999;52(suppl 2):A384.
46.
Huber M, Kittner B, Hojer C, Fink GR, Neveling M, Heiss WD: Effect of propentophylline on cerebral regional glucose metabolism on acute ischemic stroke. J Cereb Blood Flow Metab 1993;13:526–530.
47.
Squire IB, Lees KR, Pryse-Phillips W, Kertesz A, Bamford-J, for the Lifaricine Study Group: Efficacy and tolerability of liferazine in acute ischemic stroke. A pilot study. Ann NY Acad Sci 1995;765:317–318.
48.
Scatton B, Carter C, Benavides J, Giroux C: N-methyl-D-aspartate receptor antagonists: A novel therapeutic perspective for the treatment of ischemic brain injury. Cerebrovasc Dis 1991;1:121–135.
49.
Albers GW, Atkinson RP, Kelley RE, Rosenbaum DM: Safety, tolerability, and pharmacokinetics of the N-Methyl-D-Aspartate antagonist dextrorphan in patients with acute stroke. Stroke 1995;26:254–258.
50.
Muir KW, Lees KR: A randomized, double-blind, placebo controlled pilot trial of intravenous magnesium sulphate in acute stroke. Stroke 1995;26:1183–1188.
51.
Olney JW, Labruyere J, Price MT: Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 1989;244:1360–1362.
52.
Fisher M: Cerestat (CNS 1102), a non competitive NMDA antagonist in ischemic stroke patients: Dose escalating safety study. Cerebrovasc Dis 1994;4:245.
53.
Lees KR: Cerestat and other antagonists NMDA in ischemic stroke. Neurology 1997;49(suppl 4):66–69.
54.
Markabi S: Selfotel (CGS 19755): The preliminary clinical experience; in Krieglstein J, Oberpichler-Schwenk H (eds): Pharmacology of Cerebral Ischemia. Stuttgart, Medpharm Scientific, 1994, pp 635–642.
55.
Davis SM, Alberts GW, Diener HC, Lees KR, Norris J: Termination of acute stroke studies involving selfotel treatment (letter). Lancet 1997;349:32.
56.
Giroux C, Rosen P, Scatton B: Preclinical pharmacology and clinical safety profile of eliprodil, an atypical NMDA receptor antagonist; in Krieglstein J, Oberpichler-Schwenk H (eds): Pharmacology of Cerebral Ischemia. Stuttgart, Medpharm Scientific, 1994, pp 643–648.
57.
Lees KR, Lavelle JF, Hobbiger SF, for the GAIN European Study Group: Safety and tolerabilty of GV 150526 in acute stroke. Cerebrovasc Dis 1998;8(suppl 4):20.
58.
Lees KR, Asplund K, Carolei A, Davis SM, Diener HC, Kaste M, Orgogozo JM, Whitehead J, for the GAIN International Investigator: Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: A randomised controlled trial. Lancet 2000;355:1949–1954.
59.
Warach S, Kaste M, Fisher M, on behalf of the GAIN Americas and GAIN International MRI substudy investigators and Glaxo Wellcome Collaborative Group: The effect of GV 150526 on ischemic lesion volume: The GAIN Americas and GAIN International MRI substudy. Neurology 2000;54(suppl 3):A87–A88.
60.
Schmidley JW: Free radicals in central nervous system ischemia. Stroke 1990;21:1086–1090.
61.
Siesjo BK, Agarddh CD, Bengtsson F: Free radicals and brain damage. Cerebrovasc Brain Metab Rev 1989;1:165–211.
62.
Haley EC, on behalf of the RANTTAS II Investigators: High dose tirilazad for acute stroke (RANTTAS II). Stroke 1998;29:1256–1257.
63.
The RANTTAS Investigators: A randomized trial of tirilazad mesylate in patients with acute stroke (RANTTAS). Stroke 1996;27:1453–1457.
64.
Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H, for the Ebselen Study Group: Ebselen in acute ischemic stroke. A placebo controlled, double blind clinical trial. Stroke 1998;29:12–17.
65.
Bassi S, Albizzati MG, Sbachi M, Frattola L, Massarotti M: Double-blind evaluation of monoganglioside (GM1) therapy in stroke. J Neurosci Res 1984;12:493–498.
66.
Argentino C, Sacchetti ML, Toni D, Savoini G, D’Arcangelo E, Erminio F, et al: GM1 ganglioside therapy in acute ischemic stroke. Stroke 1989;20:1143–1149.
67.
The SASS Investigators: Ganglioside GM-1 in acute ischemic stroke. Stroke 1994;25:1141–1148.
68.
Lenzi GL, Grigoletto F, Gent M, Roberts RS, Walker MD, Easton JD, et al: Early treatment of stroke with monosialoganglioside GM-1. Efficacy and safety results of the Early Stroke Trial. Stroke 1994;25:1552–1558.
69.
Candelise L, Ciccone A: Gangliosides for acute ischemic stroke. Cochrane Database Syst Rev 2000;2:CD000094.
70.
Cross AJ, Jones JA, Baldwin HA, Green AR: Neuroprotective activity of chlomethiazole following transient forebrain ischemia in the gerbil. Br J Pharmacol 1991;104:406–411.
71.
Snape MF, Balwin HA, Cross AJ, Green AR: The effects of chlomethiazole and nimodipine on cortical infarct area after focal cerebral ischemia in the rat. Neuroscience 1993;53:837–844.
72.
Wahlgren NG, the Clomethiazole Acute Stroke Study Collaborative Group: The Clomethiazole Acute Stroke Study (CLASS) (abstract). Cerebrovasc Dis 1997;7(suppl 4):19.
73.
Wahlgren NG, the Clomethiazole Acute Stroke Study Collaborative Group: The Clomethiazole Acute Stroke Study (CLASS): Efficacy results in a subgroup of 545 patients with Total Anterior Circulation Syndrome. Stroke 1998;29:287.
74.
Lyden PD, the CLASS IHT Investigators. Safety and efficacy of combined clomethiazole and t-PA for acute stroke-CLASS-T: A pilot study. Neurology 2000;54(suppl 3):A88.
75.
Ay H, Ay Y, Koroshetz WJ, Finklestein SP: Potential usefulness of basic fibroblast growth factor as a treatment for stroke. Cerebrovasc Dis 1999;9:131–135.
76.
Koketsu N, Berlove DJ, Moskowitz MA, Kowall NW, Caday CG, Finklestein SP: Pretreatment with intraventricular basic fibroblast growth factor decreases infarct size following focal cerebral ischemia in rats. Ann Neurol 1994;35:451–457.
77.
Clark WM, Schim JD, Kasner SE, Victor SJ, the Fiblast Stroke Study Investigators: Trafermin in acute ischemic stroke: Results of a phase II/III randomized efficacy study. Neurology 2000;54(suppl 3):A88.
78.
Bogousslavsky J, Donnnan GA, Fieschi C, Kaste M, Orgogozo JM, Chamorro A, Victor SJ: Fiblast (trafermin) in acute stroke: Results of the European-Australian phase II/III safety and efficacy trial. Cerebrovasc Dis 2000;10 (suppl 2):106.
79.
D’Orlando JK, Sandadge BW: Citicoline (CDP-Choline): Mechanisms of action and effects ischemic brain injury. Neurol Res 1995;17:281–284.
80.
Clark WM, Warach SJ, Pettigrew LC, Gammans RE, Sabounjian LA: A randomized dose-response trial of citicoline in acute ischemic stroke patients. Neurology 1997;49:671–678.
81.
Gammans RE, Sherman, ECCO 2000 Investigators: ECCO 2000 study of citicoline for treatment of acute ischemic stroke: Final results. 25th International Stroke Conference. New Orleans, February 2000.
82.
Warach SJ, Sabounjian LA, ECCO 2000 Investigators: ECCO 2000 study of citicoline for treatment of acute ischemic stroke: Effects on infarcts volumes measured by MRI. 25th International Stroke Conference. New Orleans, February 2000.
83.
Müller WE, Koch S, Scheuer K, Rostock A, Bartsch R: Effects of piracetam on membrane fluidity in the aged mouse, rat and human brain. Biochem Pharmacol 1997;53:135–140.
84.
de Deyn PP, de Reuck, Debert W, et al: Treatment of acute ischemic stroke with piracetam. Stroke 1997;28:2347–2352.
85.
Dawson DA: Nitric oxide and focal cerebral ischemia. Cerebrovasc Brain Metab Rev 1994;6:299–324.
86.
Nishikawa T, Kirsch JR, Koehler RC, Miyabe M, Trystman RJ: Nitric oxide synthase inhibition reduces caudate injury following transient focal ischemia in cats. Stroke 1994;25:877–885.
87.
O`Mahony D, Kendall MJ: Nitric oxide in acute ischemic stroke: A target for neuroprotection. J Neurol Neurosurg Psychiatry 1999;67:1–3.
88.
Teal P, on behalf of the BRAIN Study Group: BRAINS, a phase II study of the neuroprotectant BAY 3102 in patients with ischemic stroke. Cerebrovasc Dis 1998;8(suppl 4):20.
89.
Olinger CP, Adams HP, Brott TG, Biller J, Barsan WG, Toffol GJ, et al: High-dose intravenous naloxone for the treatment of acute ischemic stroke. Stroke 1990;21:721–725.
90.
Clark WM, Raps EC, Tong DC, Kelly RE: Cervene (nalmefene) in acute ischemic stroke: Final results of a phase III efficacy study. The Cervene Stroke Study Investigators. Stroke 2000;31:1234–1239.
91.
Fayad P, Caplik J, Culligan N, Edwards K, Maisel J, Moonis M, Newman G, Srinivas N, Wirkowski E, Bozik M: Safety, tolerability, and pharmacokinetics of intravenous BMS-204352, a novel maxi-K channel opener, in patients up to 48 hours after acute ischemic stroke. Cerebrovasc Dis 2000;10(suppl 2):71.
92.
Barthus RT: The calpain hypothesis of neurodegeneration: Evidence for a common cytotoxic pathway. Neuroscientist 1997;3:342–349.
93.
Markgraf CG, Velayo NIL, Johnson MP, et al: Six hour window of opportunity for calpain inhibition in focal cerebral ischemia in rats. Stroke 1998;29:152–158.
94.
Lee JM, Zipfel GJ, Choi DW: The changing landscape of ischemic brain injury mechanisms. Nature 1999;399(suppl):A7–A14.
95.
Kuschinsky W, Gillardon F: Apoptosis and cerebral ischemia. Cerebrovasc Dis 2000;11:165–169.
96.
Chen H, Chopp M, Zhang RL, Bodzin G, Chen Q, Rusche JR, Todd RF: Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 1994;35:458–463.
97.
Bowes MP, Zivin JA, Rothlein R: Monoclonal antibody to the ICAM-1 adhesion site reduced neurological damage in a rabbit cerebral embolism model. Exp Neurol 1993;119:215–219.
98.
The Enlimolab Acute Stroke Trial Investigastors: The Enlimolab Acute Stroke Trial: Final results (abstract). Neurology 1997;48:A270.
99.
Saxena R, Wijnhoud AD, Carton H, Hacke W, Kaste M, Przybelski RJ, Stern KN, Koudstaal PJ: Controlled safety study of a hemoglobin-based oxygen carrier, DCL Hb, in acute ischemic stroke. Stroke 1999;30:993–996.
100.
Castillo J, Martinez F, Leira R, Prieto JM, Lema M, Noya M: Mortality and morbidity of acute cerebral infarction related to temperature and basal analytic parameters. Cerebrovasc Dis 1994;4:56–71.
101.
Kammersgaard LP, Rasmussen BH, Jorgensen HS, Reith J, Weber U, Olsen TS: Feasibility and safety of introducing modest hypothermia in awake patients with acute stroke through surface cooling: A case-control study. The Copenhagen Stroke Study. Stroke 2000;31:2251–2256.
102.
Vaughan CJ, Delanty N: Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke 1999;30:1969–1973.
103.
Toung TJ; Traystman RJ, Hurn PD: Estrogen-mediated neuroprotection after experimental stroke in male rats. Stroke 1998;29:1666–1670.
104.
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.
105.
Lindsberg PJ, Roine RO, Tatlisumak T, Sairanen T, Kaste M: The future of stroke treatment. Neurol Clin 2000;19:495–510.
106.
Sacchetti ML, Toni D, Fiorelli M, Argentino C, Fieschi C: The concept of combination therapy in acute ischemic stroke. Neurology 1997;49(suppl 4):70–77.
107.
Fisher M, Jonas S, Sacco RL: Prophylactic neuroprotection to improve stroke outcome. Cerebrovasc Dis 1994;4(suppl 4):20–23.
108.
Martin R: Neuroprotección preventiva. Rev Neurol 1995;23:30–32.
109.
Muir KW, Grosset DG: Neuroprotection for acute stroke. Making clinical trials work. Stroke 1999;30:180–182.
110.
DeGraba TJ, Pettigrew LC: Why do neuroprotective drugs work in animals but not in humans? Neurol Clin 2000;19:475–493.
111.
Stroke Therapy Academic Industry Roundtable (STAIR): Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999;30:2752–2758.
112.
Caplan LR: Stroke treatment. Promising but still struggling. JAMA 1998;279:1304–1306.
113.
Gorelick PB: Neuroprotection in acute ischemic stroke: A tale of for whom the bell tolls? Lancet 2000;355:1925–1926.
114.
Goldstein LB, Brott TG, Kothari RU, Smith WS: Clinical stroke trials. Guarding against bias. Stroke 1999;30:1165–1166.
© 2001 S. Karger AG, Basel
2001
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