Acute stroke therapy: Combination drugs and multifunctional neuroprotectants

Current Neuropharmacology

Volumn 2, Issue 3, 2004, Pages 277-294

  Callaway, Jennifer K ^a  

^a UNIVERSITY OF MELBOURNE   (Australia)

Author keywords

Antioxidants; Combination therapy; Hybrid drugs; Neuroprotection; Pharmacotherapy; Stroke

Indexed keywords

ALTEPLASE; ANTICONVULSIVE AGENT; ANTIOXIDANT; CALCIUM CHANNEL BLOCKING AGENT; CASPASE 3 INHIBITOR; CD18 ANTIGEN; DISUFENTON SODIUM; DIZOCILPINE; EBSELEN; FIBRINOLYTIC AGENT; GLUTATHIONE PEROXIDASE; INTERCELLULAR ADHESION MOLECULE 1 ANTIBODY; LACTACYSTIN BETA LACTONE; LAMOTRIGINE; LUBELUZOLE; MEXILETINE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; NEUROPROTECTIVE AGENT; NIMODIPINE; NORPHENAZONE; PHENYTOIN; PLACEBO; REACTIVE OXYGEN METABOLITE; ROVELIZUMAB; SIPATRIGINE; SODIUM CHANNEL BLOCKING AGENT; TACROLIMUS; TENECTEPLASE; TIRILAZAD; UNINDEXED DRUG;

BLEEDING; BRAIN INFARCTION; BRAIN ISCHEMIA; CEREBROVASCULAR ACCIDENT; CLINICAL TRIAL; DEATH; DIFFUSION WEIGHTED IMAGING; DISEASE COURSE; DISEASE SEVERITY; DRUG DESIGN; DRUG HALF LIFE; DRUG MECHANISM; DRUG RESEARCH; GERBIL; HUMAN; HYPOTENSION; INDUCED HYPOTHERMIA; INDUSTRIALIZATION; MENTAL DISEASE; MOUSE; NERVE CELL LESION; NEUROLOGIC DISEASE; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; PATHOPHYSIOLOGY; PHYSICAL DISABILITY; POSITRON EMISSION TOMOGRAPHY; RABBIT; RAT; REVIEW;

EID: 3242657223     PISSN: 1570159X     EISSN: None     Source Type: Journal    
DOI: 10.2174/1570159043359602     Document Type: Review

References (260)

1. Allan, S. M., and Rothwell, N. J. (2003) Inflammation in central nervous system injury. Philosophical Transactions of the Royal Society of London - Series B. Biological Sciences 358, 1669-1677.
2. Alps, B. J., Calder, C., Wilson, A. D., McBean, D. E., and Armstrong, J. M. (1995) Reduction by lifarizine of the neuronal damage induced by cerebral ischaemia in rodents. Brit. J. Pharmacol. 115, 1439-1446.
3. Andersen, M., Overgaard, K., Meden, P., and Boysen, G. (1999) Effects of citicoline combined With thrombolytic therapy in a rat embolic stroke model. Stroke 30, 1464-1471.
4. Ang, Y. H., Chan, D. K., Heng, D. M., and Shen, Q. (2003) Patient outcomes and length of stay in a stroke unit offering both acute and rehabilitation services. Med. J. Aust. 178, 333-336.
5. 2+ channel blocker with antioxidant activity. J. Med. Chem. 43, 3372-3376.
6. 2+ channel dual blockers with highly potent anti-ischemic effects. Bio. Med. Chem. Lett. 9, 2999-3002.
7. Arboix, A., Garcia-Eroles, L., Massons, J., Oliveres, M., and Comes, E. (1997) Predictive factors of early seizures after acute cerebrovascular disease. Stroke 28, 1590-1594.
8. Archer S. (1993) Measurement of nitric oxide in biological models. FASEB J. 7, 349-360.
9. Aronowski, J., Strong, R., Shirzadi, A., and Grotta, J. C. (2003) Ethanol plus caffeine (caffeinol) for treatment of ischemic stroke: preclinical experience. Stroke 34, 1246-1251.
10. Ataus, S. A., Onal, M. Z., Ozdem, S. S., Locke, K. W., and Balkan, S. (2004) The effects of citicoline and lamotrigine alone and in combination following permanent middle cerebral artery occlusion in rats. Int. J. Neurosci. 114, 183-196.
11. Auvin, S., Augent, M., Navet, E., Harnett, J. J., Voiossat, I., Schulz, J., Bigg, D., and Chabrier, P. E. (2003) Novel inhibitiors of neuronal nitric oxide synthase with potent antioxidant properties. Bio. Med. Chem. Lett. 13, 209-212.
12. Bacon, P. J., Love, S. A., Gupta, A. K., Kirkpatrick, P. J., and Menon, D. K. (1996) Plasma antioxidant consumption associated with ischemia/reperfusion during carotid endarterectomy. Stroke 27, 1808-1811.
13. Baird, A. E., Austin, M. C., McKay, W. J., and Dorman, G. A. (1997) Sensitivity and specificity of 99mTc-HMPAO SPECT cerebral perfusion measurements during the first 48 hours for the localization of cerebral infarction. Stroke 28, 976-980.
14. Barber, P., Zhang, J., Demchuk, A., Hill, M.D., and Buchan, A.M. (2001) Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurol. 56, 1015-1020.
15. Barinaga, M. (1998) Stroke-damaged neurons may commit cellular suicide. Science 281, 1302-1303.
16. Barone, F. C., and Feuerstein, G. Z. (1999) Inflammatory mediators and stroke: new opportunities for novel therapeutics. J. Cereb. Blood Flow Metab. 9, 819-834.
17. Becker, K. J. (2002) Anti-leukocyte antibodies: LeukArrest (Hu23F2G) and Enlimomab (R6.5) in acute Stroke Curr. Med. Res. Opin. 18, s18-22.
18. Becker, K. J., Kindrick, D., Relton, J., Harlan, J., and Winn, R. (2001) Antibody to the alpha-4 intregrin decreases infarct size in transient focal cerebral ischemia in rats. Stroke 32, 206-211.
19. Benoit, E., and Escande, D. (1991) Riluzole specifically blocks inactivated Na+ channels in myelinated nerve fibers. Pflugers Arch. 419, 603-609.
20. Benveniste, H., Drejer, J., Schousboe, A., and Diemer, N. H. (1984) Elevation of extracellular concentrations of glutamate and aspartate in rat hipppocampus during transient cerebral ischemia. J. Neurochem. 43, 1369-1374.
21. Berger, C., Schabitz, W. R., Wolf, M., Mueller, H., Sommer, C., and Schwab, S. (2004) Hypothermia and brain-derived neurotrophic factor reduce glutamate synergistically in acute stroke. Exp. Neurol. 185, 305-312.
22. Bogaert, Y. E., Rosenthal, R. E., and Fiskum, G. (1994) Postischemic inhibition of cerebral cortex pyruvate dehydrogenase. Free Rad. Biol Med. 6, 811-820.
23. Bogousslavsky, J., Victor, S. J., Salinas, E. O., Pallay, A., Donnan, G. A., Fieschi, C., Kaste, M., Orgogozo, J. M., Chamorro, A., and Desmet, A. (2002) European-Australian Fiblast (Trafermin) in Acute Stroke Group. Fiblast (trafermin) in acute stroke: results of the European-Australian phase II/III safety and efficacy trial. Cerebrovasc. Dis. 14, 239-251.
24. Boutin, H., LeFeuvre, R. A., Horai, R., Asano, M., Iwakura, Y., and Rothwell, N. J. (2001) Role of IL-1alpha and IL-1beta in ischemic brain damage. J. Neurosci. 21, 5528-5534.
25. Bowes, M. P., Rothlein, R., Fagan, S. C., and Zivin, J. A. (1995) Monoclonal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy. Neurol. 45, 815-819.
26. Branston, N. M., Strong, A. J., and Symon, L. (1977) Extracellular potassium activity, evoked potential and tissue blood flow. Relationships during progressive ischaemia in baboon cerebral cortex. J. Neurol. Sci. 32, 305-321.
27. Bril, A., Slivjak, M., DiMartino, M. J., Feuerstein, G. Z., Linec, P., Poyser, R. H., Ruffolo, R. R. Jr., and Smith, E. F., 3rd (1992) Cardioprotective effects of carvedilol, a novel beta adrenoceptor antagonist with vasodilating properties, in anaesthetised minipigs: comparison with propranolol. Cardiovasc. Res. 26, 518-525.
28. Broadley, S. A., and Thompson, P. D. (2003) Time to hospital admission for acute stroke: an observational study. Med. J. Aust. 178, 329-331.
29. Busch, E., Gyngell, M. L., Eis, M., Hoehn, Berlage, M., and Hossmann, K. A. (1996) Potassium-induced cortical spreading depressions during focal cerebral ischemia in rats: contribution to lesion growth assessed by diffusion-weighted NMR and biochemical imaging. J. Cereb. Blood Flow Metab. 16, 1090-1099.
30. Callaway, J. K. (2001) Investigation of AM-36: A novel neuroprotective agent. Clin. Exp. Pharmac. Physiol. 28, 913-918.
31. Callaway, J. K., Beart, P. M., Jarrott, B., and Giardina, S. F. (2001) Incorporation of sodium channel blocking and free radical scavenging activities into a single drug, AM-36, results in profound inhibition of neuronal apoptosis. Brit. J. Pharmacol. 132, 1691-1698.
32. Callaway, J. K., Knight, M. J., Watkins, D. J., Beart, P. M., and Jarrott, B. (1999) Delayed treatment with AM-36, a novel neuroprotective agent, reduces neuronal damage after endothelin-1-induced middle cerebral artery occlusion in conscious rats. Stroke 30, 2704-2712.
33. Callaway, J. K., Lawrence, A. J., and Jarrott, B. (2003) AM-36, a novel neuroprotective agent, profoundly reduces reactive oxygen species formation and dopamine release in the striatum of consious rats after endothelin-1-induced middle cerebral artery occlusion. Neuropharm. 44, 787-800.
34. Capani, F., Loidl, C. F., Piehl, L. L., Facorro, G., De Paoli, T., and Hager, A. (2003) Long term production of reactive oxygen species during perinatal asphyxia in the rat central nervous system: effects of hypothermia. Int. J. Neurosci. 113, 641-654.
35. Carter, A. J. (1998) The importance of voltage-dependent sodium channels in cerebral ischaemia. Amino Acids 14, 159-169.
36. Chabrier, P. E., Auguet, M., Spinnewyn, B., Auvin, S., Cornet, S., Demerle-Pallardy, C., Guilmard-Favre, C., Marin, J. G., Pignol, B., Gillard-Roubert, V., Roussillot-Charnet, C., Schulz, J., Viossat, I., Bigg, D., and Moncada, S. (1999) BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: a promising neuroprotective strategy. Proc. Natl. Acad. Sci. USA 96, 10824-10829.
37. Chabrier, P. E., Demerle-Pallardy, C., and Auguet, M. (1999) Nitric oxide synthases: targets for therapeutic strategies in neurological diseases. Cell. Molec. Life Sci. 55, 1029-1035.
38. Chalmers, J. and MacMahon, S. (2003) Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS): interpretation and implementation. J. Hyperten. 21, S9-S14.
39. Chan, P. H. (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J. Cereb. Blood Flow Metab. 21, 2-14.
40. Chang, D.-I., Hosomi, N., Lucero, J., Heo, J.-H., Abumiya, T., Mazar, A. P., and del Zoppo, G. J. (2003) Activation systems for latent matrix metalloproteinase-2 are upregulated immediately after focal cerebral ischemia. J. Cereb. Blood Flow Metab. 23, 1408-1419.
41. Charriaut-Marlangue, C., Margaill, I., Represa, A., Popovici, T., Plotkine, M., and Ben-Ari, Y. (1996) Apoptosis and necrosis after reversible focal ischemia: An in situ DNA fragmentation analysis. J. Cereb. Blood Flow Metab. 16, 186-194.
42. Cheng, Y., Deshmukh, M., D'Costa, A., and al. e. (1998) Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury. J. Clin. Invest. 101, 1992-1999.
43. Chopp, M., Zhang, R. L., Chen, H., and al e. (1994) Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats. Stroke 25, 869-875.
44. Clark, W. M., Albers, G. W., Hamilton, S. A., and For the STARS Study Investigators G., Inc, San Francisco. (2000) Post-approval experience of intracerebral hemorrhage following intravenous t-PA therapy for acute ischemic stroke: CT risk factors. Stroke 31, 275-346.
45. Clemens, J.-A., Saunders, R. D., Ho, P. P., Phebus, L. A., and Panetta, J. A. (1993) The antioxidant LY231617 reduces global ischemic neuronal injury in rats. Stroke 24, 716-723.
46. Collins, R., and MacMahon, S. (1994) Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Brit. Med. Bull. 50, 272-298.
47. Coombes, J. S., Powers, S. K., Demirel, H. A., Jessup, J., Vincent, H. K., Hamilton, K. L., Naito, H., Shanely, R. A., Sen, C. K., Packer, L., and Ji, L. L. (2000) Effect of combined supplementation with vitamin E and alpha-lipoic acid on myocardial performance during in vivo ischaemia-reperfusion. Acta Physiol. Scand. 169, 261-269.
48. Danton, G. H., and Dietrich, W. D. (2003) Inflammatory mechanisms after ischemia and Stroke. J. Neuropatho. Exp. Neurol. 62, 127-136.
49. Davalos, A., Castillo, J., Serena, J., and Noya, M. (1997) Duration of glutamate release after acute ischemic stroke. Stroke 28, 708-710.
50. Davis, S., Helfaer, M. A., Traystmann, R. J., and Hurn, P. D. (1997) Parallel antioxidant and antiexcitotoxic therapy improves outcome after incomplete global cerebral ischemia in dogs. Stroke 28, 198-205.
51. D'Cruz, B. J., Fertig, K. C., Filiano, A. J., Hicks, S. D., DeFranco, D. B., and Callaway, C. W. (2002) Hypothermic reperfusion after cardiac arrest augments brain-derived neurotrophic factor activation. J. Cereb. Blood Flow Metab. 22, 843-851.
52. De Keyser, J., Sulter, G., and Luiten, P. G. (1999) Clinical trials with neuroprotective drugs in acute ischemic stroke: are we doing the right thing? TINS 22, 535-540.
53. De Ryck, M., Keersmaekers, R., Duytschaever, H., Claes, C., Clincke, G., Janssen, M., and Van Reet, G. (1996) Lubeluzole protects sensory motor function and reduces infarct size in a photochemical stroke model in rats. J. Pharm. Exp. Ther. 279, 748-758.
54. De Ryck, M., Van Reempts, J., Borgers, M., Wauquier, A., and Janssen, P. A. J. (1989) Photochemical stroke model: funarizine prevents sensorimotor deficits after neocortical infarcts in rats. Stroke 20, 1383-1390.
55. DeGraba, T. J., and Pettigrew, L. C. (2000) Why do neuroprotective drugs work in animals but not humans? Neurol. Clin. 18, 475-493.
56. del Zoppo, G. J., Schmid-Schonbein, G. W., Mori, E., Copeland, B. R., and Chang, C. M. (1991) Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22, 1276-1283.
57. Dewar, D., Yam, P., and McCulloch, J. (1999) Drug development for stroke: importance of protecting cerebral white matter. Eur. J. Pharmac. 375, 41-50.
58. Diener, H. C. (1999) Lubeluzole in acute stroke: lack of efficacy in a large phase III study with an 8 hour window. [abstract]. Stroke 30, 234.
59. Diener H. C., Cortens M., Ford G., Grotta J., Hacke, W., Kaste, M., Koudstaal, P. J., and Wessel, T. (2000) Lubeluzole in acute ischemic stroke treatment: A double-blind study with an 8-hour inclusion window comparing a 10-mg daily dose of lubeluzole with placebo. Stroke 31, 2543-2541.
60. Ding-Zhou, L., Marchand-Verrecchia, C., Croci N., Plotkine M., and Margaill I. (2002) L-NAME reduces infarction, neurological deficit and blood brain barrier disruption following cerebral ischemia in mice. Eur. J. Pharmac. 457, 137-146.
61. Dirnagl, U., Iadecola, C., and Moskowitz, M. A. (1999) Pathobiology of ischaemic stroke: an integrated view. TINS 22, 391-397.
62. Donnan, G. A., Howells, D. W., Markus,R., Toni, D., and Davis, S. M. (2003) Can the time window for administration of thrombolytics in stroke be increased? CNS Drugs 17, 995-1011.
63. Doughty, R. N., MacMahon, S., and Sharpe, N. (1994) Beta-blockers in heart failure: promising or proved? J. Am. Col. Cardio. 23, 814-821.
64. Du C., Hu R., Csernansky C. A., Hsu C. Y., and Choi D. W. (1996) Very delayed infarction after mild focal cerebral ischemia: role for apoptosis? J. Cereb. Blood Flow Metab. 16, 195-201.
65. Eastern, Stroke, and, Coronary, Heart, Disease, Collaborative, Research, and Group. (1998) Blood pressure, cholesterol, and stroke in Eastern Asia. Lancet 352, 1801-1807.
66. Eberspacher, E., Werner, C., Engelhard, K., Pape, M., Gelb, A., Hutzler, P., Henke, J., and Kochs, E. (2003) The effect of hypothermia on the expression of the apoptosis-regulating protein Bax after incomplete cerebral ischemia and reperfusion in rats. J. Neurosurg. Anesth. 15, 200-208.
67. Eichhorn, E. J. (1998) Restoring function in failing hearts: the effects of beta blockers. Am. J. Med. 104, 163-169.
68. Ferrer, I., and Planas, A. M. (2003) Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. J. Neuropath. Exp. Neurol. 62, 329-339.
69. Feuerstein, G. Z., Hamburger, S. A., Smith, E. F., 3rd, Bril, A., and Ruffolo, R. R. Jr. (1992) Myocardial protection with carvedilol. J. Cardiovasc. Pharmac. 19, S138-141.
70. Fisher, M. (2003) Recommendations for advancing development of acute stroke therapies stroke therapy academic industry roundtable III. Stroke 34, 1539-1546.
71. Forster, C., Clark, H. B., Ross, M. E., and Iadecola, C. (1999) Inducible nitric oxide synthase expression in human cerebral infarcts. Acta Neuropath. (Berl.) 97, 215-220.
72. Friedlander, R. M. (2003) Apoptosis and caspases in neurodegenerative diseases. New Eng. J. Med. 348, 1365-1375.
73. Furuya, K., Takeda, H., Azhar, S., McCarron, R. M., Chen, Y., Ruetzler, C. A., Wolcott, K. M., DeGraba, T. J., Rothlein, R., Hugli, T. E., del Zoppo, G. J., and Hallenbeck, J. M. (2001) Examination of several potential mechanisms for the negative outcome in a clinical stroke trial of enlimomab, a murine anti-human intercellular adhesion molecule-1 antibody: a bedside-to-bench study. Stroke 32, 2665-2674.
74. Garcia-Estrada, J., Gonzalez-Perez, O., Gonzalez-Casteneda, R. E., Martinez-Contreras, A., Luquin, S., Garzon de la Mora, P., and Navarro-Ruiz, A. (2003) An alpha-lipoic acid-vitamin E mixture reduces post-embolism lipid peroxidation, cerebral infarction, and neurological deficit in rats. Neurosci. Res. 47, 219-224.
75. Gladstone, D. J., Black, S. E., and Hakim, A. M. (2002) Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33, 2123-2136.
76. Goldstein, S. (1997) Clinical studies on beta blockers and heart failure preceding the MERIT-HF Trial. Metoprolol CR/XL Randomized Intervention Trial in Heart Failure. Am. J. Cardiol. 80, 50J-53J.
77. Gonzalez-Perez, O., Gonzalez-Casteneda, R. E., Huerta, R. E., Luquin, S., Gomez-Pinedo, U., Sanchez-Almaraz, E., Navarro-Ruiz, A., and Garcia-Estrada, J. (2002) Beneficial effects of alpha-lipoic acid plus vitamin E on enurological deficit, reactive gliosis and neuronal remodelling in the penumbra of the ischemic rat brain. Neurosci. Lett. 321, 100-104.
78. Graham, S. H., Chen, J., Lan, J., Leach, M. J., and Simon, R. P. (1994) Neuroprotective effects of a use-dependent blocker of voltage-dependent sodium channels, BW619C89, in rat middle cerebral artery occlusion. J. Pharm. Exp. Ther. 269, 854-859.
79. Gresle, M. M., Jarrott, B., and Callaway, J. K. (2003) AM-36 reduces cerebral white matter damage in the endothelin-1 model of stroke in conscious rats. Proc. Aust. Neurosci. Soc. 14, 354.
80. Grotta, J. (2001) for the Combination Therapy Stroke Trial Investigators. Combination Therapy Stroke Trial: recombinant tissue-type plasminogen activator with/without lubeluzole. Cerebrovasc. Dis. 12, 258-263.
81. Hamann, G. F., Burggraf, D., Liebetrau, M., and al e. (2004) Hypothermia in combination with rt-PA completely protects the microvascular basal lamina from the effects of focal cerebral ischemia and reperfusion in the rat. Stroke 35, 249-249.
82. Hammer, M. D., and Krieger, D. W. (2002) Acute ischemic stroke: is there a role for hypothermia? Cleve. Clin. J. Med. 69, 773-777.
83. Haramaki, N., Packer, L., Assadnazari, H., and Zimmer, G. (1993) Cardiac recovery during post-ischemic reperfusion is improved by combination of vitamin E with dihydrolipoic acid. Biochem. Biophys. Res. Comm. 196, 1101-1107.
84. Hartings, J. A., Rolli, M. L., Lu, X. C., and Tortella, F. C. (2003) Delayed secondary phase of peri-infarct depolarizations after focal cerebral ischemia: relation to infarct growth and neuroprotection. J. Neurosci. 23, 11602-11610.
85. Heiss, W. D., Huber, M., Fink, G. R., Herholz, K., Pietrzyk, U., Wagner, R., and Wienhard, K. (1992) Progressive derangement of periinfarct viable tissue in ischemic stroke. J. Cereb. Blood Flow Metab. 12, 193-203.
86. Heiss, W.-D., Thiel, A., Grond, M., and Graf, R. (1999) Which targets are relevant for therapy of acute ischemic stroke? Stroke 30, 1486-1489.
87. Herr, I., Martin-Villalba, A., Kurz, E., Roncainoli, P., Schenkel, J., Cifone, M. G., and Debatin, K. M. (1999) FK506 prevents stroke-induced generation of ceramide and apoptosis signaling. Brain Res. 826, 210-219.
88. Hewitt, K., and Corbett, D. (1992) Combined treatment with MK-801 and nicardipine reduces global ischemic damage in the gerbil. Stroke 23, 82-86.
89. Hicks, C. A., Ward, M. A., Swettenham, J. B., and O'Neill, M. J. (1999) Synergistic effects by combining an NMDA or AMPA receptor antagonist with nitric oxide synthase inhibitors in global cerebral ischemia. Eur. J. Pharmac. 381, 113-119.
90. Hopkins, S. J. (2003) The pathophysiological role of cytokines. Legal Med. 5, S45-57.
91. Hopkins S. J. and Rothwell N. J. (1995) Cytokines and the nervous system, I: expression and recognition. TINS 18, 83-88.
92. Horn, J., de Haan, R. J., Vermeulen, M., and Limburg, M. (2001) Very Early Nimodipine Use in Stroke (VENUS): a randomized, double-blind, placebo-controlled trial. Stroke 32, 461-465.
93. Horn, J., and Limburg, M. (2000) Calcium antagonists for acute ischemic stroke. Cochrane Database Syst. Rev. CD001928.
94. Hossmann, K. A. (1996) Periinfarct depolarizations. Cerebrovasc. Brain Metab. Rev. 8, 195-208.
95. http://www.dpharm.com.
96. http://www.nobexcorp.com.
97. http://www.strokecenter.org/trials/.
98. Iadecola, C. and Alexander, M. (2001) Cerebral ischemia and inflammation. Curr. Opin. Neurol. 14, 89-94.
99. Iadecola, C., Niwa, K., Nogawa, S., Zhao, X., Nagayama, M., Araki, E., Morham, S., and Ross, M. E. (2001) Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc. Natl. Acad. Sci. USA 98, 1294-1299.
100. Iadecola, C., Zhang, F., Casey, R., Nagayama, M., and Ross, M. E. (1997) Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. Neurosci. 17, 9157-9164.
101. Iijima, T., Mies, G., and Hossmann, K. A. (1992) Repeated negative DC deflections in rat cortex following middle cerebral artery occlusion are abolished by MK-801: effect on volume of ischemic injury. J. Cereb. Blood Flow Metab. 12, 727-733.
102. Ikeda, T., Xia, Y. X., Kaneko, M., Sameshima, H., and Ikenoue, T. (2002) Effect of the free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one(MCI-186), on hypoxia-ischemia-induced brain injury in neonatal rats. Neurosci. Lett. 329, 33-36.
103. Indredavik, B., Fjærtoft, H., Ekeberg, G., Loge, A. D., and Morch, B. (2000) Benefit of an extended stroke unit service with early supported discharge. A randomized, controlled trial. Stroke 31, 2989-2994.
104. Jarrott, B., Callaway, J., Jackson, W., and Beart, P. (1999) Development of a novel arylalkylpiperazine compound (AM-36) as a hybrid neuroprotective drug. Drug Dev. Res. 46, 261-267.
105. Jiang, N., Chopp, M., and Chahwala, S. (1998) Neutrophil inhibitory factor treatment of focal cerebral ischemia in the rat. Brain Res. 788, 25-34.
106. Jin, Y. J., Mima, T., Raicu, V., Park, K. C., and Shimizu, K. (2002) Combined argatroban and edaravone caused additive neuroprotection against 15 minutes of forebrain ischemia in gerbils. Neurosci. Res. 43, 75-79.
107. Joffres, M. R., Hamet, P., MacLean, D. R., L'Italien, G J., and Fodor, G. (2001) Distribution of blood pressure and hypertension in Canada and the United States. Am. J. Hyperten. 14, 1099-1105.
108. Karabiyikoglu, M., Han, H. S., Yenari, M. A., and Steinberg, G. K. (2003) Attenuation of nitric oxide synthase isoform expression by mild hypothermia after focal cerebral ischemia: variations depending on timing of cooling. J. Neurosurg. 98, 1271-1276.
109. Kawai, H., Nakai, H., Suga, M., Yuki, S., Watanabe, T., and Saito, K. (1997) Effect of a novel free radical scavenger, MCI-186, on ischemic brain damage in the rat distal middle cerebral artery occlusion model. J. Pharm. Exp. Ther. 281, 921-927.
110. Kermer, P., Klocker, N., and Bahr, M. (1999) Neuronal death after brain injury. Models, mechanisms, and therapeutic strategies in vivo. Cell Tiss. Res. 298, 383-395.
111. Kinouchi, H., Epstein, C. J., Mizui, T., Carlson, E. J., Chen, S. F., and Chan, P. H. (1991) Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. Proc. Natl. Acad. Sci. USA 88, 11158-11162.
112. Klein, L., O'Connor, C. M., Gattis, W. A., Zampino, M., de Luca, L., Vitarelli, A., Fedele, F., and Gheorghiade, M. (2003) Pharmacologic therapy for patients with chronic heart failure and reduced systolic function: review of trials and practical considerations. Am. J. Cardiol. 91 Suppl., 18F-40F.
113. Krupinski, J., Kaluza, J., Kumar, P., Kumar, S., and Wang, J.M. (1993) Some remarks on the growth-rate and angiogenesis of microvessels in ischemic Stroke Morphometric and immunocytochemical studies. Patol. Pol. 44, 203-209.
114. Kuroda, S. and Siesjo, B. K. (1997) Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows. Clin. Neurosci. 4, 199-212.
115. Lacourciere, Y., Gil-Extremera, B., Mueller, O., Byrne, M., and Williams, L. (2003) Efficacy and tolerability of fixed-dose combinations of telmisartan plus HCTZ compared with losartan plus HCTZ in patients with essential hypertension. Int. J. Clin. Prac. 57, 273-279.
116. Langhorne, P., Williams, B. O., Gilchrist, W., and Howie, K. (1993) Do stroke units save lives? Lancet 342, 395-398.
117. Lapchak, P. A., Araujo, D. M., Song, D., Wei, J., and Zivin J. A. (2002) Neuroprotective effects of the spin trap agent disodium-(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke 33, 1411-1415.
118. Lazzarino, G., Raatikainen, P., Nuutinen, M., Nissinen, J., Tavazzi, B., Di Pierro, D., Giardina, B., and Peuhkurinen, K. (1994) Myocardial release of malondialdehyde and purine compounds during coronary bypass surgery. Circ. 90, 291-297.
119. Leach, M. J., Swan, J. H., Eisenthal, D., Dopson, M., and Nobbs, M. (1993) BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage. Stroke 24, 1063-1067.
120. Lee, D. H., Jo, K. D., Kim, H. G., Choi, S. J., Jung, S. M., Ryu, D. S., and Park, M. S. (2002) Local intraarterial urokinase thrombolysis of acute ischemic stroke with or without intravenous abciximab: a pilot study. J. Vasc. Interven. Rad. 13, 769-774.
121. Lees, K. R., Barer, D., Ford, G. A., Hacke, W., Kostulas, V., Sharma, A. K., Odergren, T., and Investigators, S.-N. (2003) Tolerability of NXY-059 at higher target concentrations in patients with acute stroke. Stroke 34, 482-487.
122. Levy, M. L., Rabb, C., Couldwell, W. T., Zelman, V., and Apuzzo, M. L. J. (1993) Protection of the neuronal pool. In: Brain Surgery: Complication Avoidance and Management (ed. M. L. J. Appuzzo), pp. 857-889. Churchill Livingstone. New York.
123. Li, Y.-J., Zhang, L. M., Gu, J., Zhang, A. Z., and Sun, F. Y. (1997) Melatonin decreases production of hydroxyl radical during cerebral ischemia-reperfusion. Zhongguo Yao Li Xue Bao 18, 394-396.
124. Lindsberg, P. J., Carpen, O., Paetau, A., Karjalainen-Lindsberg, M.L., and Kaste, M. (1996) Endothelial ICAM-1 expression associated with inflammatory cell responses in human ischemic stroke. Stroke 94, 939-945.
125. Lipton, P. (1999) Ischemic cell death in brain neurons. Physiol. Rev. 79, 1431-1568.
126. Lyden, P., Jacoby, M., Schim, J., Albers, G., Mazzeo, R., Ashwood, T., Nordlund, A., and Odergren, T. (2001) The Clomethiazole Acute Stroke Study in tissue-type plasminogen activator-treated stroke (CLASS-T): final results. Neurol. 57, 1199-1205.
127. Lyden, P. D., Jackson-Friedman, C., Shin, C., and Hassid, S. (2000) Synergistic combinatorial stroke therapy: a quantal bioassay of a GABA agonist and a glutamate antagonist. Exp. Neurol. 163, 477-489.
128. Lyden, P. D. and Lonzo, L. (1994) Combination therapy protects ischemic brain in rats. A glutamate antagonist plus a gamma-aminobutyric acid agonist. Stroke 25, 189-196.
129. Lyden, P. D., Zivin, J. A., Kochhar, A., and Mazzarella, V. (1988) Effects of calcium channel blockers on neurologic outcome after focal ischemia in rabbits. Stroke 19, 1020-1026.
130. Lysko, P. G., Lysko, K. A., Webb, C. L., and Feuerstein, G. (1992) Neuroprotective effects of carvedilol, a new antihyper-tensive, at the N-methyl-D-aspartate receptor. Neurosci. Lett. 148, 34-38.
131. Lysko, P. G., Lysko, K. A., Yue, T. L., Webb, C. L., Gu, J. L., and Feuerstein, G. (1992) Neuroprotective effects of carvedilol, a new antihypertensive agent, in cultured rat cerebellar neurons and in gerbil global brain ischemia. Stroke 23, 1630-1635.
132. Lysko, P. G., Webb, C. L., and Feuerstein, G. (1994) Neuroprotective effects of carvedilol, a new antihypertensive, as a Na+ channel modulator and glutamate transport inhibitor. Neurosci. Lett. 171, 77-80.
133. Ma, J., Endres, M., and Moskowitz, M. A. (1998) Synergistic effects of caspase inhibitors and MK-801 in brain injury after transient focal cerebral ischaemia in mice. Brit. J. Pharmacol. 124, 756-762.
134. Ma, J., Qui, J., Hirt, L., Dalkara, T., and Moskowitz, M. A. (2001) Synergistic protective effect of caspase inhibitors and bFGF against brain injury induced by transient focal ischemia. Brit. J. Pharmacol. 133, 345-350.
135. Maeda, M., Furuichi, Y., Ueyama, N., Moriguichi, A., Satoh, N., Matsuoka, N., Goto, T., and Yanagihara, T. (2002) A combined treatment with tarcolimus (FK506) and recombinant tissue plasminogen activator for thrombotic focal cerebral ischemia in rats: increased neuroprotective efficacy and extended therapeutic time window. J. Cereb. Blood Flow Metab. 22, 1205-1211.
136. Malgouris, C., Daniel, M., and Doble, A. (1994) Neuroprotective effects of riluzole on N-methyl-D-aspartate- or veratridine-induced neurotoxicity in rat hippocampal slices. Eur. J. Pharmacol. 177, 95-99.
137. Mansour, T. S. (1996) Emerging anti-HIV agents and targets. Exp. Opin. Ther. Pat. 6, 137-159.
138. Marchal, G., Furlan, M., Beaudouin, V., Rioux, P., Hauttement, J. L., Serrati, C., de la Sayette, V., Le Doze, F., Viader, F., Derlon, J. M., and Baron, J. C. (1996) Early spontaneous hyperperfusion after Stroke A marker of favourable tissue outcome? Brain 119, 409-419.
139. Marshall, J. W., Duffin, K. J., Green, A. R., and Ridley, R. M. (2001) NXY-059, a free radical-trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species. Stroke 32, 190-198.
140. Martin-Villalba, A., Hahne, M., Kleber, S., Vogel, J., Falk, W., Schenkel, J., and Krammer, P. H. (2001) Therapeutic neutralisation of CD95-ligand and TNF attenuates brain damage in stroke. Cell Death Diff 8, 679-686.
141. Martin-Villalba, A., Herr, I., Jeramias, I., Hahne, M., Brandt, R., Vogel, J., Schenkel, J., Herdegen, T., and Debatin, K. M. (1999) CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J. Neurosci. 19, 3809-3817.
142. Matsuo, Y., Kihara, T., Ikeda, M., Nonomiya, M., Onodera, H., and Kogure, K. (1995) Role of neurotrophils in radical production during ischemia and reperfusion of the rat brain: effect of neutrophil depletion on extracellular ascorbyl radical formation. J. Cereb. Blood Flow Metab. 15, 941-947.
143. Matsuo, Y., Onodera, H., Shiga, Y., Shozuhara, H., Ninomiya, M., Kihara, T., Tamatani, T., and Miyasaka, M. (1994) Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion. Brain Res. 656, 344-349.
144. Mattson, M. P., Culmsee, C., and Yu, Z. F. (2000) Apoptotic and antiapoptotic mechanisms in stroke. Cell Tis. Res. 301, 173-187.
145. McCulloch, J., Ozyurt, E., Kun Park, C., Nehls, D. G., Teasdale, G. M., and Graham, D. I. (1993) Glutamate receptor antagonists in experimental focal cerebral ischemia. Acta Neurochir. Suppl. 57, 73-79.
146. 2+ channels by the neuroprotective agent BW619C89 (Sipatrigine). Neuropharmacol. 39, 1247-1253.
147. Meden, P., Overgaard, K., Pedersen, H., and Boysen, G. (1996) Effect of early treatment with tirilazad (U74006F) combined with delayed thrombolytic therapy in rat embolic stroke. Cerebrovasc. Dis. 6, 141-148.
148. Meissner, I., Whisnant, J. P., Khandheria, B. K., Spittell, P. C., O'Fallon, W. M., Pascoe, R. D., Enriquez-Sarano, M., Seward, J. B., Covalt, J. L., Sicks, J. D., and Wiebers, D. O. (1999) Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a Community. Mayo Clin. Proc. 74, 862-869.
149. Meschia, J. F., Miller, D. A., and Brott, T. G. (2002) Thrombolytic treatment of acute ischemic stroke. Mayo Clin. Proc. 77, 542-551.
150. Minami, M. and Satoh, M. (2003) Chemokines and their receptors in the brain: pathophysiological roles in ischemic brain injury. Life Sci. 74, 321-327.
151. Miyazawa, T., Tamura, A., Fukui, S., and Hossmann, K. A. (2003) Effect of mild hypothermia on focal cerebral ischemia. Review of experimental studies. Neurol. Res. 25, 457-464.
152. Mohr, J. P., Orgogozo, J. M., Harrison, M. J. G., Hennerici, M., Wahlgren, N. G., Gelmers, J. H., Martinez-Vila, E., Dycka, J., and Tettenborn, D. (1994) Meta-analysis of oral nimodipine trials in acute ischemic stroke. Cereb. Dis. 4, 197-203.
153. Montaner, J., Rovira, A., Molina, C. A., Arenillas, J. F., Ribó, M., Pilar Chacón, P., Monasterio, J., and Alvarez-Sabín, J. (2003) Plasmatic level of neuroinflammatory markers predict the extent of diffusion-weighted image lesions in hyperacute stroke. J. Cereb. Blood Flow Metab. 23, 1403-1407.
154. Mori, E., del Zoppo, G. J., Chambers, J. D., Copeland, B. R., and Arfors, K. E. (1992) Inhibition of polymorphonuclear leukocyte adherence supresses no-reflow after focal cerebral ischemia in baboons. Stroke 23, 712-718.
155. Morimoto, T., Globus, M. Y.-T., Busto, R., Martinez, E., and Ginsberg, M. D. (1996) Simultaneous measurement of salicylate hydroxylation and glutamate release in the penumbral cortex following transient middle cerebral artery occlusion. J. Cereb. Blood Flow Metab. 16, 92-99.
156. Muir, K. W., Holzapfel, L., and Lees, K. R. (2000) Phase II clinical trial of sipatrigine (619C89) by continuous infusion in acute stroke. Cerebrovasc. Dis. 10, 431-436.
157. Muir, K. W. and Lees, K. R. (1995) Clinical experience with excitatory amino acid antagonist drugs. Stroke 26, 503-513.
158. Nicotera, P. (2002) Apoptosis and age-related disorders: role of caspase-dependent and caspase-independent pathways. Toxicol. Lett. 127, 189-195.
159. Nicotera, P., Leist, M., Fava, E., Berliocchi, L., and Volbracht, C. (2000) Energy requirement for caspase activation and neuronal cell death. Brain Path. 10, 276-282.
160. NINDS (1995) National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for ischemic stroke. New Engl. J. Med. 333, 1581-1587.
161. Nito, C., Kamiya, T., Amemiya, S., Katoh, K., and Katayama, Y. (2003) The neuroprotective effect of a free radical scavenger and mild hypothermia following transient focal ischemia in rats. Acta Neurochir. Suppl. 86, 199-203.
162. Nurmi, A., Lindsberg, P. J., Koistinaho, M., Zhang, W., Juettler, E., Karjalainen-Lindsberg, M.-L., Weih, F., Frank, N., Schwaninger, M., and Koistinaho, J. (2004) Nuclear factor- kb contributes to infarction after permanent focal ischemia. Stroke 35, 987-991.
163. Ohkawa, S., Fukatsu, K., Miki, S., Hashimoto, T., Sakamoto, J., Doi, T., Nagai, Y., and Aono, T. (1997) 5-Aminocoumarans: dual inhibitors of lipid peroxidation and dopamine release with protective effects against central nervous system trauma and ischemia. J. Med. Chem. 40, 559-573.
164. Okada, Y., Copeland, B. R., Mori, E., and Tung, M. M. (1994) P-selectin and intracellular adhesion molecule-1 expression after focal brain ischemia and reperfusion. Stroke 25, 202-211.
165. Oktem, I. S., Menku, A., Akdemir, H., Kontas, O., Kurtsoy, A., and Koc, R. K. (2000) Therapeutic effect of tirilazad mesylate (U-74006F), mannitol, and their combination on experimental ischemia. Res. Exp. Med. 199, 231-242.
166. Onal, M. Z., Li, F., Tatlisumak, T., Locke, K. W., Sandage, B. W. Jr., and Fisher, M. (1997) Synergistic effects of citicoline and MK-801 in temporary experimental focal ischemia in rats. Stroke 28, 1060-1065.
167. Onteniente, B., Couriaud, C., Braudeau, J., Benchoua, A., and Guegan, C. (2003) The mechanisms of cell death in focal cerebral ischemia highlight neuroprotective perspectives by anti-caspase therapy. Biochem. Pharmacol. 66, 1643-1649.
168. Padosch, S. A., Popp, E., Vogel, P., and Bottiger, B. W. (2003) Altered protein expression levels of Fas? CD95 and Fas ligand in differentially vulnerable brain areas in rats after global cerebral ischemia. Neurosci. Lett. 338, 247-251.
169. Pahlmark, K. and Seisjo, B. K. (1996) Effects of spin trap-a-phenyl-N-tert-butylnitrone (PBN) in transient forebrain ischemia in the rat. Acta Physiol. Scand. 157, 41-51.
170. Pantoni, L. and Garcia, J. H. (1997) Pathogenesis of leukoaraiosis: a review. Stroke 28, 652-659.
171. Parsons, M. W., Yang, Q., Barber, P. A., Darby, D. G., Desmond, P. M., Gerraty, R. P., Tress, B. M., and Davis, S. M. (2001) Perfusion magnetic resonance imaging maps in hyperacute Stroke Relative cerebral blood flow most accurately identifies tissue destined to infarct. Stroke 32, 1581-1587.
172. Peeling, J., Del Bigio, M. R., Corbett, D., Green, A. R., and Jackson, D. M. (2001) Efficacy of disodium 4-[(tert-butylimino) methyl] benzene-1,3-disulfonate N-oxide (NXY-059), a free radical trap-ping agent, in a rat model of hemorrhagic stroke. Neuropharmacol. 40, 433-439.
173. Pendleberry, S. T., Blamire, A. M., Lee, M. A., Styles, P., and Matthews, P. M. (1999) Axonal injury in the internal capsule correlates with motor impairment after stroke. Stroke 30, 956-962.
174. Petty, M. A., and Wettstein, J. G. (1999) White matter ischemia. Brain Res. Rev. 31, 58-64.
175. Pinard, E., Nallet, H., MacKenzie, E. T., Seylaz, J., and Roussel, S. (2002) Penumbral microcirculatory changes associated with peri-infarct depolarizations in the rat. Stroke 33, 606-612.
176. Piriyawat, P., Labiche, L. A., Burgin, W. S., Aronowski, J. A., and Grotta, J. C. (2003) Pilot dose-escalation study of caffeine plus ethanol (caffeinol) in acute ischemic stroke. Stroke 34, 1242-1245.
177. Poole-Wilson, P. A., Swedberg, K., Cleland, J. G., Di Lenarda, A., Hanrath, P., Komajda, M., Lubsen, J., Lutiger, B., Metra, M., Remme, W. J., Torp-Pedersen, C., Scherhag, A., and Skene, A. (2003) Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 362, 7-13.
178. PROGRESS, Collaborative, and Group. (2001) Randomised trial of perindopril-based blood pressure lowering regimen among 6105 patients with previous stroke or transient ischemic attack. Lancet 358, 1033-1041.
179. Rajesh, K. G., Sasaguri, S., Suzuki, R., and Maeda, H. (2003) Antioxidant MCI-186 inhibits mitochondrial permeability transition pore and upregulates Bcl-2 expression. Am. J. Physiol. Heart Circ. Physiol. 285, H2171-2178.
180. Rami, A., Sims, J., Botez, G., and Winckler, J. (2003) Spatial resolution of phospholipid scramblase 1 (PLSCR1), caspase-3 activation and DNA-fragmentation in the human hippocampus after cerebral ischemia. Neurochem. Int. 43, 79-87.
181. Rataud, J., Debarnot, F., Mary, V., Pratt, J., and Stutzmann, J.-M. (1994) Comparative study of voltage-sensitive sodium channel blockers in focal ischemia and electric convulsions in rodents. Neurosci. Lett. 172, 19-23.
182. Rodgers, A., MacMahon, S., Gamble, G., Slattery, J., Sandercock, P., and Warlow, C. on behalf of the UKTIA Collaborative Group. (1996) Blood pressure and the risk of stroke in patients with cardiovascular disease. Brit. Med. J. 313, 147.
183. Rosenbaum, D. M., Gupta, G., D'Amore, J., Singh, M., Weidenheim, K., Zhang, H., and Kessler, J. A. (2000) Fas (CD95/APO-1) plays a role in the pathophysiology of focal cerebral ischemia. J. Neurosci. Res. 61. 686-692.
184. Rosenberg, G., Angel, I., and Kozak, A. (2004) Evaluation of safety and changes in the NIH stroke scale, Rankin, and Barthel scores following DP-b99 administration to acute stroke patients. Stroke 35, 338.
185. Ruffolo, R. R. Jr., Gellai, M., Hieble, J. P., Willette, R. N., and Nichols, A. J. (1990) The pharmacology of carvedilol. Eur. J. Clin. Pharm. 38, S82-88.
186. Sairanen, T., Carpen, O., Karjalainen-Lindsberg, M. L., Paetau, A., Turpeinen, U., Kaste, M., and Lindsberg, P. J. (2001) Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke. Stroke 32, 1750-1758.
187. Sarker, K. P., Biswas, K. K., Rosales, J. L., Yamaji, K., Hashiguchi, T., Lee, K. Y., and Maruyama, I. (2003) Ebselen inhibits NO-induced apoptosis of differentiated PC12 cells via inhibition of ASK1-p38 MAPK-p53 and JNK signaling and activation of p44/42 MAPK and Bcl-2. J. Neurochem. 87, 1345-1353.
188. Satoh, M., Kashihara, N., Fujimoto, S., Horike, H., Tokura, T., Namikoshi, T., Sasaki, T., and Makino, H. (2003) A novel free radical scavenger, edarabone, protects against cisplatin-induced acute renal damage in vitro and in vivo. J. Pharm. Exp. Ther. 305, 1183-1190.
189. Sauter, A., and Rudin, M. (1986) Calcium antagonists reduce the extent of infarction in rat middle cerebral artery occlusion model as determined by quantitative magnetic resonance imaging. Stroke 17, 1228-1234.
190. Saver, J. L., Kidwell, C. S., Leary, M. C., Ovbiagele, B., Tremwel, M. F., Eckstein, M., Ferguson, K. N., Gough, K. J., Llanes, J. N., and Eraklis, E. M. (2002) Results of the Field Administration of Stroke Treatment-Magnesium (FAST-MAG) pilot trial: a study of prehospital neuroprotective therapy. Stroke 33, 363-364.
191. Savitz, S. I., Erhardt, J. A., Anthony, J. V., Gupta, G., Li, X., Barone, F. C., and Rosenbaum, D. M. (2000) The novel betablocker, carvedilol, provides neuroprotection in transient focal stroke. J. Cereb. Blood Flow Metab. 20, 1197-1204.
192. Savitz, S. I. and Kessler, J. A. (2000) Leukemia inhibitory factor requires concurrent p75LNTR signaling to induce apoptosis of cultured sympathetic neurons. J. Neurosci. 20, 4198-4205.
193. Schabitz, W. R., Li, F., Irie, K., Sandage, B. W., Locke, K. W., and Fischer, M. (1999) Synergistic effects of a combination of low-dose basic fibroblast growth factor and citicoline after temporary experimental focal ischemia. Stroke 30, 427-432.
194. Schleuning, W. D. (2001) Vampire bat plasminogen activator DSPA-alpha-1 (desmoteplase): a thrombolytic drug optimized by natural selection. Haemostas. 31, 118-122.
195. Schmid-Elsaesser, R., Hungerhuber, E., Zausinger, S., Baethmann, A., and Reulen, H. J. (1999) Combination drug therapy and mild hypothermia: a promising treatment strategy for reversible, focal cerebral ischemia. Stroke 30, 1891-1899.
196. Schmid-Elsaesser, R., Hungerhuber, E., Zausinger, S., Baethmann, A., and Reulen, H. J. (2000) Neuroprotective effects of a novel brain-penetrating antioxidant U-101033E and the spin-trapping agent a-phenyl-N-tert-butyl nitrone (PBN). Exp. Brain Res. 130, 60-66.
197. Schmid-Elsaesser, R., Zausinger, S., Hungerhuber, E., Baethmann, A., and Reulen, H. J. (1998) Monotherapy with dextromethorphan or tirilazad-but not a combination of both-improves outcome after transient focal cerebral ischemia in rats. Exp. Brain Res. 122, 121-127.
198. Schmid-Elsaesser, R., Zausinger, S., Hungerhuber, E., Baethmann, A., and Reulen, H. J. (1999) Neuroprotective effects of combination therapy with tirilazad and magnesium in rats subjected to reversible focal cerebral ischemia. Neurosurg. 44, 163-171.
199. Scholich, H., Murphy, M. E., and Sies, H. (1989) Antioxidant activity of dihydrolipoate against microsomal lipid peroxidation and its dependence on alpha-tochopherol. Biochem. Biophys. Acta 1001, 256-261.
200. Schulz, J. B., Weller, M., and Moskowitz, M. A. (1999) Caspases as treatment targets in stroke and neurodegenerative diseases. Ann. Neurol. 45, 421-429.
201. Sharar, S. R., Winn, R. K., and Harlan, J. M. (1995) The adhesion cascade and anti-adhesion therapy: an overview. Springer Sem. Immunopath. 16, 359-378.
202. Sherman, D. G. (2001) Enlimomab Acute Stroke Trial Investigators. Use of anti-ICAM-1 therapy in acute ischemic strokes: results of the enlimomab in acute strok trial. Neurol. 57, 1428-1434.
203. Shima, H., Fujisawa, H., Suehiro, E., Uetsuka, S., Maekawa, T., and Suzuki, M. (2003) Mild hypothermia inhibits exogenous glutamate-induced increases in nitric oxide synthesis. J. Neurotrauma 20, 1179-1187.
204. Shimakura, A., Kamanaka, Y., Ikeda, I., Kondo, K., Suzuki, Y., and Umemura, K. (2000) Neutrophil elastase inhibition reduces cerebral ischemic damage in the middle cerebral artery occlusion. Brain Res. 858, 55-60.
205. Shimizu, K., Rajapakse, N., Horiguchi, T., Payne, R. M., and Busija, D. W. (2003) Protective effect of new nonpeptidyl mimetic of SOD, M40401, against focal cerebral ischemia in the rat. Brain Res. 963, 8-14.
206. Shuaib, A., Yang, Y., and Li, Q. (2000) Evaluating the efficacy of citicoline in embolic ischemic stroke in rats: neuroprotective effects when used alone or in combination with urokinase. Exp. Neurol. 161, 733-739.
207. Siesjo, B. K. (1992) Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. J. Neurosurg. 77, 169-184.
208. Siesjo, B. K. (1992) Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment. J. Neurosurg. 77, 337-354.
209. Smith, S. E., Hodges, H., Sowinski, P., Man, C.-M., Leach, M. J., Sinden, J. D., Gray, J. A., and Meldrum, B. S. (1996) Long-term beneficial effects of BW619C89 on neurological deficit, cognitive deficit and brain damage after middle cerebral artery occlusion in the rat. Neurosci. 77, 1123-1135.
210. Smith, S. E. and Meldrum, B. S. (1995) Cerebroprotective effect of lamotrigine after focal cerebral ischemia in rats. Stroke 26, 117-122.
211. Solenski, N. J. and Kwan, A.-L. (2000) Attenuation of free radical generation during reversible focal cerebral ischemia with the nitric oxide inhibitior, L-NAME (L-NG-nitro-L-arginine methyl ester). Brain Res. 862, 262-265.
212. Solenski, N. J., Kwan, A.-L., Yanamoto, H., Bennett, J. P., Kassell, N. F., and Lee, K. S. (1997) Differential hydroxylation of salicylate in the core and penumbra regions during focal reversible cerebral ischemia. Stroke 28, 2545-2551.
213. Somjen G. G. (2001) Mechanisms of spreading depression and hypoxic spreading depression-like depolarization. Physiol. Rev. 81, 1065-1096.
214. Soong, C. V., Young, I. S., Hood, J. M., Rowlands, B. J., Trimble, E. R., and Barros D'Sa, A. A. B. (1996) The generation of by-products of lipid peroxidation following carotid endarterectomy. Eur. J. Vasc. Endovasc. Surg. 12, 455-458.
215. Squire, I. B., Lees, K. R., Pryse-Phillips, W., Kertesz, A., and Bamford, J. (1996) The effects of lifarizine in acute cerebral infarction: a pilot safety study. Cerebrovasc. Dis. 6, 156-160.
216. STAIR (2003) Stroke Therapy Academic Industry Roundtable III Group. Stroke In press.
217. STAIR-II (2001) Stroke Therapy Academic Industry Roundtable II (STAIR-II): recommendations for clinical trial evaluation of acute stroke therapies. Stroke 32, 1598-1606.
218. Steiner, T. and Hacke, W. (1998) Combination therapy with neuroprotectants and thrombolytics in acute ischaemic stroke. Eur. Neurol. 40, 1-8.
219. Stroke, Unit, Trialists, and Collaboration (1997) How do stroke units improve patient outcomes? A collaborative systematic review of the randomized trials. Stroke 28, 2139-2144.
220. Strong, A. J., Fabricius, M., Boutelle, M. G., Hibbins, S. J., Hopwood, S. E., Jones, R., Parkin, M. C., and Lauritzen, M. (2002) Spreading and synchronous depressions of cortical activity in acutely injured human brain. Stroke 33, 2738-2743.
221. Stys, P. K. and Lopachin, R. M. (1998) Mechanisms of calcium and sodium fluxes in anoxic myelinated central nervous system axons. Neurosci. 82, 21-32.
222. Sulter, G., Elting, J. W., Langedijk, M., Maurits, N. M., and De Keyser, J. (2003) Admitting acute ischemic stroke patients to a stroke care monitoring unit versus a conventional stroke unit: a randomized pilot study. Stroke 34, 101-104.
223. Sung, C. P., Arleth, A. J., Eichman, C., Truneh, A., and Ohlstein, E. H. (1997) Carvedilol, a multiple-action neurohumoral antagonist, inhibits mitogen-activated protein kinase and cell cycle progression in vascular smooth muscle cells. J. Pharm. Exp. Ther. 283, 910-917.
224. Suzuki, M., Sasamata, M., and Miyata, K. (2003) Neuroprotective effects of YM872 coadministered with t-PA in a rat embolic stroke model. Brain Res. 959, 169-172.
225. Takahashi, M., Kohara, A., Shishikura, J., Kawasaki-Yatsugi, S., Ni, J. W., Yatsugi, S., Sakamoto, S., Okada, M., Shimizu-Sasamata, M., and Yamaguchi, T. (2002) YM872: a selective, potent and highly water-soluble alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist. CNS Drug Rev. 8, 337-352.
226. Takasago, T., Peters, E. E., Graham, D. I., Masayasu, H., and Macrae, I. M. (1997) Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion. Brit. J. Pharmacol. 122, 1251-1256.
227. Taylor, C. P. and Meldrum, B. S. (1995) Sodium channels as targets for neuroprotective drugs. TIPS 16, 309-316.
228. Teichner, A., Ovadia, H., Lavie, G., and Leker, R. R. (2003) Combination of dexanabinol and tempol in focal cerebral ischemia: is there a ceiling effect? Exp. Neurol. 182, 353-360.
229. Uematsu, D., Araki, N., Greenberg, J. H., Sladky, J., and Reivich, M. (1991) Combined therapy with MK-801 and nimodipine for protection of ischemic brain damage. Neurol. 41, 88-94.
230. Uematsu, D., Greenberg, J. H., Hickey, W. F., and Reivich, M. (1989) Nimodipine attenuates both increase in cytosolic free calcium and histologic damage following focal cerebral ischemia and reperfusion in cats. Stroke 20, 1531-1537.
231. Umemura, K., Wada, K., Uematsu, T., Mizuno, A., and Nakashima, M. (1994) Effect of 21-aminosteroid lipid peroxidation inhibitor U74006F, in the middle cerebral artery occlusion model. Eur. J. Pharmac. 251, 69-74.
232. + channels: a rational and effective strategy against ischaemic brain damage. Pharmacol. Rev. 48, 21-67.
233. van der Worp, H. B., Bar, P. R., Kappelle, L. J., and de Wildt, D. J. (1998) Dietary vitamin E levels affect outcome of permanent focal cerebral ischemia in rats. Stroke 29, 1002-1005.
234. Wagner, S., Nagel, S., Kluge, B., Schwab, S., Heiland, S., Koziol, J., Gardner, H., and Hacke, W. (2003) Topographically graded postischemic presence of metalloproteinases is inhibited by hypothermia. Brain Res. 984, 63-75.
235. Wang, G. J., Deng, H. Y., Maier, C. M., Sun, G. H., and Yenari, M. A. (2002) Mild hypothermia reduces ICAM-1 expression, neutrophil infiltration and microglia/monocyte accumulation following experimental stroke. Neurosci. 114, 1081-1090.
236. Warach, S. J. and Sabounjian, L. A. (2000) ECCO 2000 Study of Citicoline for treatment of acute ischemic stroke: Effects on infarct volumes measured by MRI. Stroke 31, 283.
237. Watanabe, T., Yuki, S., Egawa, M., and Nishi, H. (1994) Protective effects of MCI-186 on cerebral ischemia: possible involvement of free radical scavenging and antioxidant actions. J. Pharm. Exp. Ther. 268, 1597-1604.
238. Watanabe, T., Yuki, S., Saito, I., Sato, S., Sugimoto, J., and Ohori, Y. (1997) Pharmacological studies of MCI-186, a new drug for acute stroke. Jap. Pharm. Ther. 25, S1691-1698.
239. Weigand, M. A., Laipple, A., Plaschke, K., Eckstein, H.-H., Martin, E., and Bardenheuer, H. J. (1999) Concentration changes of malondialdehyde across the cerebral vascular bed and shedding of L-selectin during carotid endarterectomy. Stroke 30, 306-311.
240. Weisner, T. (2002) AMPA receptor antagonists with additional mechanisms of action: new oportunities for neuroprotective drugs. Curr. Neuropharm. Des. 8, 941-951.
241. Weston, R. M., Jarrott, B., and Callaway, J. K. (2002) Neutrophil infiltration is reduced by AM-36 in a middle cerebral artery model of stroke in conscious rats. Proc. Aust. Neurosci. Soc. 13, 149.
242. Williams, A. J. and Tortella, F. C. (2002) Neuroprotective effects of the sodium channel blocker RS100642 and attenuation of ischemia-induced brain seizures in the rat. Brain Res. 932, 45-55.
243. Wolz, P. and Krieglstein, J. (1996) Neuroprotective effects of alpha-lipoic acid and its enantiomers demonstrated in rodent models of focal cerebral ischemia. Neuropharmacol. 35, 369-375.
244. Xing, Y., Zhang, Y., Stabernack, C. R., Eger, E. I. 2nd, and Gray, A. T. (2003) The use of the potassium channel activator riluzole to test whether potassium channels mediate the capacity of isoflurane to produce immobility. Anes. Anal. 97, 1020-1024.
245. Yamaguchi, T., Sano, K., Takakura, K., Saito, I., Shinohara, Y., Asano, T., and Yasuhara, H. (1998) Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group. Stroke 29, 12-17.
246. Yang, Y., Li, Q., and Shuaib, A. (2000) Enhanced neuroprotection and reduced hemorrhagic incidence in focal cerebral ischemia of rat by low dose combination therapy of urokinase and topiramate. Neuropharmacol. 39, 881-888.
247. Yoshizumi, M., Fujita, Y., Izawa, Y., Suzaki, Y., Kyaw, M., Ali, N., Tsuchiya, K., Kagami, S., Yano, S., Sone, S., and Tamaki, T. (2004) Ebselen inhibits tumor necrosis factor-alpha-induced c-Jun N-terminal kinase activation and adhesion molecule expression in endothelial cells. Exp. Cell Res. 292, 1-10.
248. Yue, T. L., Lysko, P. G., Barone, F. C., Gu, J. L., Ruffolo, R. R., Jr., and Feuerstein, G. Z. (1994) Carvedilol, a new antihypertensive drug with unique antioxidant activity: potential role in cerebroprotection. Ann. N.Y. Acad. Sci. 738, 230-242.
249. Yue, T. L., McKenna, P. J., Lysko, P. G., Ruffolo, R. R. Jr., and Feuerstein, G. Z. (1992) Carvedilol, a new antihypertensive, prevents oxidation of human low density lipoprotein by macrophages and copper. Atherosc. 97, 209-216.
250. Yue, T. L., McKenna, P. J., Ruffolo, R. R. Jr., and Feuerstein, G. (1992) Carvedilol, a new beta-adrenoceptor antagonist and vasodilator antihypertensive drug inhibits superoxide release from human neutrophils. Eur. J. Pharmac. 214, 277-280.
251. Yue, T. L., Wang, C., Romanic, A. M., Kikly, K., Keller, P., DeWolf, W. E. Jr., Hart, T. K., Thomas H. C., Storer B., Gu J. L., Wang X., and Feuerstein G. Z. (1998) Staurosporine-induced apoptosis in cardiomyocytes: A potential role of caspase-3. J. Mol. Cell. Cardiol. 30, 495-507.
252. Zausinger, S., Westermaier, T., Plesnila, N., Steiger, H. J., and Schmid-Elsaesser, R. (2003) Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia: comparison with customary therapeutic regimen. Stroke 34, 1526-1532.
253. Zhang, L., Zhang, Z. G., Zhang, R. L., Lu, M., Adams, J., Elliott, P. J., and Chopp, M. (2001) Postischemic (6-Hour) treatment with recombinant human tissue plasminogen activator and proteasome inhibitor PS-519 reduces infarction in a rat model of embolic focal cerebral ischemia. Stroke 32, 2926-2931.
254. Zhang, R. L., Zhang, L., Jiang, Q., Zhang, Z. G., Goussev, A., and Chopp, M. (2000) Postischemic intracarotid treatment with TNK-tPA reduces infarct volume and improves neurological deficits in embolic stroke in the unanesthetized rat. Brain Res. 878, 64-71.
255. Zhang, R. L., Zhang, Z. G., Chopp, M., and Zivin, J. A. (1999) Thrombolysis with tissue plasminogen activator alters adhesion molecule expression in the ischemic rat brain. Stroke 30, 624-629.
256. Zhao, H., Yenari, M. A., Sapolsky, R. M., and Steinberg, G. K. (2004) Mild postischemic hypothermia prolongs the time window for gene therapy by inhibiting cytochrome c release. Stroke 35, 572-577.
257. Zhao, Q., Pahlmark, K., Smith, M.-L., and Siesjo, B. K. (1994) Delayed treatment with the spin trap a-phenyl-N-tert-butyl nitrone (PBN) reduces infarct size following transient middle cerebral artery occlusion in rats. Acta Physiol. Scand 152, 349-350.
258. Zhao, R., Masayasu, H., and Holmgren, A. (2002) Ebselen: a substrate for human thioredoxin reductase strongly stimulating its hydroperoxide reductase activity and a superfast thioredoxin oxidant. Proc. Natl. Acad. Sci. USA 99, 8579-8584.
259. Zhao, Z., Cheng, M., Maples, K. R., Ma, J. Y., and Buchan, A. M. (2001) NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat. Brain Res. 909, 46-50.
260. Zheng, T. S., Hunot, S., Kuida, K., and Flavell, R. A. (1999) Caspase knockouts: matters of life and death. Cell Death Diff. 6. 1043-1053.