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Neuroprotective Effects of Free Radical Scavengers in Stroke

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Abstract

Acute ischaemic stroke is a leading cause of death in the majority of industrialised countries and also in many developing countries. Free radicals are generated in the brain during ischaemic injury and these radicals are involved in the secondary injury processes. Several free radical scavengers have been developed and some of them have progressed into clinical trials. One of them, edaravone, has been approved by the regulatory authority in Japan for the treatment of stroke patients. Another scavenger, disodium 4-[(tert-butylimino)methyl] benzene-1,3-disulfonate N-oxide (NXY-059; disufenton), has demonstrated efficacy in a phase III clinical trial (SAINT [Stroke Acute Ischaemic NXY-059 Treatment study]-I) involving a large number of stroke patients. Unfortunately, SAINT II did not show efficacy in the treatment of stroke patients. The purpose of this article is to review the current development of antioxidant strategies, update recent findings for NXY-059 in the treatment of stroke patients, and discuss the future development of neuroprotective agents. Although the development of neuroprotective strategies for the treatment of stroke is challenging, progress in molecular and cellular neuroscience will uncover new information about stroke mechanisms, which should result in the realisation of neuroprotective therapy for this disease.

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References

  1. Green AR, Shuaib A. Therapeutic strategies for the treatment of stroke. Drug Discov Today 2006 Aug; 11(15–16): 681–93

    Article  PubMed  CAS  Google Scholar 

  2. He J, Klag MJ, Wu Z, et al. Stroke in the People’s Republic of China I: geographic variations in incidence and risk factors. Stroke 1995 Dec; 26(12): 2222–7

    Article  PubMed  CAS  Google Scholar 

  3. Flamm ES, Demopoulos HB, Seligman ML, et al. Free radicals in cerebral ischemia. Stroke 1978 Sep–Oct; 9(5): 445–7

    Article  PubMed  CAS  Google Scholar 

  4. Morimoto T, Globus MY, Busto R, et al. Simultaneous measurement of salicylate hydroxylation and glutamate release in the penumbral cortex following transient middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab 1996 Jan; 16(1): 92–9

    Article  PubMed  CAS  Google Scholar 

  5. Watson BD, Busto R, Goldberg WJ, et al. Lipid peroxidation in vivo induced by reversible global ischemia in rat brain. J Neurochem 1984 Jan; 42(1): 268–74

    Article  PubMed  CAS  Google Scholar 

  6. Nelson CW, Wei EP, Povlishock JT, et al. Oxygen radicals in cerebral ischemia. Am J Physiol 1992 Nov; 263 (5 Pt 2): H1356–62

    PubMed  CAS  Google Scholar 

  7. Cao W, Carney JM, Duchon A, et al. Oxygen free radical involvement in ischemia and reperfusion injury to brain. Neurosci Lett 1988 May 26; 88(2): 233–8

    Article  PubMed  CAS  Google Scholar 

  8. Kato N, Yanaka K, Nagase S, et al. The antioxidant EPC-K1 ameliorates brain injury by inhibiting lipid peroxidation in a rat model of transient focal cerebral ischaemia. Acta Neurochir (Wien) 2003 Jun; 145(6): 489–93

    CAS  Google Scholar 

  9. Lancelot E, Callebert J, Revaud ML, et al. Detection of hydroxyl radicals in rat striatum during transient focal cerebral ischemia: possible implication in tissue damage. Neurosci Lett 1995 Sep 8; 197(2): 85–8

    Article  PubMed  CAS  Google Scholar 

  10. Schmid-Elsaesser R, Zausinger S, Hungerhuber E, et al. Neuroprotective effects of combination therapy with tirilazad and magnesium in rats subjected to reversible focal cerebral ischemia. Neurosurgery 1999 Jan; 44(1): 163–71

    Article  PubMed  CAS  Google Scholar 

  11. Hallenbeck JM, Dutka AJ, Tanishima T, et al. Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke 1986 Mar–Apr; 17(2): 246–53

    Article  PubMed  CAS  Google Scholar 

  12. Green AR, Ashwood T, Odergren T, et al. Nitrones as neuroprotective agents in cerebral ischemia, with particular reference to NXY-059. Pharmacol Ther 2003 Dec; 100(3): 195–214

    Article  PubMed  CAS  Google Scholar 

  13. Yang Y, Li Q, Shuaib A. Neuroprotection by 2-h postischemia administration of two free radical scavengers, alpha-phenyl-ntert-butyl-nitrone (PBN) and N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN), in rats subjected to focal embolic cerebral ischemia. Exp Neurol 2000 May; 163(1): 39–45

    Article  PubMed  CAS  Google Scholar 

  14. Yang G, Chan PH, Chen J, et al. Human copper-zinc Superoxide dismutase transgenic mice are highly resistant to reperfusion injury after focal cerebral ischemia. Stroke 1994 Jan; 25(1): 165–70

    Article  PubMed  Google Scholar 

  15. Kinouchi H, Epstein CJ, Mizui T, et al. Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn Superoxide dismutase. Proc Natl Acad Sci U S A 1991 Dec 15; 88(24): 11158–62

    Article  PubMed  CAS  Google Scholar 

  16. Siesjo BK, Agardh CD, Bengtsson F. Free radicals and brain damage. Cerebrovasc Brain Metab Rev 1989 Fall; 1(3): 165–211

    PubMed  CAS  Google Scholar 

  17. Rodrigo J, Fernandez AP, Serrano J, et al. The role of free radicals in cerebral hypoxia and ischemia. Free Radic Biol Med 2005 Jul 1; 39(1): 26–50

    Article  PubMed  CAS  Google Scholar 

  18. Alexandrova ML, Bochev PG. Oxidative stress during the chronic phase after stroke. Free Radic Biol Med 2005 Aug 1; 39(3): 297–316

    Article  PubMed  CAS  Google Scholar 

  19. Schaller B. Introduction to serial reviews on free radicals and stroke. Free Radic Biol Med 2005 Feb 15; 38(4): 409–10

    Article  PubMed  CAS  Google Scholar 

  20. Moro MA, Almeida A, Bolanos JP, et al. Mitochondrial respiratory chain and free radical generation in stroke. Free Radic Biol Med 2005 Nov 15; 39(10): 1291–304

    Article  PubMed  CAS  Google Scholar 

  21. Chan PH. Role of oxidants in ischemic brain damage. Stroke 1996 Jun; 27(6): 1124–9

    Article  PubMed  CAS  Google Scholar 

  22. Stadtman ER, Oliver CN. Metal-catalyzed oxidation of proteins: physiological consequences. J Biol Chem 1991 Feb 5; 266(4): 2005–8

    PubMed  CAS  Google Scholar 

  23. Freeman BA, Crapo JD. Biology of disease: free radicals and tissue injury. Lab Invest 1982 Nov; 47(5): 412–26

    PubMed  CAS  Google Scholar 

  24. Kehrer JP. Free radicals as mediators of tissue injury and disease. Crit Rev Toxicol 1993; 23(1): 21–48

    Article  PubMed  CAS  Google Scholar 

  25. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 2003 May; 4(5): 399–415

    Article  PubMed  CAS  Google Scholar 

  26. Hengartner MO. The biochemistry of apoptosis. Nature 2000 Oct 12; 407(6805): 770–6

    Article  PubMed  CAS  Google Scholar 

  27. Yuan J, Yankner BA. Apoptosis in the nervous system. Nature 2000 Oct 12; 407(6805): 802–9

    Article  PubMed  CAS  Google Scholar 

  28. Beckman JS. Interactions of oxidants, nitric oxide and antioxidant defences in cerebral ischemia and injury. In: Ginsberg M, Bogousslavsky J, editors. Maiden: Blackwell Science, 1998: 455–70

  29. Margaill I, Plotkine M, Lerouet D. Antioxidant strategies in the treatment of stroke. Free Radic Biol Med 2005 Aug 15; 39(4): 429–43

    Article  PubMed  CAS  Google Scholar 

  30. Noguchi N, Yoshida Y, Kaneda H, et al. Action of ebselen as an antioxidant against lipid peroxidation. Biochem Pharmacol 1992 Jul 7; 44(1): 39–44

    Article  PubMed  CAS  Google Scholar 

  31. Dawson DA, Masayasu H, Graham DI, et al. The neuroprotective efficacy of ebselen (a glutathione peroxidase mimic) on brain damage induced by transient focal cerebral ischaemia in the rat. Neurosci Lett 1995 Feb 6; 185(1): 65–9

    Article  PubMed  CAS  Google Scholar 

  32. Takasago T, Peters EE, Graham DI, et al. Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion. Br J Pharmacol 1997 Nov; 122(6): 1251–6

    Article  PubMed  CAS  Google Scholar 

  33. Imai H, Masayasu H, Dewar D, et al. Ebselen protects both gray and white matter in a rodent model of focal cerebral ischemia. Stroke 2001 Sep; 32(9): 2149–54

    Article  PubMed  CAS  Google Scholar 

  34. Lapchak PA, Chapman DF, Zivin JA. Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator-induced hemorrhage after thromboembolic stroke. Stroke 2000 Dec; 31(12): 3034–40

    Article  PubMed  CAS  Google Scholar 

  35. Salom JB, Perez-Asensio FJ, Burguete MC, et al. Single-dose ebselen does not afford sustained neuroprotection to rats subjected to severe focal cerebral ischemia. Eur J Pharmacol 2004 Jul 8; 495(1): 55–62

    Article  PubMed  CAS  Google Scholar 

  36. Ogawa A, Yoshimoto T, Kikuchi H, et al. Ebselen in acute middle cerebral artery occlusion: a placebo-controlled, double-blind clinical trial. Cerebrovasc Dis 1999 Mar–Apr; 9(2): 112–8

    Article  PubMed  CAS  Google Scholar 

  37. Yamaguchi T, Sano K, Takakura K, et al. Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group. Stroke 1998 Jan; 29(1): 12–7

    Article  PubMed  CAS  Google Scholar 

  38. Schmid-Elsaesser R, Zausinger S, Hungerhuber E, et al. Monotherapy with dextromethorphan or tirilazad — but not a combination of both — improves outcome after transient focal cerebral ischemia in rats. Exp Brain Res 1998 Sep; 122(1): 121–7

    Article  PubMed  CAS  Google Scholar 

  39. Bath PM, Iddenden R, Bath FJ, et al. Tirilazad for acute ischaemic stroke. Cochrane Database Syst Rev 2001; (4): CD002087

    Google Scholar 

  40. van der Worp HB, Kappelle LJ, Algra A, et al. The effect of tirilazad mesylate on infarct volume of patients with acute ischemic stroke. Neurology 2002 Jan 8; 58(1): 133–5

    Article  PubMed  Google Scholar 

  41. Zhu C, Wang X, Huang Z, et al. Apoptosis-inducing factor is a major contributor to neuronal loss induced by neonatal cerebral hypoxia-ischemia. Cell Death Differ 2007; 14: 775–84

    Article  PubMed  CAS  Google Scholar 

  42. Noor JI, Ikeda T, Mishima K, et al. Short-term administration of a new free radical scavenger, edaravone, is more effective than its long-term administration for the treatment of neonatal hypoxic-ischemic encephalopathy. Stroke 2005; 36: 2468–74

    Article  PubMed  CAS  Google Scholar 

  43. Shichinohe H, Kuroda S, Yasuda H, et al. Neuroprotective effects of the free radical scavenger edaravone (MCI-186) in mice permanent focal brain ischemia. Brain Res 2004 Dec 17; 1029(2): 200–6

    Article  PubMed  CAS  Google Scholar 

  44. Zhang N, Komine-Kobayashi M, Tanaka R, et al. Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain. Stroke 2005; 36: 2220–5

    Article  PubMed  CAS  Google Scholar 

  45. Amemiya S, Kamiya T, Nito C, et al. Anti-apoptotic and neuroprotective effects of edaravone following transient focal ischemia in rats. Eur J Pharmacol 2005 Jun 1; 516(2): 125–30

    Article  PubMed  CAS  Google Scholar 

  46. Edaravone Acute Infarction Study Group. Randomized, placebo-controlled, double-blind study at multicenters: effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Cerebrovasc Dis 2003; 15(3): 222–9

    Article  Google Scholar 

  47. Maples KR, Ma F, Zhang YK. Comparison of the radical trapping ability of PBN, S-PPBN and NXY-059. Free Radic Res 2001 Apr; 34(4): 417–26

    Article  PubMed  CAS  Google Scholar 

  48. Green AR, Ashwood T. Free radical trapping as a therapeutic approach to neuroprotection in stroke: experimental and clinical studies with NXY-059 and free radical scavengers. Curr Drug Targets CNS Neurol Disord 2005 Apr; 4(2): 109–18

    Article  PubMed  CAS  Google Scholar 

  49. Kuroda S, Tsuchidate R, Smith ML, et al. Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 1999 Jul; 19(7): 778–87

    Article  PubMed  CAS  Google Scholar 

  50. Yoshimoto T, Kanakaraj P, Ying Ma J, et al. NXY-059 maintains Akt activation and inhibits release of cytochrome C after focal cerebral ischemia. Brain Res 2002 Aug 30; 947(2): 191–8

    Article  PubMed  CAS  Google Scholar 

  51. Yoshimoto T, Kristian T, Hu B, et al. Effect of NXY-059 on secondary mitochondrial dysfunction after transient focal ischemia; comparison with cyclosporin A. Brain Res 2002 Apr 5; 932(1–2): 99–109

    Article  PubMed  CAS  Google Scholar 

  52. Zhao Z, Cheng M, Maples KR, et al. NXY-059, a novel free radical trapping compound, reduces cortical infarction after permanent focal cerebral ischemia in the rat. Brain Res 2001 Aug 3; 909(1—2): 46–50

    Article  PubMed  CAS  Google Scholar 

  53. Marshall JW, Cummings RM, Bowes LJ, et al. Functional and histological evidence for the protective effect of NXY-059 in a primate model of stroke when given 4 hours after occlusion. Stroke 2003 Sep; 34(9): 2228–33

    Article  PubMed  CAS  Google Scholar 

  54. Marshall JW, Duffin KJ, Green AR, et al. NXY-059, a free radical: trapping agent, substantially lessens the functional disability resulting from cerebral ischemia in a primate species. Stroke 2001 Jan; 32(1): 190–8

    Article  PubMed  CAS  Google Scholar 

  55. Lees KR, Zivin JA, Ashwood T, et al. NXY-059 for acute ischemic stroke. N Engl J Med 2006 Feb 9; 354(6): 588–600

    Article  PubMed  CAS  Google Scholar 

  56. Peeling J, Del Bigio MR, Corbett D, et al. Efficacy of disodium 4-[(tert-butylimino)methyl]benzene-1,3-disulfonate N-oxide (NXY-059), a free radical trapping agent, in a rat model of hemorrhagic stroke. Neuropharmacology 2001 Mar; 40(3): 433–9

    Article  PubMed  CAS  Google Scholar 

  57. Hankey GJ. Neuroprotection for acute ischaemic stroke: hope reignited. Lancet Neurol 2006 Apr; 5(4): 287–8

    Article  PubMed  Google Scholar 

  58. Schaller B, Graf R, Jacobs AH. Ischaemic tolerance: a window to endogenous neuroprotection? Lancet 2003 Sep 27; 362(9389): 1007–8

    Article  PubMed  Google Scholar 

  59. Saver JL, Kidwell C, Eckstein M, et al. Physician-investigator phone elicitation of consent in the field: a novel method to obtain explicit informed consent for prehospital clinical research. Prehosp Emerg Care 2006 Apr–Jun; 10(2): 182–5

    Article  PubMed  Google Scholar 

  60. American Stroke Association. Major ongoing stroke trials. Stroke 2006 Feb; 37(2): e18–26

    Google Scholar 

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Acknowledgements

This work is supported by grants from the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada and AstraZeneca. Dr Wang and Dr Shuaib have received grants from AstraZeneca. Dr Shuaib has also acted as a consultant to AstraZeneca.

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  1. Stroke Research Laboratory, 533 HMRC, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada

    Chen X. Wang & Ashfaq Shuaib

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  1. Chen X. Wang
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Correspondence to Chen X. Wang.

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Wang, C.X., Shuaib, A. Neuroprotective Effects of Free Radical Scavengers in Stroke. Drugs Aging 24, 537–546 (2007). https://doi.org/10.2165/00002512-200724070-00002

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