Antioxidants: The new frontier for translational research in cerebroprotection

Journal of Anaesthesiology Clinical Pharmacology

Volumn 30, Issue 2, 2014, Pages 160-171

  Tewari, Anurag ^a   Mahendru, Vidhi ^b   Sinha, Ashish ^c   Bilotta, Federico ^d  

^a DAYANAND MEDICAL COLLEGE AND HOSPITAL   (India)

^b ALL INDIA INSTITUTE OF MEDICAL SCIENCES   (India)

^c DREXEL UNIVERSITY COLLEGE OF MEDICINE   (United States)

^d SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

Antioxidants; cerebroprotection; neuro anesthesiology; neurocritical care

Indexed keywords

ACETYLCYSTEINE; ALPHA TOCOPHEROL; APOLIPOPROTEIN E; ASCORBIC ACID; BETA CAROTENE; CATALASE; CYANOCOBALAMIN; DEFEROXAMINE; DEFEROXAMINE MESYLATE; DISUFENTON SODIUM; EBSELEN; FLAVANOID; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LUTEOLIN; MATRIX METALLOPROTEINASE; MELATONIN; MINOCYCLINE; NITRONE DERIVATIVE; NORPHENAZONE; PLACEBO; PROTEIN P47; QUERCETIN; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; SELENIUM; SUPEROXIDE DISMUTASE; THIOCTIC ACID; TRACE ELEMENT; UBIDECARENONE; UNINDEXED DRUG;

ANESTHESIST; ANTIOXIDANT ACTIVITY; BLOOD BRAIN BARRIER; BRAIN HYPOXIA; BRAIN ISCHEMIA; BRAIN PROTECTION; CENTRAL NERVOUS SYSTEM; CEREBROVASCULAR ACCIDENT; CONTINUOUS INFUSION; HUMAN; IMMUNOMODULATION; IRON CHELATION; LIPID PEROXIDATION; MIDDLE CEREBRAL ARTERY OCCLUSION; MULTIPLE ORGAN FAILURE; NEPHROTOXICITY; NEUROLOGIC DISEASE; NONHUMAN; OXIDATIVE STRESS; PATHOPHYSIOLOGY; POLYMERASE CHAIN REACTION; REPERFUSION INJURY; REVIEW; SPINAL CORD INJURY; SUBARACHNOID HEMORRHAGE; TRANSLATIONAL RESEARCH; TRAUMATIC BRAIN INJURY;

EID: 84898991247     PISSN: 09709185     EISSN: 22312730     Source Type: Journal    
DOI: 10.4103/0970-9185.130001     Document Type: Review

References (130)

1. Hatwalne MS. Free radical scavengers in anaesthesiology and critical care. Indian J Anaesth 2012;56:227-33.
2. Coleman NA. Antioxidants in critical care medicine. Environ Toxicol Pharmacol 2001;10:183-8.
3. Harris RA, Amor S. Sweet and sour-oxidative and carbonyl stress in neurological disorders. CNS Neurol Disord Drug Targets 2011;10:82-107.
4. Hanafy KA, Selim MH. Antioxidant strategies in neurocritical care. Neurotherapeutics 2012;9:44-55.
5. Gelain DP, de Bittencourt Pasquali MA, M Comim C, Grunwald MS, Ritter C, Tomasi CD, et al. Serum heat shock protein 70 levels, oxidant status, and mortality in sepsis. Shock 2011;35:466-70.
6. Ghosh N, Ghosh R, Mandal SC. Antioxidant protection: A promising therapeutic intervention in neurodegenerative disease. Free Radic Res 2011;45:888-905.
7. Schiller HJ, Reilly PM, Bulkley GB. Tissue perfusion in critical illnesses. Antioxidant therapy. Crit Care Med 1993;21(2 Suppl):S92-102.
8. Cheeseman KH, Slater TF. An introduction to free radical biochemistry. Br Med Bull 1993;49:481-93.
9. Dizdaroglu M. Chemical determination of free radical-induced damage to DNA. Free Radic Biol Med 1991;10:225-42.
10. Fink MP, Payen D. the role of nitric oxide in sepsis and ARDS: Synopsis of a roundtable conference held in Brussels on 18-20 March 1995. Intensive Care Med 1996;22:158-65.
11. Halliwell B, Murcia MA, Chirico S, Aruoma OI. Free radicals and antioxidants in food and in vivo: What they do and how they work. Crit Rev Food Sci Nutr 1995;35:7-20.
12. Szabó C. Multiple pathways of peroxynitrite cytotoxicity. Toxicol Lett 2003;140-141:105-12.
13. Baggiolini M, Thelen M. The phagocytes and the respiratory burst. In: Sies H, editor. Oxidative Stress: Oxidants and Antioxidants. San Diego: Academic Press; 1991. p. 399-420.
14. Ferrari R, Ceconi C, Curello S, Cargnoni A, Pasini E, De Giuli F, et al. Role of oxygen free radicals in ischemic and reperfused myocardium. Am J Clin Nutr 1991;53(1 Suppl):215S-22.
15. Cochrane CG. Cellular injury by oxidants. Am J Med 1991;91:23-30S.
16. Halliwell B, Gutteridge JM, Cross CE. Free radicals, antioxidants and human disease: Where are we now? J Lab Clin Med 1992;119:598-620.
17. Rangan U, BulkleyGB. Prospects of treatment of free radical-mediated tissue injury. Br Med Bull 1993;49:700-18.
18. Chang CY, Chen JY, Ke D, Hu ML. Plasma levels of lipophilic antioxidant vitamins in acute ischemic stroke patients: Correlation to inflammation markers and neurological deficits. Nutrition 2005;21:987-93.
19. Taffi R, Nanetti L, Mazzanti L, Bartolini M, Vignini A, Raffaelli F, et al. Plasma levels of nitric oxide and stroke outcome. J Neurol 2008;255:94-8.
20. Chan PH. Mitochondria and neuronal death/survival signalling pathways in cerebral ischemia. Neurochem Res 2004;29:1943-9.
21. Huang FP, Xi G, Keep RF, Hua Y, Nemoianu A, Hoff JT. Brain edema after experimental intracerebral hemorrhage: Role of haemoglobin degradation products. J Neurosurg 2002;96:287-93.
22. Goldstein L, Teng ZP, Zeserson E, Patel M, Regan RF. Hemin induces an iron-dependent, oxidative injury to human neuron like cells. J Neurosci Res 2003;73:113-21.
23. Polidori MC, Mecocci P, Frei B. Plasma vitamin C levels are decreased and correlated with brain damage in patients with intracranial hemorrhage or head trauma. Stroke 2001;32:898-902.
24. Biffi A, Anderson CD, Jagiella JM, Schmidt H, Kissela B, Hansen BM, et al. APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: A genetic association study. Lancet Neurol 2011;10:702-9.
25. Laskowitz DT, Lei B, Dawson HN, Wang H, Bellows ST, Christensen DJ, et al. The apoE-mimetic peptide, COG1410, improves functional recovery in a murine model of intracerebral hemorrhage. Neurocrit Care 2011;16:316-26.
26. Aoki T, Nishimura M, Kataoka H, Ishibashi R, Nozaki K, Hashimoto N. Reactive oxygen species modulate growth of cerebral aneurysms: A study using the free radical scavenger edaravone and p47phox(-/-) mice. Lab Invest 2009;89:730-41.
27. Erahin M, Toklu HZ, Cetinel S, Yüksel M, Erzik C, Berkman MZ, et al. Alpha lipoic acid alleviates oxidative stress and preserves blood brain permeability in rats with subarachnoid hemorrhage. Neurochem Res 2010;35:418-28.
28. Kontos HA, Wei EP. Superoxide production in experimental brain injury. J Neurosurg 1986;64:803-7.
29. Wali B, Sayeed I, Stein DG. Improved behavioral outcomes after progesterone administration in aged male rats with traumatic brain injury. Restor Neurol Neurosci 2011;29:61-71.
30. Roof RL, Hoffman SW, Stein DG. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol Chem Neuropathol 1997;31:1-11.
31. Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, et al. ProTECT: A randomized clinical trial of progesterone for acute traumatic brain injury. Ann Emerg Med 2007;49:391-402.
32. Poirier J. Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. Trends Neurosci 1994;17:525-30.
33. Hoane MR, Pierce JL, Holland MA, Birky ND, Dang T, Vitek MP, et al. The novel apolipoprotein E-based peptide COG1410 improves sensorimotor performance and reduces injury magnitude following cortical contusion injury. J Neurotrauma 2007;24:1108-18.
34. Smith C, Graham DI, Murray LS, Stewart J, Nicoll JA. Association of APOE e4 and cerebrovascular pathology in traumatic brain injury. J Neurol Neurosurg Psychiatry 2006;77:363-6.
35. Traber MG, Sies H. Vitamin E in humans: Demand and delivery. Annu Rev Nutr 1996;16:321-47.
36. De AK, Darad R. Physiological antioxidants and antioxidative enzymes in vitamin E-deficient rats. Toxicol Lett 1988;44:47-54.
37. Rose RC, Bote AM. Biology of free radical scavengers: An evaluation of Ascorbate. FASEB J 1993;7:1135-42.
38. Chan AC. Partners in defense. Vitamin E and vitamin C. Can J Physiol Pharmacol 1993;7:725-31.
39. Manzanares W, Hardy G. Vitamin B12: The forgotten micronutrient for critical care. Curr Opin Clin Nutr Metab Care 2010;13:662-8.
40. Crimi E, Liguori A, Condorelli M, Cioffi M, Astuto M, Bontempo P, et al. The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: A prospective, randomized, double-blind, placebo controlled trial. Anesth Analg 2004;99:857-63.
41. Crimi E, Sica V, Williams-Ignarro S, Zhang H, Slutsky AS, Ignarro LJ, et al. The role of oxidative stress in adult critical care. Free Radic Biol Med 2006;40:398-406.
42. Andrews PJ, Avenell A, Noble DW, Campbell MK, Croal BL, Simpson WG, et al. Scottish Intensive Care Glutamine or Selenium Evaluative Trial Trials Group. Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ 2011;342:d1542.
43. Heyland DK, Dhaliwal R, Suchner U, Berger MM. Antioxidant nutrients: A systematic review of trace elements and vitamins in the critically ill patient. Intensive Care Med 2005;31:327-37.
44. Dyatlov VA, Makovetskaia VV, Leonhardt R, Lawrence DA, and Carpenter DO. Vitamin E enhances Ca (2+)-mediated vulnerability of immature cerebellar granule cells to ischemia. Free Radic Biol Med 1998;25:793-802.
45. Rice ME. Ascorbate regulation and its neuroprotective role in the brain. Trends Neurosci 2000;23:209-16.
46. Ernster L, Dallner G. Biochemical, physiological and medical aspects of ubiquinon function. Biochem Biophys Acta 1995;127:195-204.
47. Lance J, McCabe S, Clancy RL, Pierce J. Coenzyme Q10-a therapeutic agent. Medsurg Nurs 2012;21:367-71.
48. Ogawa N, Tsukamoto S, Hirose Y, Kuroda H. Survival effect of coenzyme Q10, and naloxone on experimental stroke. Pharmacol Biochem Behav 1986;24:315-7.
49. Grieb P, Ryba MS, Sawicki J, Chrapusta SJ. Oral coenzyme Q10 administration prevents the development of ischemic brain lesions in rabbit model of symptomatic vasospasm. Acta Neuropathol 1997;94:363-8.
50. Kalayci M, Unal MM, Gul S, Acikgoz S, Kandemir N, Hanci V, et al. Effect of coenzyme Q10 on ischemia and neuronal damage in an experimental traumatic brain-injury model in rats. BMC Neurosci 2011;12:75.
51. Packer L. New horizons in antioxidant research: Action of the thioctic acid/dihydrolipoic acid couple in biological systems, in Thioctsaure. In: Schmidt K, Ulrich H, editors. 2 nd International Thictic Acid Workshop. Frankfurt: Universimed Verlag GmbH; 1992. p. 35-44.
52. Packer L. Alpha-Lipoic acid: A metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury. Drug Metab Rev 1998;30:245-75.
53. Prehn JH, Karkoutly C, Nuglisch J, Peruche B, Krieglstein J. Dihydrolipoate reduces neuronal injury after cerebral ischemia. J Cereb Blood Flow Metab 1992;12:78-87.
54. Cao X, Phillis JW. The free radical scavenger alpha-lipoic acid protects against cerebral ischemia-reperfusion injury in gerbils.Free Radic Res 1995;23:365-70.
55. Woltz P, Krieglstein J. Neuroprotective effects of alpha-lipoic acid and its enantiomers demonstrated in rodent models of focal cerebral ischemia. Neuropharmacology 1996;35:369-75.
56. Connell BJ, Saleh M, Khan BV, Saleh TM. Lipoic acid protects against reperfusion injury in the early stages of cerebral ischemia. Brain Res 2011;1375:128-36.
57. Kostoglou-Athanassiou I. Therapeutic applications of melatonin. Ther Adv Endocrinol Metab 2013;4:13-24.
58. Nair SM, Rahman RM, Clarkson AN, Sutherland BA, Taurin S, Sammut IA, et al. Melatonin treatment following stroke induction modulates L-arginine metabolism. J Pineal Res 2011;51:313-23.
59. Borlongan CV, Yamamoto M, Takei N, Kumazaki M, Ungsuparkorn C, Hida H, et al. Glial survival is enhanced during melatonin induced neuroprotection against cerebral ischemia. FASEB J 2000;14:1307-17.
60. Kilic E, Ozdemir YG, Bolay H, Kelestimur H, Dalkara T. Pinealectomy aggravates and melatonin administration attenuates brain damage in focal ischemia. J Cereb Blood Flow Metab 1999;19:511-6.
61. Samantaray S, Das A, Thakore NP, Matzelle DD, Reiter RJ, Ray SK, et al. Therapeutic potential of melatonin in traumatic central nervous system injury. J Pineal Res 2009;47:134-42.
62. Halliwell B. Free radicals, antioxidants, and human disease: Curiosity, cause or consequence? Lancet 1994;344:721-4.
63. Ye N, Liu S, Lin Y, Rao P. Protective effects of intraperitoneal injection of TAT-SOD against focal cerebral ischemia/reperfusion injury in rats. Life Sci 2011;89:868-74.
64. Young B, Runge JW, Waxman KS, Harrington T, Wilberger J, Muizelaar JP, et al. Effects of pegorgotein on neurologic outcome of patient with severe head injury: A multicenter, randomized controlled trial. JAMA 1996;276:538-43.
65. Meister A, Anderson ME. Glutathione. Annu Rev Biochem 1983;52:711-60.
66. Larsson A, Orrenius S, Holngren A, Mannervik B. Functions of glutathione.biochemical physiological toxicological and clinical aspects. New York: Raven Press; 1983.
67. Mizui T, Kinouchi H, Chan PH. Depletion of brain glutathione by buthionine sulfoximine enhances cerebral ischemic injury in rats. Am J Physiol 1992;262:H313-7.
68. Zaidan E, Sims NR. Alternations in the glutathione content of mitochondria following short term forebrain ischemia in rats. Neurosci Lett 1996;218:75-8.
69. Yamamoto M, Sakamoto N, Iwai A, Yatsugi S, Hidaka K, Noguchi K, et al. Protective actions of YM737, a new glutathione analog, against cerebral ischemia in rats. Res Commun Chem Pathol Pharmacol 1993;81:221-32.
70. Anderson MF, Nilsson M, Eriksson PS, Sims NR. Glutathione monoethyl ester provides neuroprotection in a rat model of stroke. Neurosci Lett 2004;354:163-5.
71. Rivera F, Costa G, Abin A, Urbanavicius J, Arruti C, Casanova G, et al. Reduction of ischemic brain damage and increase of glutathione by a liposomal preparation of quercetin in permanent focal ischemia in rats. Neurotox Res 2008;13:105-14.
72. Bilgihan A, Turkozkan N, Aricioglu A, Aykol S, Cevik C, Göksel M. The effect of deferoxamine on brain lipid peroxide levels and Na-K ATPase activity following experimental subarachnoid hemorrhage. Gen Pharmacol 1994;25:495-7.
73. Selim M. Deferoxamine mesylate: A new hope for intracerebral hemorrhage: From bench to clinical trials. Stroke 2009;40(3 Suppl):S90-1.
74. Xing Y, Hua Y, Keep RF, Xi G. Effects of deferoxamine on brain injury after transient focal cerebral ischemia in rats with hyperglycemia. Brain Res 2009;1291:113-21.
75. Okauchi M, Hua Y, Keep RF, Morgenstern LB, Xi G. Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats. Stroke 2009;40:1858-63.
76. Chen Z, Gao C, Hua Y, Keep RF, Muraszko K, Xi G. Role of iron in brain injury after intraventricular hemorrhage. Stroke 2011;42:465-70.
77. Lee JY, Keep RF, He Y, Sagher O, Hua Y, Xi G. Hemoglobin and iron handling in brain after subarachnoid hemorrhage and the effect of deferoxamine on early brain injury. J Cereb Blood Flow Metab 2010;30:1793-803.
78. Selim M, Yeatts S, Goldstein JN, Gomes J, Greenberg S, Morgenstern LB, et al. Deferoxamine Mesylate in Intracerebral Hemorrhage Investigators. Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Stroke 2011;42:3067-74.
79. Méthy D, Bertrand N, Prigent-Tessier A, Mossiat C, Stanimirovic D, Beley A, et al. Beneficial effect of dipyridyl, a liposoluble iron chelator against focal cerebral ischemia: In vivo and in vitro evidence of protection of cerebral endothelial cells. Brain Res 2008;1193:136-42.
80. Janzen E. Spin trapping. Acc Chem Res 1971;4:31-40.
81. Hensley K, Carney JM, Stewart CA, Tabatabaie T, Pye Q, Floyd RA. Nitrone-based free radical traps as neuroprotective agents in cerebral ischemia and other pathologies. Int Rev Neurobiol 1997;40:299-317.
82. Kotake Y. Pharmacologic properties of phenyl N-tert-butylnitrone. Antioxid Redox Signal 1999;1:481-99.
83. Carney JM, Floyd RA. Protection against oxidative damage to CNS by alpha-phenyl-tert-butyl nitrone (PBN) and other spin trapping agents: A novel series of nonlipid free radical scavengers. J Mol Neurosci 1991;3:47-57.
84. Zhao Q, Pahlmark K, Smith ML, Siesjo BK. Delayed treatment with the spin trap alpha-phenyl-tert-butyl nitrone (PBN) reduces infarct size following transient middle cerebral artery occlusion in rats. Acta Physiol Scand 1994;152:349-50.
85. Pahlmark K, Siesjo BK. Effect of the spin trap-alpha-phenyl-N-tert- butylnitrone (PBN) in transient forebrain ischemia in the rat. Acta Physiol Scand 1996;157:41-51.
86. Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Diener HC, et al. Stroke-Acute Ischemic NXY Treatment (SAINT I) Trial Investigators. NXY-059 for acute ischemic stroke. N Engl J Me 2006;354:588-600.
87. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, et al. SAINT II Trial Investigators. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 2007;357:562-71.
88. Savitz SI. A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: A need for more rigorous testing of neuroprotective agents in animal models of stroke. Exp Neurol 2007;205:20-5.
89. Parnham M, Sies H. Ebselen: Prospective therapy for cerebral ischaemia. Expert Opin Investig Drugs 2000;9:607-19.
90. Takasago T, Peters EE, Graham DI, Masayasu H, Macrae IM. Neuroprotective efficacy of ebselen an antioxidant with anti-inflammatory actions, in rodent model of permanent middle cerebral artery occlusion. Br J Pharmacol 1997;122:1251-6.
91. Saito I, Asano T, Takakura K, Abe H, Yoshimoto T, Kikuchi H, et al. Neuroprotective efficacy of an antioxidant ebselen, in patients with delayed neurological deficits after aneurysmal subarachnoid hemorrhage. Neurosurgery 1998;42:269-77.
92. Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara T, Asano T, et al. Ebselen in acute ischemic stroke: A placebo-controlled double-blind clinical trial. Ebselen study group. Stroke 1998;29:12-7.
93. Ogawa A, Yoshimoto T, Kikuchi H, Sano K, Saito I, Yamaguchi T, et al. Ebselen in acute middle cerebral artery occlusion: A placebo-controlled double-blind clinical trial. Cerebrovas Dis 1999;9:112-8.
94. Sheffner AL. The mucolytic action of acetylcysteine. Tuberculol Thorac Dis 1966;23:31-3.
95. Molnár Z, Shearer E, Lowe D. N-Acetylcysteine treatment to prevent the progression of multisystem organ failure: A prospective, randomized, placebo-controlled study. Crit Care Med 1999;27:1100-4.
96. Sadowska AM, Verbraecken J, Darquennes K, De Backer WA. Role of N-acetylcysteine in the management of COPD. Int J Chron Obstruct Pulmon Dis 2006;1:425-34.
97. Fishbane S. N-acetylcysteine in the prevention of contrast-induced nephropathy. Clin J Am Soc Nephrol 2008;3:281-7.
98. Khan M, Sekhon B, Jatana M, Giri S, Gilg AG, Sekhon C, et al. Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J Neurosci Res 2004;76:519-27.
99. Hicdonmez T, Kanter M, Tiryaki M, Parsak T, Cobanoglu S. Neuroprotective effects of N-acetylcysteine on experimental closed head trauma in rats. Neurochem Res 2006;31:473-81.
100. Firuzi O, Lacanna A, Petrucci R, Marrosu G, Saso L. Evaluation of the antioxidant activity of flavonoids by ferric reducing antioxidant power assay and cyclic voltammetry. Biochim Biophys Acta 2005;1721:174-84.
101. Benavente-Garcia O, Castillo J. Update on uses and properties of citrus flavonoids: New findings in anticancer, cardiovascular, and anti-inflammatory activity. J Agric Food Chem 2008;56:6185-205.
102. Vlasov TD. Mechanisms of cerebral protection from ischemia by tea constituents. Ross Fiziol Zh Im I M Sechenova 2012;98:929-42.
103. Li S, Wu C, Zhu L, Gao J, Fang J, Li D, et al. By improving regional cortical blood flow, attenuating mitochondrial dysfunction and sequential apoptosis galangin acts as a potential neuroprotective agent after acute ischemic stroke. Molecules 2012;17:13403-23.
104. Pandey AK, Patnaik R, Muresanu DF, Sharma A, Sharma HS. Quercetin in hypoxia-induced oxidative stress: Novel target for neuroprotection. Int Rev Neurobiol 2012;102:107-46.
105. Qiao H, Dong L, Zhang X, Zhu C, Zhang X, Wang L, et al. Protective effect of luteolin in experimental ischemic stroke: Upregulated SOD1, CAT, Bcl-2 and claudin-5, down-regulated MDA and Bax expression. Neurochem Res 2012;37:2014-24.
106. Qian Y, Guan T, Huang M, Cao L, Li Y, Cheng H, et al. Neuroprotection by the soy isoflavone, genistein, via inhibition of mitochondria-dependent apoptosis pathways and reactive oxygen induced-NF-êB activation in a cerebral ischemia mouse model. Neurochem Int 2012;60:759-67.
107. Yen TL, Hsu CK, Lu WJ, Hsieh CY, Hsiao G, Chou DS, et al. Neuroprotective effects of xanthohumol, a prenylated flavonoid from hops (Humulus lupulus), in ischemic stroke of rats. J Agric Food Chem 2012;60:1937-44.
108. Plane JM, Shen Y, Pleasure DE, Deng W. Prospects for minocycline neuroprotection. Arch Neurol 2010;67:1442-8.
109. Chen-Roetling J, Chen L, Regan RF. Minocycline attenuates iron neurotoxicity in cortical cell cultures. Biochem Biophys Res Commun 2009;386:322-6.
110. Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, et al. Minocycline treatment in acute stroke: An open-label, evaluator-blinded study. Neurology 2007;69:1404-10.
111. Fagan SC, Waller JL, Nichols FT, Edwards DJ, Pettigrew LC, Clark WM, et al. Minocycline to improve neurologic outcome in stroke (MINOS): A dose-finding study. Stroke 2010;41:2283-7.
112. Switzer JA, Hess DC, Ergul A, Waller JL, Machado LS, Portik-Dobos V, et al. Matrix Metalloproteinase-9 in an exploratory trial of intravenous minocycline for acute ischemic stroke. Stroke 2011;42:2633-5.
113. Watanabe T, Tahara M, Todo S. The novel antioxidant edaravone: From bench to bedside. Cardiovasc Ther 2008;26:101-14.
114. Hishida A. Clinical analysis of 207 patients who developed renal disorders during or after treatment with edaravone reported during post-marketing surveillance. Clin Exp Nephrol 2007;11:292-6.
115. Unno Y, Katayama M, Shimizu H. Does functional outcome in acute ischaemic stroke patients correlate with the amount of free-radical scavenger treatment? A retrospective study of edaravone therapy. Clin Drug Investig 2010;30:143-55.
116. Ono S, Okazaki K, Sakurai M, Inoue Y. Density Functional Study of the Radical Reactions of 3-Methyl-1-phenyl-2-pyrazolin-5-one (MCI-186): Implication for the Biological Function of MCI-186 as a Highly Potent Antioxidative Radical Scavenger. J Phys Chem 1997;101:3769-75.
117. Ishikawa A, Yoshida H, Metoki N, Toki T, Imaizumi T, Matsumiya T, et al. Edaravone inhibits the expression of vascular endothelial growth factor in human astrocytes exposed to hypoxia. Neurosci Res 2007;59:406-12.
118. Kikuchi K, Tancharoen S, Matsuda F, Biswas KK, Ito T, Morimoto Y, et al. Edaravone attenuates cerebral ischemic injury by suppressing aquaporin-4. Biochem Biophys Res Commun 2009;390:1121-5.
119. Yoshida H, Metoki N, Ishikawa A, Imaizumi T, Matsumiya T, Tanji K, et al. Edaravone improves the expression of nerve growth factor in human astrocytes subjected to hypoxia/reoxygenation. Neurosci Res 2010;66:284-9.
120. Zhang P, Li W, Li L, Wang N, Li X, Gao M, et al. Treatment with edaravone attenuates ischemic brain injury and inhibits neurogenesis in the subventricular zone of adult rats after focal cerebral ischemia and reperfusion injury. Neuroscience 2012;201:297-306.
121. Ohta Y, Takamatsu K, Fukushima T, Ikegami S, Takeda I, Ota T, et al. Efficacy of the free radical scavenger, edaravone, for motor palsy of acute lacunar infarction. Intern Med 2009;48:593-6.
122. Kavanagh RJ, Kam PC. Lazaroids: Efficacy and mechanism of action of the 21-aminosteroids in neuroprotection. Br J Anaesth 2001;86:110-9.
123. Sanada T, Nakamura T, Nishimura MC, Isayama K, Pitts LH. Effects of U-74006F on neurologic function and brain edema after fluid percussion injury in rats. Neurotrauma 1993;10:65-71.
124. Xue D, Bruederlin B, Heinecke E, Li H, Slivka A, Buchan AM. U-74006F reduces neocortical infarction, but does not attenuate selective hippocampal CA1 necrosis. Stroke 1990;21:178.
125. Matsui T, Kaizu H, Itoh S, Asano T. The role of active smooth muscle contraction in the occurrence of chronic vasospasm in the canine two-hemorrhage model. J Neurosurg 1994;80:276-82.
126. A randomized trial of tirilazad mesylate in patients with acute stroke (RANTTAS). The RANTTAS Investigators. Stroke 1996;27:1453-8.
127. Haley EC Jr. High-dose tirilazad for acute stroke (RANTTAS II). RANTTAS II Investigators. Stroke 1998;29:1256-7.
128. Kassell NF, Haley EC, Apperson-Hansen C, Alves WM. Randomised double-blind vehicle controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid haemorrhage: A co-operative study in Europe, Australia and New Zealand. J Neurosurg 1996;84:221.
129. Haley EC, Kassell NF, Apperson-Hansen C, Maile MH, Alves WM. A randomised double blind vehicle controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid haemorrhage: A co-operative study in North America. J Neurosurg 1997;86:467.
130. Lanzino G, Kassell NF. Double blind randomised, vehicle controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid haemorrhage. Part 2. A co-operative study in North America. J Neurosurg 1999;90:1018.