治疗缺血性脑卒中的自由基清除剂类药物研究进展

摘要/Abstract

摘要： 缺血性脑卒中已成为世界上导致人类死亡的第二大疾病,大量研究证明,缺血及再灌注过程中产生的自由基在脑损伤中起关键作用,使得自由基清除剂成为治疗缺血性脑血管病的研究热点,很多自由基清除剂类药物被合成并先后进入临床试验,包括代表药物依达拉奉成功在日本上市。本文将综述有关治疗缺血性脑卒中的自由基清除剂的最新研究进展,探讨此类药物在研究过程中所遇到的问题并展望此类药物在治疗缺血性脑卒中疾病中的治疗前景。

关键词: 自由基, 自由基清除剂, 缺血性脑卒中

Abstract: Ischemic stroke is the second leading cause of death worldwide. Plenty of studies supported that free radicals are generated in the brain during ischemic-reperfusion injury and these radicals play important roles in the 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. The purpose of this article is to review the current development of the radical scavengers treating with cerebral ischemic, and discuss the problems encountered and look into the future development of the free radical scavengers in the treatment of ischemic stroke.

Key words: Free radical , Free radical scavenger , Ischemic stroke

中图分类号:

R969

王晓金, 孙建国, 彭英, 王广基. 治疗缺血性脑卒中的自由基清除剂类药物研究进展[J]. 中国临床药理学与治疗学, 2011, 16(4): 461-467.

WANG Xiao-jin , SUN Jian-guo , PENG Ying , WANG Guang-ji. Research progresses of free radical scavengers treating with ischemic stroke[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2011, 16(4): 461-467.

参考文献

[1] Lopez AD, Mathers CD, Ezzati M,et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data[J]. Lancet, 2006,367(9524):1747-1757.
[2] Doeppner TR ,Hermann DM. Free radical scavengers and spin traps - therapeutic implications for ischemic stroke[J]. Best Practice & Research Clinical Anaesthesiology, 2010,24(2010):511-520.
[3] 王志平,孙红斌. 氧自由基与缺血性卒中[J]. 西南军医, 2010,12(3):534-536.
[4] Otomo E, Tohgi H, Kogure K,et al. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters[J]. Cerebrovasc Dis, 2003,15(3):222-229.
[5] Abe M,Kaizu K ,Matsumoto K. A case report of acute renal failure and fulminant hepatitis associated with edaravone administration in a cerebral infarction patient[J]. Ther Apher Dial, 2007,11(3):235-240.
[6] Hishida A. Clinical analysis of 207 patients who developed renal disorders during or after treatment with edaravone reported during post-marketing surveillance[J]. Clin Exp Nephrol, 2007,11(4):292-296.
[7] Mitsubishi Tanabe Pharma Corporation.Safety and pharmacokinetics of MCI-186 in subjects with acute ischemic stroke[EB/OL].2010; Available from: http://www.clinicaltrials.gov/ct2/.
[8] 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[J]. Clin Drug Investig, 2010,30(3):143-155.
[9] Kikuchi K, Kawahara K, Miyagi N,et al. Edaravone: a new therapeutic approach for the treatment of acute stroke[J]. Med Hypotheses, 2010,75(6):583-585.
[10] Watanabe T,Tahara M ,Todo S. The novel antioxidant edaravone: from bench to bedside[J]. Cardiovasc Ther, 2008,26(2):101-114.
[11] Hess DC. NXY-059: a hopeful sign in the treatment of stroke[J]. Stroke, 2006,37(10):2649-2650.
[12] Shuaib A, Lees KR, Lyden P,et al. NXY-059 for the treatment of acute ischemic stroke[J]. N Engl J Med, 2007,357(6):562-571.
[13] Wang CX ,Shuaib A. Neuroprotective effects of free radical scavengers in stroke[J]. Drugs Aging, 2007,24(7):537-546.
[14] Diener HC, Lees KR, Lyden P,et al. NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II Trials[J]. Stroke, 2008,39(6):1751-1758.
[15] Ginsberg MD, Becker DA, Busto R,et al. Stilbazulenyl nitrone, a novel antioxidant, is highly neuroprotective in focal ischemia[J]. Ann Neurol, 2003,54(3):330-342.
[16] Ley JJ, Belayev L, Saul I,et al. Neuroprotective effect of STAZN, a novel azulenyl nitrone antioxidant, in focal cerebral ischemia in rats: dose-response and therapeutic window[J]. Brain Res, 2007,1180:101-110.
[17] Sun Y, Jiang J, Zhang Z,et al. Antioxidative and thrombolytic TMP nitrone for treatment of ischemic stroke[J]. Bioorg Med Chem, 2008,16(19):8868-8874.
[18] 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[J]. Exp Brain Res, 1998,122(1):121-127.
[19] van der Worp HB, Kappelle LJ, Algra A,et al. The effect of tirilazad mesylate on infarct volume of patients with acute ischemic stroke[J]. Neurology, 2002,58(1):133-135.
[20] Zhang S, Wang L, Liu M,et al. Tirilazad for aneurysmal subarachnoid haemorrhage[J]. Cochrane Database Syst Rev, 2010(2):CD006778.
[21] 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[J]. Eur J Pharmacol, 2004,495(1):55-62.
[22] Green AR ,Shuaib A. Therapeutic strategies for the treatment of stroke[J]. Drug Discov Today, 2006,11(15/16):681-693.
[23] Thiyagarajan M,Kaul CL ,Sharma SS. Neuroprotective efficacy and therapeutic time window of peroxynitrite decomposition catalysts in focal cerebral ischemia in rats[J]. Br J Pharmacol, 2004,142(5):899-911.
[24] Sheng H, Enghild JJ, Bowler R,et al. Effects of metalloporphyrin catalytic antioxidants in experimental brain ischemia[J]. Free Radic Biol Med, 2002,33(7):947-961.
[25] Tsubokawa T, Jadhav V, Solaroglu I,et al. Lecithinized superoxide dismutase improves outcomes and attenuates focal cerebral ischemic injury via antiapoptotic mechanisms in rats[J]. Stroke, 2007,38(3):1057-1062.
[26] Reddy MK ,Labhasetwar V. Nanoparticle-mediated delivery of superoxide dismutase to the brain: an effective strategy to reduce ischemia-reperfusion injury[J]. FASEB J, 2009,23(5):1384-1395.
[27] Chen TY, Lee MY, Chen HY,et al. Melatonin attenuates the postischemic increase in blood-brain barrier permeability and decreases hemorrhagic transformation of tissue-plasminogen activator therapy following ischemic stroke in mice[J]. J Pineal Res, 2006,40(3):242-250.
[28] Lin HW,Lee EJ. Effects of melatonin in experimental stroke models in acute, sub-acute, and chronic stages[J]. Neuropsychiatr Dis Treat, 2009,5:157-162.
[29] Kilic E, Kilic U, Reiter RJ,et al. Prophylactic use of melatonin protects against focal cerebral ischemia in mice: role of endothelin converting enzyme-1[J]. J Pineal Res, 2004,37(4):247-251.
[30] Tai SH, Hung YC, Lee EJ,et al. Melatonin protects against transient focal cerebral ischemia in both reproductively active and estrogen-deficient female rats: the impact of circulating estrogen on its hormetic dose-response[J]. J Pineal Res, 2011,50(3):292-303.
[31] Prokai L,Prokai-Tatrai K, Perjesi P,et al. Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection[J]. Proc Natl Acad Sci U S A, 2003,100(20):11741-11746.
[32] Wang MG, Li CS, Gao CJ,et al. [The therapeutic effect of small dose of estrogen on cerebral infarction] [J]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue, 2008,20(11):671-673.
[33] Raval AP, Hirsch N, Dave KR,et al. Nicotine and estrogen synergistically exacerbate cerebral ischemic injury[J]. Neuroscience, 2011 Feb 18. [Epub ahead of print]
[34] Jamieson DG ,Skliut M. Gender considerations in stroke management[J]. Neurologist, 2009,15(3):132-141.
[35] Taipei Medical University WanFang Hospital.Polymorphism of Estrogen Genes in Stroke[EB/OL].2010; Available from: http://www.clinicaltrials.gov/ct2/.
[36] Chamorro A, Planas AM, Muner DS,et al. Uric acid administration for neuroprotection in patients with acute brain ischemia[J]. Med Hypotheses, 2004,62(2):173-176.
[37] Romanos E, Planas AM, Amaro S,et al. Uric acid reduces brain damage and improves the benefits of rt-PA in a rat model of thromboembolic stroke[J]. J Cereb Blood Flow Metab, 2007,27(1):14-20.
[38] Amaro S, Soy D, Obach V,et al. A pilot study of dual treatment with recombinant tissue plasminogen activator and uric acid in acute ischemic stroke[J]. Stroke, 2007,38(7):2173-2175.
[39] Fundacion Clinic per a la Recerca Biomédica .Efficacy Study of Combined Treatment With Uric Acid and rtPA in Acute Ischemic Stroke (Urico-Ictus) [EB/OL].2009; Available from: http://www.clinicaltrials.gov/ct2/.
[40] Harrison FE ,May JM. Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2[J]. Free Radic Biol Med, 2009,46(6):719-730.
[41] Ersahin M, Toklu HZ, Cetinel S,et al. Alpha lipoic acid alleviates oxidative stress and preserves blood brain permeability in rats with subarachnoid hemorrhage[J]. Neurochem Res, 2009,35(3):418-428.
[42] Packer L,Tritschler HJ ,Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid[J]. Free Radic Biol Med, 1997,22(1/2):359-378.
[43] Zhang S, Liu Y, Zhao Z,et al. Effects of green tea polyphenols on caveolin-1 of microvessel fragments in rats with cerebral ischemia[J]. Neurol Res, 2010,32(9):963-970.
[44] 高平章,吴洪,黄俊来. 黄芩中黄酮类成分在组织损伤中抗氧化作用的研究进展[J]. 海峡药学, 2009,21(6):1-4.
[45] 刘畅,闽连秋,季占胜. 丹参对局灶性脑缺血大鼠氧化应激反应的保护效应[J]. 中国临床康复, 2006,10(3):37-39.
[46] Kuang P,Tao Y,Tian Y. Effect of radix Salviae miltiorrhizae on nitric oxide in cerebral ischemic-reperfusion injury[J]. J Tradit Chin Med, 1996,16(3):224-227.
[47] Rong ZT, Gong XJ, Sun HB,et al. Protective effects of oleanolic acid on cerebral ischemic damage in vivo and H(2)O(2)-induced injury in vitro[J]. Pharm Biol, 2010 Aug 5. [Epub ahead of print]
[48] Shin JA, Lee H, Lim YK,et al. Therapeutic effects of resveratrol during acute periods following experimental ischemic stroke[J]. J Neuroimmunol, 2011,227(1/2):93-100.
[49] 马宏跃, 李伟霞, 尚尔鑫,等. 基于抗氧化活性的不同制法当归-川芎药对配伍比例研究[J]. 中国临床药理学与治疗学, 2010,15(6): 631-635.
[50] 顾兵, 程翔, 金建波,等. 脑缺血动物模型及其实验治疗学应用[J]. 中国临床药理学与治疗学, 2010, 15(9) : 1074-1080.
[51] Evenson KR, Foraker RE, Morris DL,et al. A comprehensive review of prehospital and in-hospital delay times in acute stroke care[J]. Int J Stroke, 2009,4(3):187-199.