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Reviews

Small molecule inhibitors in the treatment of cerebral ischemia

, BS, , MS, , BS, , MD PhD, , MD PhD & , MD PhD

Bibliography

  • Kanekar SG, Zacharia T, Roller R. Imaging of stroke: part 2, pathophysiology at the molecular and cellular levels and corresponding imaging changes. AJR Am J Roentgenol 2012;198:63-74
  • Pires PW, Dams Ramos CM, Matin N, et al. The effects of hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol 2013;304:H1598-614
  • Buchanan ID, James-Herry A, Osunkwo I. The other side of abnormal: a case series of low transcranial doppler velocities associated with stroke in children with sickle cell disease. J Pediatr Hematol Oncol 2013;35(7):543-6
  • Winters A, Taylor JC, Ren M, et al. Transient focal cerebral ischemia induces long-term cerebral vasculature dysfunction in a rodent experimental stroke model. Transl Stroke Res 2012;3:279-85
  • Terpolilli NA, Kim SW, Thal SC, et al. Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles. Circ Res 2012;110:727-38
  • Turner RC, Lucke-Wold B, Lucke-Wold N, et al. Neuroprotection for ischemic stroke: moving past shortcomings and identifying promising directions. Int J Mol Sci 2013;14:1890-917
  • Montaner J, Mendioroz M, Ribo M, et al. A panel of biomarkers including caspase-3 and D-dimer may differentiate acute stroke from stroke-mimicking conditions in the emergency department. J Intern Med 2011;270:166-74
  • Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-29
  • Bond LM, Tumbarello DA, Kendrick-Jones J, et al. Small-molecule inhibitors of myosin proteins. Future Med Chem 2013;5:41-52
  • Dougherty T. Handbook of antibiotic discovery and development. 2012 edtion. Springer, 2011
  • Broussalis E, Trinka E, Killer M, et al. Current therapies in ischemic stroke. Part B. Future candidates in stroke therapy and experimental studies. Drug Discov Today 2012;17:671-84
  • Xu SY, Pan SY. The failure of animal models of neuroprotection in acute ischemic stroke to translate to clinical efficacy. Med Sci Monit Basic Res 2013;19:37-45
  • Jerry B, Lefkowitz M. Coagulation pathway and physiology. In: Kottke-Marchant K, editor, An algorithmic approach to hemostasis testing. CAP Press, Northfield, IL; 2008. p. 3-12
  • Sinauridze EI, Panteleev MA, Ataullakhanov FI. Anticoagulant therapy: basic principles, classic approaches and recent developments. Blood Coagul Fibrinolysis 2012;23:482-93
  • Mayer SA. Ultra-early hemostatic therapy for intracerebral hemorrhage. Stroke 2003;34:224-9
  • Zhang JH, Badaut J, Tang J, et al. The vascular neural network–a new paradigm in stroke pathophysiology. Nat Rev Neurol 2012;8:711-16
  • Finn AV, Nakano M, Narula J, et al. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 2010;30:1282-92
  • Didangelos A, Simper D, Monaco C, et al. Proteomics of acute coronary syndromes. Curr Atheroscler Rep 2009;11:188-95
  • Elkind MS. Inflammatory mechanisms of stroke. Stroke 2010;41:S3-8
  • Del Bene A, Palumbo V, Lamassa M, et al. Progressive lacunar stroke: review of mechanisms, prognostic features, and putative treatments. Int J Stroke 2012;7:321-9
  • Wilke T, Groth A, Mueller S, et al. Incidence and prevalence of atrial fibrillation: an analysis based on 8.3 million patients. Europace 2013;15:486-93
  • Savage N. Physiology: beating stroke. Nature 2013;493:S12-13
  • Le Heuzey JY. Antithrombotic treatment of atrial fibrillation: new insights. Thromb Res 2012;130(Suppl 1):S59-60
  • Stemer A, Lyden P. Evolution of the thrombolytic treatment window for acute ischemic stroke. Curr Neurol Neurosci Rep 2010;10:29-33
  • Keric N, Maier GS, Samadani U, et al. Tissue plasminogen activator induced delayed edema in experimental porcine intracranial hemorrhage: reduction with plasminogen activator inhibitor-1 administration. Transl Stroke Res 2012;3:88-93
  • Diener HC, Ringelstein EB, von Kummer R, et al. Treatment of acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the TOPAS trial. Therapy of Patients with Acute Stroke (TOPAS) Investigators. Stroke 2001;32:22-9
  • Eisert WG, Hauel N, Stangier J, et al. Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol 2010;30:1885-9
  • Boudes PF. The challenges of new drugs benefits and risks analysis: lessons from the ximelagatran FDA Cardiovascular Advisory Committee. Contemp Clin Trials 2006;27:432-40
  • Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51
  • Hart RG, Diener HC, Yang S, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke 2012;43:1511-17
  • Diener HC, Connolly SJ, Ezekowitz MD, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol 2010;9:1157-63
  • Butcher K. Dabigatran treatment following transient ischemic attack and Minor stroke (DATAS). 2012. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01769703?term=Dabigatran+Treatment+Following+Transient+Ischemic+Attack+and+Minor+Stroke+%28DATAS%29&rank=1
  • David Haines M. Dabigatran versus warfarin anticoagulation before and after catheter ablation for the treatment of atrial fibrillation. 2012. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01607359?term=Dabigatran+stroke&rank=7
  • Eriksson BI, Borris LC, Dahl OE, et al. A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation 2006;114:2374-81
  • Piccini JP, Stevens SR, Lokhnygina Y, et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol 2013;61:1998-2006
  • Kansal AR, Zheng Y, Pokora T, et al. Cost-effectiveness of new oral anticoagulants in the prevention of stroke in patients with atrial fibrillation. Best Pract Res Clin Haematol 2013;26:225-37
  • Bayer. Non-interventional local study on prescription behavior of anticoagulation therapy in secondary stroke prevention in atrial fibrillation patients (NEURO-XAR). 2013. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01925755?term=Rivaroxaban+stroke&rank=3
  • Bayer. Satisfaction/quality of life with rivaroxaban in SPAF (stroke prevention in atrial fibrillation) indication (SAFARI). 2013. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01805531?term=Rivaroxaban+stroke&rank=6
  • Gonsalves WI, Pruthi RK, Patnaik MM. The new oral anticoagulants in clinical practice. Mayo Clin Proc Mayo Clin 2013;88:495-511
  • Flaker GC, Eikelboom JW, Shestakovska O, et al. Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: the apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment (AVERROES) trial. Stroke 2012;43:3291-7
  • Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92
  • FDA. FDA approves Eliquis to reduce the risk of stroke, blood clots in patients with non-valvular atrial fibrillation. 2012. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333634.htm
  • Wolpert SM, Bruckmann H, Greenlee R, et al. Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. The rt-PA Acute Stroke Study Group. AJNR Am J Neuroradiol 1993;14:3-13
  • Pancioli AM, Brott TG. Therapeutic potential of platelet glycoprotein IIb/IIIa receptor antagonists in acute ischaemic stroke: scientific rationale and available evidence. CNS Drugs 2004;18:981-8
  • Choudhri TF, Hoh BL, Zerwes HG, et al. Reduced microvascular thrombosis and improved outcome in acute murine stroke by inhibiting GP IIb/IIIa receptor-mediated platelet aggregation. J Clin Invest 1998;102:1301-10
  • Abumiya T, Fitridge R, Mazur C, et al. Integrin alpha(IIb)beta(3) inhibitor preserves microvascular patency in experimental acute focal cerebral ischemia. Stroke 2000;31:1402-9; discussion 09-10
  • Ding G, Jiang Q, Zhang L, et al. Analysis of combined treatment of embolic stroke in rat with r-tPA and a GPIIb/IIIa inhibitor. J Cereb Blood Flow Metab 2005;25:87-97
  • Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II. Lancet 1997;349:1422-8
  • O'Shea JC, Hafley GE, Greenberg S, et al. Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial. JAMA 2001;285:2468-73
  • Tcheng JE, Harrington RA, Kottke-Marchant K, et al. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker Integrelin in elective coronary intervention. IMPACT Investigators. Circulation 1995;91:2151-7
  • Pancioli AM, Broderick J, Brott T, et al. The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: the CLEAR stroke trial. Stroke 2008;39:3268-76
  • Lowenberg EC, Meijers JC, Monia BP, et al. Coagulation factor XI as a novel target for antithrombotic treatment. J Thromb Haemost 2010;8:2349-57
  • Leung PY, Hurst S, Berny-Lang MA, et al. Inhibition of factor XII-mediated activation of factor XI provides protection against experimental acute ischemic stroke in mice. Transl Stroke Res 2012;3:381-9
  • Wong PC, Crain EJ, Watson CA, et al. A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits. J Thromb Thrombolysis 2011;32:129-37
  • Martin RL, Lloyd HG, Cowan AI. The early events of oxygen and glucose deprivation: setting the scene for neuronal death? Trends Neurosci 1994;17:251-7
  • Pradeep H, Diya JB, Shashikumar S, et al. Oxidative stress - assassin behind the ischemic stroke. Folia Neuropathol 2012;50:219-30
  • Onwuekwe I, Ezeala-Adikaibe B. Ischemic stroke and neuroprotection. Ann Med Health Sci Res 2012;2:186-90
  • Di Fabio R, Capelli AM, Conti N, et al. Substituted indole-2-carboxylates as in vivo potent antagonists acting as the strychnine-insensitive glycine binding site. J Med Chem 1997;40:841-50
  • Bordi F, Terron A, Reggiani A. The neuroprotective glycine receptor antagonist GV150526 does not produce neuronal vacuolization or cognitive deficits in rats. Eur J Pharmacol 1999;378:153-60
  • Bordi F, Pietra C, Ziviani L, et al. The glycine antagonist GV150526 protects somatosensory evoked potentials and reduces the infarct area in the MCAo model of focal ischemia in the rat. Exp Neurol 1997;145:425-33
  • Reggiani A, Pietra C, Arban R, et al. The neuroprotective activity of the glycine receptor antagonist GV150526: an in vivo study by magnetic resonance imaging. Eur J Pharmacol 2001;419:147-53
  • Dyker AG, Lees KR. Safety and tolerability of GV150526 (a glycine site antagonist at the N-methyl-D-aspartate receptor) in patients with acute stroke. Stroke 1999;30:986-92
  • The North American Glycine Antagonist in Neuroprotection (GAIN) Investigators. Phase II studies of the glycine antagonist GV150526 in acute stroke: the North American experience. Stroke 2000;31:358-65
  • Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 2008;55:363-89
  • Iseri LT, French JH. Magnesium: nature's physiologic calcium blocker. Am Heart J 1984;108:188-93
  • Altura BM, Altura BT, Carella A, et al. Mg2+-Ca2+ interaction in contractility of vascular smooth muscle: mg2+ versus organic calcium channel blockers on myogenic tone and agonist-induced responsiveness of blood vessels. Can J Physiol Pharmacol 1987;65:729-45
  • Yang Y, Li Q, Ahmad F, et al. Survival and histological evaluation of therapeutic window of post-ischemia treatment with magnesium sulfate in embolic stroke model of rat. Neurosci Lett 2000;285:119-22
  • Eriksson S, Osterman G, Asplund K, et al. Pulmonary-artery cineangiocardiography to demonstrate cardiac thrombi in patients with cerebral infarction. Acta Neurol Scand 1984;69:27-33
  • Woods KL, Fletcher S, Roffe C, et al. Intravenous magnesium sulphate in suspected acute myocardial infarction: results of the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet 1992;339:1553-8
  • Muir KW, Lees KR, Ford I, et al. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Lancet 2004;363:439-45
  • Aslanyan S, Weir CJ, Muir KW, et al. Magnesium for treatment of acute lacunar stroke syndromes: further analysis of the IMAGES trial. Stroke 2007;38:1269-73
  • Saver JL, Kidwell C, Eckstein M, et al. Prehospital neuroprotective therapy for acute stroke: results of the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) pilot trial. Stroke 2004;35:e106-8
  • Saver JL. Field administration of stroke therapy - magnesium (FAST-MAG) Trial. 12 Current December 2003. 2011. Available from: http://clinicaltrials.gov/ct2/show/NCT00059332?term=Magnesium+stroke&rank=1
  • Lockman JA, Geldenhuys WJ, Bohn KA, et al. Differential effect of nimodipine in attenuating iron-induced toxicity in brain- and blood-brain barrier-associated cell types. Neurochem Res 2012;37:134-42
  • Bekker A, Haile M, Li YS, et al. Nimodipine prevents memory impairment caused by nitroglycerin-induced hypotension in adult mice. Anesth Analg 2009;109:1943-8
  • Lindsay RW, Heaton JT, Edwards C, et al. Nimodipine and acceleration of functional recovery of the facial nerve after crush injury. Arch Facial Plast Surg 2010;12:49-52
  • Aslan A, Gurelik M, Cemek M, et al. Nimodipine can improve cerebral metabolism and outcome in patients with severe head trauma. Pharmacol Res 2009;59:120-4
  • Zhang XL, Zheng SL, Dong FR, et al. Nimodipine improves regional cerebral blood flow and suppresses inflammatory factors in the hippocampus of rats with vascular dementia. J Int Med Res 2012;40:1036-45
  • Choi SK, Lee GJ, Choi S, et al. Neuroprotective effects by nimodipine treatment in the experimental global ischemic rat model : real time estimation of glutamate. J Korean Neurosurg Soc 2011;49:1-7
  • Horn J, de Haan RJ, Vermeulen M, et al. Very early nimodipine use in stroke (VENUS): a randomized, double-blind, placebo-controlled trial. Stroke 2001;32:461-5
  • Ministry of Science and Technology of the People´s Republic of China. Efficacy and safety study of nimodipine to prevent mild cognitive impairment after acute ischemic strokes (NICE). 2010. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01220622?term=Nimodipine+stroke&rank=1
  • FDA. FDA approves Nymalize—first nimodipine oral solution for use in certain brain hemorrhage patients. 2013. Available from: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm352280.htm
  • Nacher J, Alonso-Llosa G, Rosell DR, et al. NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol Aging 2003;24:273-84
  • Hilmas C, Pereira EF, Alkondon M, et al. The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: physiopathological implications. J Neurosci 2001;21:7463-73
  • Mok MH, Fricker AC, Weil A, et al. Electrophysiological characterisation of the actions of kynurenic acid at ligand-gated ion channels. Neuropharmacology 2009;57:242-9
  • Stone TW. Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection. Trends Pharmacol Sci 2000;21:149-54
  • Borza I, Kolok S, Galgoczy K, et al. Kynurenic acid amides as novel NR2B selective NMDA receptor antagonists. Bioorg Med Chem Lett 2007;17:406-9
  • Vamos E, Pardutz A, Varga H, et al. l-kynurenine combined with probenecid and the novel synthetic kynurenic acid derivative attenuate nitroglycerin-induced nNOS in the rat caudal trigeminal nucleus. Neuropharmacology 2009;57:425-9
  • Gellert L, Fuzik J, Goblos A, et al. Neuroprotection with a new kynurenic acid analog in the four-vessel occlusion model of ischemia. Eur J Pharmacol 2011;667:182-7
  • Kilic U, Yilmaz B, Reiter RJ, et al. Effects of memantine and melatonin on signal transduction pathways vascular leakage and brain injury after focal cerebral ischemia in mice. Neuroscience 2013;237:268-76
  • Thomas SJ, Grossberg GT. Memantine: a review of studies into its safety and efficacy in treating Alzheimer's disease and other dementias. Clin Interv Aging 2009;4:367-77
  • Wroge CM, Hogins J, Eisenman L, et al. Synaptic NMDA receptors mediate hypoxic excitotoxic death. J Neurosci 2012;32:6732-42
  • Volbracht C, van Beek J, Zhu C, et al. Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity. Eur J Neurosci 2006;23:2611-22
  • Dijkhuizen RM, Knollema S, van der Worp HB, et al. Dynamics of cerebral tissue injury and perfusion after temporary hypoxia-ischemia in the rat: evidence for region-specific sensitivity and delayed damage. Stroke 1998;29:695-704
  • Kumral E, Evyapan D, Balkir K. Acute caudate vascular lesions. Stroke 1999;30:100-8
  • Caplan LR, Schmahmann JD, Kase CS, et al. Caudate infarcts. Arch Neurol 1990;47:133-43
  • Payabvash S, Souza LC, Wang Y, et al. Regional ischemic vulnerability of the brain to hypoperfusion: the need for location specific computed tomography perfusion thresholds in acute stroke patients. Stroke 2011;42:1255-60
  • Lancelot E, Callebert J, Plotkine M, et al. Striatal dopamine participates in glutamate-induced hydroxyl radical generation. Neuroreport 1995;6:1033-6
  • Gerriets T, Stolz E, Walberer M, et al. Neuroprotective effects of MK-801 in different rat stroke models for permanent middle cerebral artery occlusion: adverse effects of hypothalamic damage and strategies for its avoidance. Stroke 2003;34:2234-9
  • Gerasimov VD, Artemenko DP, Krishtal OA. Therapeutic time window for the neuroprotective action of MK-801 after decapitation ischemia: hippocampal slice data. Brain Res 2004;1017:92-7
  • Kluska MM, Witte OW, Bolz J, et al. Neurogenesis in the adult dentate gyrus after cortical infarcts: effects of infarct location, N-methyl-D-aspartate receptor blockade and anti-inflammatory treatment. Neuroscience 2005;135:723-35
  • Janac B, Selakovic V, Radenovic L. Temporal patterns of motor behavioural improvements by MK-801 in Mongolian gerbils submitted to different duration of global cerebral ischemia. Behav Brain Res 2008;194:72-8
  • Moyanova SG, Kortenska LV, Mitreva RG, et al. Multimodal assessment of neuroprotection applied to the use of MK-801 in the endothelin-1 model of transient focal brain ischemia. Brain Res 2007;1153:58-67
  • Selakovic V, Janac B, Radenovic L. MK-801 effect on regional cerebral oxidative stress rate induced by different duration of global ischemia in gerbils. Mol Cell Biochem 2010;342:35-50
  • Chauhan NK, Young AM, Gibson CL, et al. Inhibition of pre-ischeamic conditioning in the mouse caudate brain slice by NMDA- or adenosine A1 receptor antagonists. Eur J Pharmacol 2013;698:322-9
  • Breuer ME, Willems PH, Russel FG, et al. Modeling mitochondrial dysfunctions in the brain: from mice to men. J Inherit Metab Dis 2012;35:193-210
  • Namura S, Ooboshi H, Liu J, et al. Neuroprotection after cerebral ischemia. Ann NY Acad Sci 2013;1278:25-32
  • Niizuma K, Endo H, Chan PH. Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival. J Neurochem 2009;109(Suppl 1):133-8
  • Starkov AA, Fiskum G. Regulation of brain mitochondrial H2O2 production by membrane potential and NAD(P)H redox state. J Neurochem 2003;86:1101-7
  • Reed JC, Kroemer G. Mechanisms of mitochondrial membrane permeabilization. Cell Death Differ 2000;7:1145
  • Gunter TE, Yule DI, Gunter KK, et al. Calcium and mitochondria. FEBS Lett 2004;567:96-102
  • Sims NR, Muyderman H. Mitochondria, oxidative metabolism and cell death in stroke. Biochim Biophys Acta 2010;1802:80-91
  • Honda HM, Ping P. Mitochondrial permeability transition in cardiac cell injury and death. Cardiovasc Drugs Ther 2006;20:425-32
  • Sullivan PG, Rabchevsky AG, Waldmeier PC, et al. Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death? J Neurosci Res 2005;79:231-9
  • Christensen ME, Jansen ES, Sanchez W, et al. Flow cytometry based assays for the measurement of apoptosis-associated mitochondrial membrane depolarisation and cytochrome c release. Methods 2013;61:138-45
  • Srinivasula SM, Datta P, Fan XJ, et al. Molecular determinants of the caspase-promoting activity of Smac/DIABLO and its role in the death receptor pathway. J Biol Chem 2000;275:36152-7
  • Yamamoto Y, Yanagisawa M, Tak NW, et al. Repeated edaravone treatment reduces oxidative cell damage in rat brain induced by middle cerebral artery occlusion. Redox Rep 2009;14:251-8
  • Wang GH, Jiang ZL, Li YC, et al. Free-radical scavenger edaravone treatment confers neuroprotection against traumatic brain injury in rats. J Neurotrauma 2011;28:2123-34
  • Yuan WJ, Yasuhara T, Shingo T, et al. Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons. BMC Neurosci 2008;9:75
  • Mitsubishi Tanabe Pharma Corp. Edaravone-sodium ozagrel comparative post-marketing study on acute ischemic stroke. 9 December 2005. 2012. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00200356?term=Edaravone+stroke&rank=1
  • Mitta M, Goel D, Bansal KK, et al. Edaravone - citicoline comparative study in acute ischemic stroke (ECCS-AIS). J Assoc Physicians India 2012;60:36-8
  • Jiangsu Simcere Pharmaceutical Co., Ltd. Compound edaravone injection for acute ischemic stroke. 2013. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01929096?term=Edaravone&rank=6
  • Macleod MR, van der Worp HB, Sena ES, et al. Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is confounded by study quality. Stroke 2008;39:2824-9
  • Bath PM, Gray LJ, Bath AJ, et al. Effects of NXY-059 in experimental stroke: an individual animal meta-analysis. Br J Pharmacol 2009;157:1157-71
  • 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;34:2228-33
  • Han M, He QP, Yong G, et al. NXY-059, a nitrone with free radical trapping properties inhibits release of cytochrome c after focal cerebral ischemia. Cell Mol Biol (Noisy-le-grand) 2003;49:1249-52
  • Lees KR, Zivin JA, Ashwood T, et al. NXY-059 for acute ischemic stroke. N Engl J Med 2006;354:588-600
  • Shuaib A, Lees KR, Lyden P, et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med 2007;357:562-71
  • Sutherland BA, Minnerup J, Balami JS, et al. Neuroprotection for ischaemic stroke: translation from the bench to the bedside. Int J Stroke 2012;7:407-18
  • 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. Stroke 2008;39:1751-8
  • Bossy-Wetzel E, Barsoum MJ, Godzik A, et al. Mitochondrial fission in apoptosis, neurodegeneration and aging. Curr Opin Cell Biol 2003;15:706-16
  • Chen H, Chan DC. Emerging functions of mammalian mitochondrial fusion and fission. Hum Mol Genet 2005;14(Spec No. 2):R283-9
  • Karbowski M, Youle RJ. Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ 2003;10:870-80
  • Okamoto K, Shaw JM. Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu Rev Genet 2005;39:503-36
  • Smirnova E, Griparic L, Shurland DL, et al. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 2001;12:2245-56
  • Youle RJ, Karbowski M. Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol 2005;6:657-63
  • Yoon Y, Krueger EW, Oswald BJ, et al. The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol 2003;23:5409-20
  • Frank S, Gaume B, Bergmann-Leitner ES, et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 2001;1:515-25
  • Cassidy-Stone A, Chipuk JE, Ingerman E, et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 2008;14:193-204
  • Zhang N, Wang S, Li Y, et al. A selective inhibitor of Drp1, mdivi-1, acts against cerebral ischemia/reperfusion injury via an anti-apoptotic pathway in rats. Neurosci Lett 2013;535:104-9
  • Cohen P, Goedert M. GSK3 inhibitors: development and therapeutic potential. Nat Rev Drug Discov 2004;3:479-87
  • King MR, Anderson NJ, Guernsey LS, et al. Glycogen synthase kinase-3 inhibition prevents learning deficits in diabetic mice. J Neurosci Res 2013;91:506-14
  • Zhou X, Zhou J, Li X, et al. GSK-3beta inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury. Biochem Biophys Res Commun 2011;411:271-5
  • Kelly S, Zhao H, Hua Sun G, et al. Glycogen synthase kinase 3beta inhibitor Chir025 reduces neuronal death resulting from oxygen-glucose deprivation, glutamate excitotoxicity, and cerebral ischemia. Exp Neurol 2004;188:378-86
  • Watcharasit P, Thiantanawat A, Satayavivad J. GSK3 promotes arsenite-induced apoptosis via facilitation of mitochondria disruption. J Appl Toxicol 2008;28:466-74
  • Cuzzocrea S, Genovese T, Mazzon E, et al. Glycogen synthase kinase-3 beta inhibition reduces secondary damage in experimental spinal cord trauma. J Pharmacol Exp Ther 2006;318:79-89
  • Dugo L, Abdelrahman M, Murch O, et al. Glycogen synthase kinase-3beta inhibitors protect against the organ injury and dysfunction caused by hemorrhage and resuscitation. Shock 2006;25:485-91
  • Cuzzocrea S, Mazzon E, Esposito E, et al. Glycogen synthase kinase-3beta inhibition attenuates the development of ischaemia/reperfusion injury of the gut. Intensive Care Med 2007;33:880-93
  • Collino M, Thiemermann C, Mastrocola R, et al. Treatment with the glycogen synthase kinase-3beta inhibitor, TDZD-8, affects transient cerebral ischemia/reperfusion injury in the rat hippocampus. Shock 2008;30:299-307
  • Broughton BR, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke 2009;40:e331-9
  • Siow RC, Mann GE. Dietary isoflavones and vascular protection: activation of cellular antioxidant defenses by SERMs or hormesis? Mol Aspects Med 2010;31:468-77
  • Xu SZ, Zhong W, Ghavideldarestani M, et al. Multiple mechanisms of soy isoflavones against oxidative stress-induced endothelium injury. Free Radic Biol Med 2009;47:167-75
  • Qian Y, Guan T, Huang M, et al. Neuroprotection by the soy isoflavone, genistein, via inhibition of mitochondria-dependent apoptosis pathways and reactive oxygen induced-NF-kappaB activation in a cerebral ischemia mouse model. Neurochem Int 2012;60:759-67
  • Hsieh HM, Wu WM, Hu ML. Genistein attenuates D-galactose-induced oxidative damage through decreased reactive oxygen species and NF-kappaB binding activity in neuronal PC12 cells. Life Sci 2011;88:82-8
  • Liang HW, Qiu SF, Shen J, et al. Genistein attenuates oxidative stress and neuronal damage following transient global cerebral ischemia in rat hippocampus. Neurosci Lett 2008;438:116-20
  • Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med 2011;17:796-808
  • Macrez R, Ali C, Toutirais O, et al. Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol 2011;10:471-80
  • Ostrowski RP, Schulte RW, Nie Y, et al. Acute splenic irradiation reduces brain injury in the rat focal ischemic stroke model. Transl Stroke Res 2012;3:473-81
  • Jin R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 2010;87:779-89
  • Yilmaz G, Granger DN. Leukocyte recruitment and ischemic brain injury. Neuromolecular Med 2010;12:193-204
  • Mirabelli-Badenier M, Braunersreuther V, Lenglet S, et al. Pathophysiological role of inflammatory molecules in paediatric ischaemic brain injury. Eur J Clin Invest 2012;42:784-94
  • Jiang Q, Ewing JR, Chopp M. MRI of blood-brain barrier permeability in cerebral ischemia. Transl Stroke Res 2012;3:56-64
  • Green AR, Shuaib A. Therapeutic strategies for the treatment of stroke. Drug Discov Today 2006;11:681-93
  • Cho HJ, Kim YJ. Efficacy and safety of oral citicoline in acute ischemic stroke: drug surveillance study in 4,191 cases. Methods Find Exp Clin Pharmacol 2009;31:171-6
  • Trovarelli G, de Medio GE, Dorman RV, et al. Effect of cytidine diphosphate choline (CDP-choline) on ischemia-induced alterations of brain lipid in the gerbil. Neurochem Res 1981;6:821-33
  • Krupinski J, Ferrer I, Barrachina M, et al. CDP-choline reduces pro-caspase and cleaved caspase-3 expression, nuclear DNA fragmentation, and specific PARP-cleaved products of caspase activation following middle cerebral artery occlusion in the rat. Neuropharmacology 2002;42:846-54
  • Rao AM, Hatcher JF, Dempsey RJ. Does CDP-choline modulate phospholipase activities after transient forebrain ischemia? Brain Res 2001;893:268-72
  • Krupinski J, Slevin M, Badimon L. Citicoline inhibits MAP kinase signalling pathways after focal cerebral ischaemia. Neurochem Res 2005;30:1067-73
  • Davalos A, Secades J. Citicoline preclinical and clinical update 2009-2010. Stroke 2011;42:S36-9
  • Clark WM, Wechsler LR, Sabounjian LA, et al. A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients. Neurology 2001;57:1595-602
  • Davalos A, Alvarez-Sabin J, Castillo J, et al. Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet 2012;380:349-57
  • Kraft P, De Meyer SF, Kleinschnitz C. Next-generation antithrombotics in ischemic stroke: preclinical perspective on 'bleeding-free antithrombosis'. J Cereb Blood Flow Metab 2012;32:1831-40
  • Dyke HJ, Montana JG. Update on the therapeutic potential of PDE4 inhibitors. Expert Opin Investig Drugs 2002;11:1-13
  • Zhu J, Mix E, Winblad B. The antidepressant and antiinflammatory effects of rolipram in the central nervous system. CNS Drug Rev 2001;7:387-98
  • Nikulina E, Tidwell JL, Dai HN, et al. The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc Natl Acad Sci USA 2004;101:8786-90
  • Araki T, Kanai Y, Kato H, et al. Sequential alteration of [3H]rolipram binding in gerbil brain after transient cerebral ischemia. Brain Res Bull 1993;31:85-9
  • Kato H, Araki T, Murase K, et al. Alterations in [3H]MK-801, [3H]muscimol, [3H]cyclic AMP, and [3H]rolipram binding in the gerbil hippocampus following repeated ischemic insults. Neuroscience 1993;52:245-53
  • Kraft P, Schwarz T, Gob E, et al. The phosphodiesterase-4 inhibitor rolipram protects from ischemic stroke in mice by reducing blood-brain-barrier damage, inflammation and thrombosis. Exp Neurol 2013;247C:80-90
  • Dal Piaz V, Giovannoni MP. Phosphodiesterase 4 inhibitors, structurally unrelated to rolipram, as promising agents for the treatment of asthma and other pathologies. Eur J Med Chem 2000;35:463-80
  • Pages L, Gavalda A, Lehner MD. PDE4 inhibitors: a review of current developments (2005 - 2009). Expert Opin Ther Pat 2009;19:1501-19
  • Winerdal M, Winerdal ME, Kinn J, et al. Long lasting local and systemic inflammation after cerebral hypoxic ischemia in newborn mice. PLoS One 2012;7:e36422
  • Tu XK, Yang WZ, Shi SS, et al. 5-lipoxygenase inhibitor zileuton attenuates ischemic brain damage: involvement of matrix metalloproteinase 9. Neurol Res 2009;31:848-52
  • Tu XK, Yang WZ, Wang CH, et al. Zileuton reduces inflammatory reaction and brain damage following permanent cerebral ischemia in rats. Inflammation 2010;33:344-52
  • Jatana M, Giri S, Ansari MA, et al. Inhibition of NF-kappaB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia. J Neuroinflammation 2006;3:12
  • Kubavat AH, Khippal N, Tak S, et al. A randomized, comparative, multicentric clinical trial to assess the efficacy and safety of zileuton extended-release tablets with montelukast sodium tablets in patients suffering from chronic persistent asthma. Am J Ther 2013;20:154-62
  • Haddad M, Beray-Berthat V, Coqueran B, et al. Reduction of hemorrhagic transformation by PJ34, a poly(ADP-ribose)polymerase inhibitor, after permanent focal cerebral ischemia in mice. Eur J Pharmacol 2008;588:52-7
  • Hamby AM, Suh SW, Kauppinen TM, et al. Use of a poly(ADP-ribose) polymerase inhibitor to suppress inflammation and neuronal death after cerebral ischemia-reperfusion. Stroke 2007;38:632-6
  • Moroni F. Poly(ADP-ribose)polymerase 1 (PARP-1) and postischemic brain damage. Curr Opin Pharmacol 2008;8:96-103
  • Hassa PO, Hottiger MO. The functional role of poly(ADP-ribose)polymerase 1 as novel coactivator of NF-kappaB in inflammatory disorders. Cell Mol Life Sci 2002;59:1534-53
  • Chiarugi A, Moskowitz MA. Poly(ADP-ribose) polymerase-1 activity promotes NF-kappaB-driven transcription and microglial activation: implication for neurodegenerative disorders. J Neurochem 2003;85:306-17
  • Kauppinen TM, Suh SW, Berman AE, et al. Inhibition of poly(ADP-ribose) polymerase suppresses inflammation and promotes recovery after ischemic injury. J Cereb Blood Flow Metab 2009;29:820-9
  • Fisher M, Albers GW, Donnan GA, et al. Enhancing the development and approval of acute stroke therapies: stroke Therapy Academic Industry roundtable. Stroke 2005;36:1808-13
  • Landis SC, Amara SG, Asadullah K, et al. A call for transparent reporting to optimize the predictive value of preclinical research. Nature 2012;490:187-91
  • Bahjat FR, Gesuete R, Stenzel-Poore MP. Steps to translate preconditioning from basic research to the clinic. Transl Stroke Res 2013;4:89-103
  • Ibarrola D, Seegers H, Jaillard A, et al. The effect of eliprodil on the evolution of a focal cerebral ischaemia in vivo. Eur J Pharmacol 1998;352:29-35
  • Cho GS, Lee JC, Ju C, et al. N-Methyl-d-aspartate receptor antagonists memantine and MK-801 attenuate the cerebral infarct accelerated by intracorpus callosum injection of lipopolysaccharides. Neurosci Lett 2013;538:9-14
  • Kao TK, Ou YC, Raung SL, et al. Graptopetalum paraguayense E. Walther leaf extracts protect against brain injury in ischemic rats. Am J Chin Med 2010;38:495-516
  • Srinivasan K, Sharma SS. 3-Bromo-7-nitroindazole attenuates brain ischemic injury in diabetic stroke via inhibition of endoplasmic reticulum stress pathway involving CHOP. Life Sci 2012;90:154-60
  • ArunaDevi R, Ramteke VD, Kumar S, et al. Neuroprotective effect of s-methylisothiourea in transient focal cerebral ischemia in rat. Nitric Oxide 2010;22:1-10
  • Pancioli A. Study of the combination therapy of Rt-PA and eptifibatide to treat acute ischemic stroke (CLEAR-ER). 26 February 2009. 2013. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00894803?term=Study+of+the+Combination+Therapy+of+Rt-PA+and+Eptifibatide+to+Treat+Acute+Ischemic+Stroke+%28CLEAR-ER%29&rank=1
  • Johnson & Johnson Pharmaceutical Research & Development, L.L.C. An efficacy and safety study of rivaroxaban with warfarin for the prevention of stroke and non-central nervous system systemic embolism in patients with non-valvular atrial fibrillation. 22 January 2006. 2013. Availae from http://www.clinicaltrials.gov/ct2/show/NCT00403767?term=rivaroxaban+stroke&rank=1
  • AstraZeneca. Melagatran/ximelagatran versus enoxaparin for the prevention of venous thromboembolic events (EXTEND). 11 November 2005. 2010. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00206089?term=Melagatran%2FXimelagatran+Versus+Enoxaparin+for+the+Prevention+of+Venous+Thromboembolic+Events+%28EXTEND%29&rank=1
  • Saver JL. Field administration of stroke therapy - magnesium (FAST-MAG) Trial. 12 December 2013. 2011. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00059332?term=Field+Administration+of+Stroke+Therapy+-+Magnesium+%28FAST-MAG%29+Trial&rank=1
  • Albers GW, Goldstein LB, Hall D, et al. Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial. JAMA 2001;286:2673-82
  • Davis SM, Albers GW, Diener HC, et al. Termination of acute stroke studies involving selfotel treatment. ASSIST Steering Committed. Lancet 1997;349:32
  • Bath PM, Iddenden R, Bath FJ, et al. Tirilazad for acute ischaemic stroke. Cochrane Database Syst Rev 2001;CD002087
  • AstraZeneca. Safety and effectiveness of NXY-059 for the treatment of patients who have suffered from a stroke. 10 November 2003. 2010. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00119626?term=Safety+and+Effectiveness+of+NXY-059+for+the+Treatment+of+Patients+Who+Have+Suffered+From+a+Stroke.&rank=1
  • Ferrer Internacional S.A. ICTUS study: international citicoline trial on acute stroke. 19 June 2006. 2012. Available from: http://www.clinicaltrials.gov/ct2/show/NCT00331890?term=ICTUS+Study%3A+International+Citicoline+Trial+on+Acute+Stroke&rank=1

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