Annals of Clinical and Experimental NeurologyAnnals of Clinical and Experimental NeurologyАнналы клинической и экспериментальной неврологии2075-54732409-2533Eco-Vector15410.17816/psaic154ReviewsОбзорыUnknownNeuroprotection in cerebrovascular diseases: is it the search for life on Mars or a promising trend of treatment? Part 1. Acute strokeНейропротекция при цереброваскулярных заболеваниях: поиск жизни на Марсе или перспективное направление лечения? Часть 1. Острые нарушения мозгового кровообращениhttps://orcid.org/0000-0002-6338-0392PiradovMikhail A.ПирадовМихаил Александрович
Russian Federation

D. Sci. (Med.), Professor, Full Member of the Russian Academy of Sciences, Director

д.м.н., проф., академик РАН, директор

ncnmaximova@mail.ruhttps://orcid.org/0000-0002-5883-8119TanashyanMarine M.ТанашянМаринэ Мовсесовна
Russian Federation

D. Sci. (Med.), Prof., Corresponding member of RAS, Deputy Director for science, Head, 1st Neurological department

д.м.н., профессор, член-корреспондент РАН, зам. директора по научной работе, рук. 1-го неврологического отделения

ncnmaximova@mail.ruDomashenkoM. A.ДомашенкоM. A.
Russian Federation
ncnmaximova@mail.ruhttps://orcid.org/0000-0002-9130-1292SergeevDmitry V.СергеевДмитрий Владимирович
Russian Federation

Cand. Sci. (Med.), neurologist, Neurorehabilitation department with TMS group

к.м.н., врач-невролог отд. анестезиологии-реанимации с палатами реанимации и интенсивной терапии

ncnmaximova@mail.ruhttps://orcid.org/0000-0002-7682-6672MaksimovaMarina Yu.МаксимоваМарина Юрьевна
Russian Federation

D. Sci. (Med), Prof., Head, 2nd Neurology department

д.м.н., профессор, руководитель 2-го неврологического отделения

ncnmaximova@mail.ruResearch Center of NeurologyФГБНУ «Научный центр неврологии»1003201591415001022017Copyright ©; 2015, Piradov M.A., Tanashyan M.M., Domashenko M.A., Sergeev D.V., Maksimova M.Y.Copyright ©; 2015, Piradov M.A., Tanashyan M.M., Domashenko M.A., Sergeev D.V., Maksimova M.Y.2015Piradov M.A., Tanashyan M.M., Domashenko M.A., Sergeev D.V., Maksimova M.Y.Piradov M.A., Tanashyan M.M., Domashenko M.A., Sergeev D.V., Maksimova M.Y.https://creativecommons.org/licenses/by/4.0https://annaly-nevrologii.com/pathID/article/view/154

The two key strategies of specific treatment of stroke are reperfusion, aimed on the improvement of brain perfusion in the ischemic region due to the restoration of blood flow and prevention of recurrent thrombosis, and neuroprotection to maintain brain tissue metabolism and to protect it from structural damage. The evidential base of major neuroprotective drugs (nimodipine, magnesium sulfate, piracetam, ethylmethylhydroxypyridine succinate, choline alfoscerate, cerebrolysin, albumin, citicoline, edaravone) and hypothermia use in acute stroke setting is critically reviewed in the article.

Двумя стратегическими направлениями специфической терапии инсульта являются реперфузия, т.е. улучшение кровоснабжения области ишемии головного мозга за счет восстановления мозгового кровотока и профилактики тромбообразования, и нейропротекция – поддержание метаболизма ткани мозга и защита ее от структурных изменений. В статье представлен критический обзор основных нейропротекторных препаратов (нимодипин, магния сульфат, пирацетам, этилметилгидроксипиридина сукцинат, холина альфосцерат, церебролизин, альбумин, цитиколин, эдаравон), а также гипотермии, применяемых в остром периоде инсульта, с позиций доказательной медицины.

strokeneuroprotectionevidence-based medicineинсультнейропротекциядоказательная медицинаБолезни и врожденные аномалии системы кровообращения. Под ред. Л.А. Бокерия, Р.Г. Гудковой. М.: НЦССХ им. А.Н. Бакулева РАМН, 2011.Варакин Ю.Я. Эпидемиологические аспекты профилактики нарушений мозгового кровообращения. Атмосфера. Нервные болезни. 2005; 2: 4–10.Верещагин Н.В., Варакин Ю.Я. Регистры инсульта в России: результаты и методологические основы проблемы. Журн. неврол. и психиатр. им. С.С. Корсакова (приложение «Инсульт»). 2001; 1:34–40.Гусев Е.И. Проблема инсульта в России. Журн. неврол. и психиатр. им. С.С. Корсакова (приложение «Инсульт»). 2003; 9: 3–10.Доклад ВОЗ. Информационный бюллетень N 310, июль 2013;www.who.intДомашенко М.А., Максимова М.Ю., Сергеев Д.В., Пирадов М.А.Цитиколин в лечении ишемических нарушений мозгового кровообращения. Русск. медиц. журн. 2013; 30: 1540–1542.Инсульт: диагностика, лечение, профилактика. Под ред. З.А. Суслиной, М.А. Пирадова. М.: МЕДпресс-информ, 2008.Исмагилов М.Ф., Василевская О.В., Гайфутдинов Р.Т. и др. Оценка эффективности церетона в остром периоде ишемического инсульта. Журнал неврологии и психиатрии им. С.С. Корсакова, 2009; 3: 35–36.Луцкий М.А. Анализ эффективности мексидола в комплексном лечении больных с ишемическим инсультом. Журн. неврол. и психиатр. им. С.С. Корсакова, 2010; 4: 57–59.Одинак М.М., Вознюк И.А., Пирадов М.А. и др. Многоцентровое (пилотное) исследование эффективности глиатилина при остром ишемическом инсульте. Анн. клинич. и эксперим. неврол., 2010;1: 20–28.Пирадов М.А., Сергеев Д.В., Кротенкова М.В. Применение цераксона в остром периоде полушарного ишемического инсульта: клиническая и КТ-перфузионная оценка. Анн. клинич. и эксперим. неврол. 2012; 3: 31–36.Румянцева С.А., Евсеев В.Н., Елисеев Е.В. Антиоксидантная терапия при остром ишемическом инсульте. Атмосфера. Нервные болезни. 2009; 3: 8–12.Сергеев Д.В., Пирадов М.А. Цитиколин в лечении ишемического инсульта – новые доказательства эффективности. Русск. медиц. журн. 2012; 31: 1552–1554.Скворцова В.И., Стаховская Л.В., Нарциссов Я.Р. и др. Рандомизированное двойное слепое плацебо-контролируемое исследование эффективности и безопасности мексидола в комплексной терапии ишемического инсульта в остром периоде. Инсульт. Приложение к Журн. неврол. и психиатр. им. С.С. Корсакова, 2006;18: 47–54.Стародубцева О.С., Бегичева С.В. Анализ заболеваемости инсультом с использованием информационных технологий. Фундамент. иссл. 2012; 8 (2): 424–427.Alberts M.J. Secondary prevention of stroke and the expanding role of the neurologist. Cerebrovascular Diseases. 2002; 13 (Suppl 1): 12–16.Amaro S., Cánovas D., Castellanos M. et al. The URICO-ICTUS study, a phase 3 study of combined treatment with uric acid and rtPA administered intravenously in acute ischaemic stroke patients within the first 4.5 h of onset of symptoms. Int J Stroke, 2010; 5(4): 325–328.Barbagallo Sangiorgi G., Barbagallo M., Giordano M. et al. alphaGlycerophosphocholine in the mental recovery of cerebral ischemic attacks. An Italian multicenter clinical trial. Ann N Y Acad Sci. 1994;717: 253–269.Belayev L., Liu Y., Zhao V. et al. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke, 2001; 32: 553–560.Bernard S.A., Gray T.W., Buist M.D. et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med, 2002; 346: 557–563.Bravata D.M., Ho S.Y., Brass L.M. et al. Long-term mortaliry in cerebrovascular disease. Stroke. 2003; 34: 699–704.Bustamante A., Giralt D., Garcia-Bonilla L. et al. Citicoline in preclinical animal models of stroke: a meta-analysis shows the optimal neuroprotective profile and the missing steps for jumping into a stroke clinical trial. J Neurochem. 2012; 123(2): 217–225.CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. Lancet. 1997; 349: 1641–1649.Chavez J.C., Hurko O., Barone F.C. et al. Pharmacologic innterventions for stroke: looking beyond the thrombolysis time window into the penumbra with biomarkers, not a stopwatch. Stroke, 2009; 40 (10): e558–563.Clark W.M., Warach S.J., Pettigrew L.C. et al. A randomized doseresponse trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Neurology, 1997; 49 (3): 671–678.Clark W.M., Wechsler L.R., Sabounjian L.A. et al. A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients. Neurology, 2001; 57(9): 1595–1602.Clark W.M., Williams B.J., Selzer K.A. et al. A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke, 1999;30 (12): 2592–2597.Dávalos A., Alvarez-Sabín 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: 349–357.Dávalos A., Castillo J., Álvarez-Sabín J. et al. Oral Citicoline in Acute Ischemic Stroke: An Individual Patient Data Pooling Analysis of Clinical Trials. Stroke, 2002; 33: 2850–2857.De Deyn P.P., Reuck J.D., Deberdt W. et al. Treatment of acute ischemic stroke with piracetam. Members of the Piracetam in Acute Stroke Study (PASS) Group. Stroke, 1997; 28: 2347–2352.De Georgia M.A., Krieger D. W., Abou-Chebl A. et al. Cooling for Acute Ischemic Brain Damage (COOL AID): a feasibility trial of endovascular cooling. Neurology, 2004; 63: 312–317.Donnan G.A., Davis S. M. Parsons M.W. et al. How to make better use of thrombolytic therapy in acute ischemic stroke. Nat. Rev. Neurol. 2011; 7(7): 400–409.Edaravone Acute Brain Infarction Study Group. Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Cerebrovascular Diseases 2003; 15: 222–229.Feng S., Yang Q., Liu M. et al. Edaravone for acute ischaemic stroke (Review) Cochrane Database of Systematic Reviews 2011, Issue 12. CD007230.Feuerstein G.Z., Chavez J. Translational Medicine for Stroke Drug Discovery: The Pharmaceutical Industry Perspective. Stroke, 2009; 40: S121–125.Froehler M.T., Ovbiagele B. Therapeutic hypothermia for acute ischemic stroke. Expert Rev. Cardiovasc. Ther. 2010; 8 (4): 593–603.Furlan A., Higashida R., Wechsler L. et al. Intra-arterial prourokinase for acute ischemic stroke: the PROACT II study: a randomized controlled trial: Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999; 282: 2003–2011.Ginsberg M.D. Current Status of Neuroprotection for Cerebral Ischemia. Synoptic Overview. Stroke, 2009; 40: S111–114.Ginsberg M.D. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology. 2008; 55 (3): 363–369.Ginsberg M.D., Palesch Y.Y., Hill M.D. et al. High-dose albumin treatment for acute ischaemic stroke (ALIAS) part 2: a randomized, double-blind, phase 3, placebo-controlled trial. The Lancet Neurology, 2013; 12 (11): 1049–1058.Ginsberg M.D., Palesch Y.Y., Martin R.H. et al. The albumin in acute stroke (ALIAS) multicenter clinical trial: safety analysis of part 1 and rationale and design of part 2. Stroke, 2011; 42 (1): 119–127.Goas J.Y., Bastard J., Missoune A. Bilan а 90 jours du traitement des accidents vasculaires par la CDP–choline. Symposium International: Paris, 1980.Green A.R., Ashwood T. Free radical trapping as a therapeutic approach to neuroprotection in stroke: experimental and clinical studies with NXY-059 and free radical scavengers. Current Drug Targets. CNS and Neurological Disorders 2005; 4 (2): 109–118.Green A.R., Odergren T., Ashwood T. Animal models of stroke:do they have value for discovering neuroprotective agents. Trends Pharmacol Sci, 2003; 24: 402–408.Guidelines for Management of Ischaemic Stroke of the European Stroke Organisation, 2008 http://www.eso-stroke.org/recommendationsGuluma K.Z., Hemmen T.M., Olsen S.E. et al. A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology. Acad. Emerg. Med, 2006; 13: 820–827.Heiss W.-D., Brainin M., Bornstein N.M. et al. Cerebrolysin in patients with acute ischemic stroke in Asia: results of a double-blind, placebo-controlled randomized trial. Stroke, 2012; 43: 630–636.Hemmen T.M., Raman R., Guluma K.Z. et al. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke, 2010; 41(10): 2265–2270.Hong Z. The clinical efficacy of Cerebrolysin in the treatment of acute ischemic stroke. Chin J Geriatr Heart Brain Vessel Dis. 2005; 7:331–333.Hong Z., Moessler H., Bornstein N. et al. A double-blind, placebocontrolled, randomized trial to evaluate the safety and efficacy of Cerebrolysin in patients with acute ischaemic stroke in Asia-CASTA. Int J Stroke, 2009; 4 (5): 406–441.Horn J., de Haan R.J., Vermeulen M., Limburg M. Very early Nimodipine use in stroke (VENUS): a randomized, double-blinde, placebo-controlled trial. Stroke. 2001; 32: 461–465.International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet. 1997; 349: 1569–1581.Jauch E.C., Saver J.L., Adams H.P. et al. et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke A Guideline for Healthcare Professionals From the American Heart Association/ American Stroke Association. Stroke. 2013; 44: published online January 31, 2013.Kammersgaard L.P., Rasmussen B. H., Jørgensen H.S. et al. Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: A case-control study: the Copenhagen Stroke Study. Stroke, 2000; 31: 2251–2256.Ladurner G., Kalvach P., Moessler H. et al. Neuroprotective treatment with cerebrolysin in patients with acute stroke: a randomised controlled trial. J Neural Transm, 2005; 112: 415–428.Lees K.R., Zivin J.A., Ashwood T. et al. NXY-059 for acute ischemic stroke. N. Engl. J. Med, 2006; 354: 588–600.Logallo N., Naess H., Idicula T.T. et al. Serum uric acid: neuroprotection in thrombolysis. The Bergen NORSTROKE study. BMC Neurol, 2011; 11: 114.Lopez A.D., Mathers C.D., Ezzati M. et al. Global and regional burden of disease and risk factors, 2001: Systematic analysis of population health data. Lancet. 2006; 367: 1747–1757.Lu M. Assessing combination treatments in acute stroke: preclinical experiences. Behav Brain Res, 2005; 162 (2): 165–172.Martínez-Vila E., Sieira P. Current status and perspectives of neuroprotection in ischemic stroke treatment. Cerebrovasc Dis, 2001;11 (Suppl 1): 60–70.Mohr J.P., Orgogozo J.M., Harrison M.J.G. et al. Meta-analysis of oral Nimodipine trials in acute ishemic stroke. Cerebrovasc Dis 1994;4: 197–203.Muir K.W., Ford I., Reid J.L. et al. Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial. Lancet, 2004; 363: 439–445.Muller W.E., Müller W.E., Eckert G.P. et al. Piracetam: novelty in a unique mode of action. Pharmacopsychiatry, 1999; 32: 2–9.National Institute of Neurological Disorders and Stroke.Interventional Management of Stroke III Trial (IMS III). http://www.ninds.nih.gov/disorders/clinical_trials/ NCT00359424.htm. Accessed September 12, 2012.Nogueira R., Lutsep H.L., Gupta R. et al. Trevo versus Merci retrievers for thrombectomy revascularization of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomized trial. Lancet 2012; 380:1231–1240.O’Collins V.E., Macleod M.R., Donnan G.A. et al. 1026 experimental treatments in acute stroke. Ann. Neurol, 2006; 59: 467–477.Overgaard K. The effects of citicoline on acute ischemic stroke: a review. Journal of Stroke and Cerebrovasc Dis, 2014; 23 (7): 1764–1769.Ovbiagele B., Kidwell C.S., Starkman S. et al. Neuroprotective agents for the treatment of acute ischemic stroke. Curr. Neurol. Neurosci. Rep, 2003; 3: 9–20.Parnetti L., Amenta F., Gallai V. Choline alphoscerate in cognitive decline and in acute cerebrovascular disease: an analysis of published clinical data. Mech Ageing Dev, 2001; 122: 2041–2055.Philip M., Benatar M., Fisher M. et al. Methodological quality of animal studies of neuroprotective agents currently in phase II/III acute ischemic stroke trials. Stroke, 2009; 40(2): 577–581.Ren J.M., Sietsma D., Qiu S. et al. Cerebrolysin enhances functional recovery following focal cerebral infarction in rats. Restor Neurol Neurosci, 2007; 25: 25–31.Saver J., Jahan R., Levy E.I. et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet. 2012; 380: 1241–1249.Saver J.L., Starkman S., Eckstein M. et al. for the FAST-MAG Investigators. Prehospital Use of Magnesium Sulfate as Neuroprotection in Acute Stroke. N Engl J Med 2015; 372: 528–536.Saver J.L., Wilterdink J. Choline precursors in acute and subacute human stroke: a meta-analysis. Stroke 2002; 33: 353.Savitz S.I., Fisher M. Future of neuroprotection for acute stroke: in the aftermath of the SAINT trials. Ann Neurol, 2007; 61(5): 396–402.Shuaib A., Lees K.R., Lyden P. et al. NXY-059 for the treatment of acute ischemic stroke. N. Engl. J. Med. 2007; 357: 562–571.Skvortsova V.I., Stakhovskaya L.V., Shamalov N.A. et al. Results of implementation of intravenous thrombolysis in stroke patients in the Russian Federation in 2009-2010: Data of hospital registry. Cerebrovasc Dis 2011; 31 (suppl 2): 48.Smith W., Sung G., Saver J. et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008; 39: 1205–1212.Smith W., Sung G., Starkman S. et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005; 36: 1432–1438Stroke Therapy Academic Industry Roundtable. Recommendations for standards regarding pre-clinical neuroprotective and restorative drug development. Stroke, 1999; 30: 2752–2758.Stroke Therapy Academic Industry Roundtable II. Stroke Therapy Academic Industry Roundtable II (STAIR-II). Stroke, 2001; 32: 1598–1606.Sutherland B.A., Papadakis M., Chen R.-L. et al. Cerebral blood flow alteration in neuroprotection following cerebral ischaemia. J Physiol, 2011; 589: 4105–4114.Tatebayashi Y., Lee M.H., Li L. et al. The dentate gyrus neurogenesis: a therapeutic target for Alzheimer’s disease. ActaNeuropathol, 2003;105: 225–232.Tazaki Y., Sakai F., Otomo E. et al. Treatment of acute cerebral infarction with a choline precursor in a multicenter double-blind placebo-controlled study. Stroke, 1988; 19: 211–216.The Penumbra Pivotal Stroke Trial Investigators. The Penumbra Pivotal Stroke Trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke 2009; 40: 2761–2768.Van der Worp H.B., Macleod M. R., Kollmar R. Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials? J Cereb Blood Flow Metab, 2010; 30 (6): 1079–1093.Watanabe T., Yuki S., Egawa M., Nishi H. Protective effects of MCI-186 on cerebral ischemia: possible involvement of free radical scavenging and antioxidant actions. Journal of Pharmacology and Experimental Therapeutics 1994; 268 (3): 1597–1604.Winblad B. Piracetam: a review of pharmacological properties and clinical uses. CNS. Drug Rev, 2005; 11: 169–182.Woessner R., Treib J. Ischemic or hemorrhagic stroke? Rapid diagnosis improves prognosis for the patient. MMW Fortschr. Med. 2002; 144: 24–28.Wronski R., Tompa P., Hutter-Paier B. et al. Inhibitory effect of a brain derived peptide preparation on the Ca-dependent protease, calpain. J Neural Transm, 2000; 107: 145–157. www.strokecenter.orgYamamoto T., Yuki S., Watanabe T. et al. Delayed neuronal death prevented by inhibition of increased hydroxyl radical formation in a transient cerebral ischemia. Brain Research 1997; 762 (1-2): 240–242.Zhang M. Efficacy and safety evaluation of edaravone injection in treatment of acute cerebral infarction: a multicenter, double-blind, and randomized controlled clinical trial. Chinese Journal of New Drugs and Clinical Remedies 2007; 26 (2): 105–108.Zhou M., Yang J., He L. Randomized controlled trial of edaravone injection in the treatment of acute cerebral infarction. Modern Preventive Medicine 2007; 34: 966–968.Ziganshina L.E., Abakumova T., Kuchaeva A. Cerebrolysin for acute ischaemic stroke. Cochrane Database Syst. Rev, 2010 (4): CD007026.