Изучение новых нейропротекторов на модели фокальной ишемии головного мозга тема диссертации и автореферата по ВАК РФ 03.00.13, кандидат биологических наук Силачёв, Денис Николаевич

  • Силачёв, Денис Николаевич
  • кандидат биологических науккандидат биологических наук
  • 2009, Москва
  • Специальность ВАК РФ03.00.13
  • Количество страниц 204
Силачёв, Денис Николаевич. Изучение новых нейропротекторов на модели фокальной ишемии головного мозга: дис. кандидат биологических наук: 03.00.13 - Физиология. Москва. 2009. 204 с.

Оглавление диссертации кандидат биологических наук Силачёв, Денис Николаевич

Список сокращений.

ВВЕДЕНИЕ.

ОБЗОР ЛИТЕРАТУРЫ.

Глава 1. Механизмы повреждения нейронов при ишемическом инсульте.

Нарушение мозгового кровообращения и повреждение нейронов.

Глутаматная эксайтотоксичность, роль ионов кальция в гибели клеток.

Некротические и апоптотические процессы при ишемии головного мозга.

Ацидоз.

Окислительный стресс.

Механизмы клеточной защиты от АФК и АФА в нервной ткани.

Глава 2. Фармакологическая коррекция последствий ишемии головного мозга.

Фармакологическая защита нейронов от деструктивного действия глутамата.

Нейропептиды.

Защита мозга от окислительного стресса.

Глава 3. Модели экспериментальной ишемии головного мозга.

Вид животных и их физиологическое состояние.

Выбор модели.

Модели, не требующие краниотомии.

Эмболическая модель.

Модель перекрытия средней мозговой артерии нитью.

Модель фототромбоза.

Инсульт, вызванный эндотелином-1.

Модели, включающие краниотомию.

Источники вариабельности.

Факторы, связанные с видом животного.

Факторы, связанные с видом модели.

Анестезия.

Глава 4. Поведенческие тесты для оценки неврологического дефицита после ишемии головного мозга.

С енсомоторные тесты.

Когнитивные тесты.

МАТЕРИАЛЫ И МЕТОДЫ ИССЛЕДОВАНИЯ.

Операция перекрытия средней мозговой артерии нитью.

Окраска срезов мозга 2,3,5-трифенилтетразолия хлоридом.

Магнитно-резонансная томография.

Определение объема инфаркта.

Изучаемые вещества.

Тест «Цилиндр».

Тест «Стимулирования конечностей».

Тест «Сужающаяся дорожка».

Приготовление гомогенатов ткани.

Определение концентрации белка.

Вестерн-блоттинг.

Статистическая обработка данных.

РЕЗУЛЬТАТЫ.

Часть 1. Моделирование фокальной ишемии головного мозга крысы перекрытием средней мозговой артерии нитью.

1.1 Исследование формирования ишемического очага с помощью метода МРТ и окраской ТТС с анализом моторного дефицита в передних конечностях крыс.

1.2 Исследование динамики формирования ишемического очага методом МРТ.

Часть 2. Нейропротекторная коррекция последствий ишемии головного мозга.

2.1 Исследование нейропротекторной активности ионов лития.

2.2 Исследование нейропротекторной активности пептида ГК-2.

2.3 Исследование нейропротекторной активности пептида PGP.

2.4 Исследование нейропротекторной активности митохондриальнонаправленных антиоксидантов.

ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ ИССЛЕДОВАНИЯ.

ВЫВОДЫ.

Рекомендованный список диссертаций по специальности «Физиология», 03.00.13 шифр ВАК

Введение диссертации (часть автореферата) на тему «Изучение новых нейропротекторов на модели фокальной ишемии головного мозга»

Актуальность проблемы. Среди современных медико-социальных проблем инсульт занимает одно из ведущих мест. Рост числа инсультов головного мозга среди трудоспособного населения нашей страны является на данный момент одним из самых острых вопросов отечественного здравоохранения. В настоящее время в России инсульт ежегодно переносят свыше 450 тыс. человек. Среди причин смерти он занимает второе место. Показатели заболеваемости и смертности от инсульта среди лиц трудоспособного возраста в России увеличились за последние 10 лет более чем на 30%. Ранняя 30-дневная летальность после инсульта составляет 34,6%, а в течение года умирает примерно половина заболевших, что составляет более 200 тыс. человек (Гусев и др., 2007; Виленский и Яхно, 2006).

Последствиям инсульта принадлежит первое место среди причин первичной инвалидности. К труду или полноценному выполнению прежних домашних обязанностей возвращается не более 15% перенесших инсульт, а остальные вследствие инвалидности нуждаются в пожизненной медико-социальной поддержке. Число инвалидов, перенесших инсульт, приближается к 1 млн. У 25% из них имеет место выраженная деменция. Вследствие этого резко ухудшается качество жизни не только больного, но и проживающих с ним родных и близких. Кроме того, государство несет экономические и финансовые потери из-за сокращения национального валового продукта, недополученного вследствие убыли заболевших инсультом в трудоспособном возрасте, а также затрат на медико-социальную поддержку инвалидов (Виленский и Яхно, 2006).

Однако на сегодняшний день все имеющиеся нейропротекторные препараты, испытанные в мультифокальных клинических исследованиях, недостаточно эффективны (Rother, 2008). Поэтому разработка новых подходов к терапии и профилактике инсульта является острейшей задачей медицины.

Также остается не до конца изученным процесс формирования ишемического очага и продолжительность «терапевтического окна». Для полного понимания эффективности нейропротекторного препарата, в зависимости от времени его введения после ишемии головного мозга, необходимо знание остаточного размера зоны пенумбры. На различных моделях ишемии головного мозга с использованием магнитно-резонансной томографии было показано, что динамика формирования зоны пенумбры зависит от многих показателей, включая вид модели и линию животного. В связи с этим мы исследовали динамику формирования очага начиная с момента ишемии и на протяжении двух недель после нее.

Важная информация о патологических процессах, происходящих при ишемическом инсульте, и о влиянии на них нейропротекторов, была получена в исследованиях на животных, у которых экспериментально вызывали ишемию мозга. В настоящее время, во многом благодаря этим исследованиям, выявлена сложная цепь метаболических и клеточных реакций, вызываемых нарушением мозгового кровообращения. Установлено, что основными индукторами гибели нейронов при ишемии мозга являются резкое падение уровней кислорода и глюкозы в нервной ткани, лактатацидоз, глутаматная эксайтотоксичность, окислительный стресс и снижение синтеза ростовых факторов, что введет к некротической и апоптотической гибели нервных клеток.

Так как в процессе ишемического повреждения мозга задействовано несколько различные ] патологических механизмов, то очевидно, что нейропротекторная терапия должна быть направлена на различные- мишени, принимающие участие в патологических процессах.

Поэтому нами- было выбрано 3 различных направления для нейропротекторной защиты: ингибиторы апоптоза, митохондриально-адресованные антиоксиданты и регуляторные пептиды.

Целью данной работы было исследование динамики ишемического инфаркта у крыс на модели перекрытия средней мозговой артерии (СМА) с помощью магнитно-резонансной томографии (МРТ), а также изучения возможности коррекции нарушений, вызванных ишемией, при использовании новых фармакологических препаратов.

Для достижения поставленной цели в работе решались следующие задачи:

1. Исследовать динамику формирования фокального очага ишемического повреждения на модели перекрытия СМА с помощью метода МРТ.

2. Исследовать влияние внутрибрюшинного введения хлорида лития после индукции ишемии головного мозга на развитие ишемического очага и неврологического дефицита.

3. Изучить нейропротекторные свойства пептидов ГК-2 и PGP на модели фокальной ишемии головного мозга.

4. Оценить влияние митохондриально-адресованных антиоксидантов семейства SkQ на развитие ишемического очага и неврологического дефицита.

Научная новизна и практическая значимость. В данной диссертационной работе впервые осуществлен широкий комплексный подход к исследованию процесса формирования ишемического повреждения головного мозга крыс с использованием метода МРТ и выполнен сравнительный анализ двух методов оценки области повреждения (МРТ и ТТС-окрашивание) в сопоставлении с данными об уровне неврологического дефицита, оцененного в поведенческих тестах.

Установлены сроки формирования ишемического очага в модели перекрытия СМА нитью. Проведен последовательный анализ на всех стадиях процесса формирования ишемического очага с использованием МР-изображений, начиная с первых минут ишемии и заканчивая двухнедельным сроком.

Впервые на модели фокальной ишемии мозга, вызванной перекрытием СМА, выявлено нейропротекторное действие пептидов PGP и ГК-2. Данные пептиды уменьшали развитие ишемического нейродеструктивного процесса и способствовали снижению неврологического дефицита в постишемическом периоде.

В исследовании влияния митохондриально-адресованных антиоксидантов семейства SkQ (SkQl, SkQRl и SkQRB) впервые показано, что SkQRl очень эффективно защищает ткань мозга от ишемии, снижает неврологический дефицит при введении до или после индукции ишемии методом перекрытия СМА. Также выявлены некоторые молекулярные механизмы защитного действия SkQRl.

Таким образом, полученные нами данные, а также примененные в исследованиях оригинальные методические разработки имеют важное научно-практическое значение для расширения существующих представлений о патоморфологических и патофизиологических процессах, происходящих в очаге ишемического повреждения головного мозга. Результаты исследования позволяют рекомендовать пептиды PGP и ГК-2, а также митохондриально-адресованный антиоксидант SkQRl для дальнейших доклинических испытаний с целью выявления наиболее эффективных доз, способов и сроков введения препаратов.

ОБЗОР ЛИТЕРАТУРЫ

Похожие диссертационные работы по специальности «Физиология», 03.00.13 шифр ВАК

Заключение диссертации по теме «Физиология», Силачёв, Денис Николаевич

выводы

1. Отработана методика воспроизведения фокального очага ишемического повреждения головного мозга, вызванного перекрытием средней мозговой артерии питью. Показано, что ишемическое повреждение захватывает область коры, включая сенсомоторпую область, а также стриатум и вызывает стойкие нарушения сенсомоторных функций мозга.

2. Изучена динамика формирования ишемического инфаркта с помощью метода магпитно-резонансноп томографии па модели фокальной ишемии головного мозга крыс. Очаг ишемического повреждения полностью формировался к 24 ч после индукции ишемии.

3. Введение LiCl в дозе 3 мМ сразу после начала реперфузии уменьшало более чем в 2 раза зону ишемического поражения и способствовало восстановлению неврологических функций.

4. Показано, что введение пептидов PGP и ГК-2 в постишемическом периоде уменьшает объем инфаркта и снижает неврологический дефицит, что свидетельствует о наличии у данных пептидов пейропротекторного эффекта.

5. Митохондриально-адресованный антиоксидапт SkQRl проявляет ярко-выражеппый пейропротекторнып эффект при введении за 1 сутки до индукции ишемии, а также сразу после начала реперфузии. Показано, что одним из механизмов нейропротекторного действия SkQRl может быть повышение содержания эритропоэтина и фосфолирированиой GSK-3(3 в мозге.

I К*) 160 I

Список литературы диссертационного исследования кандидат биологических наук Силачёв, Денис Николаевич, 2009 год

1. Андреева, Л.И., Иванова, Л.И., Титова, М.В., и Петрова B.C. (1996). Программированная клеточная гибель (под ред. B.C. Новикова). Наука, Санкт-Петербург, 51-71.

2. Ашмарин, И.П., Каразеева, Е.П., Ляпина, Л.А., и Самонина, Г.Е. (1998). Регуляторная активность простейших пролиисодсржащих пептидов PG, GP, PGP и GPGG и возможные источники их биосинтеза. Биохимия 63, 149-155.

3. Бадмаева, С-.Е. , Копылова, Г.Н., и Абушииова, Н.Н. (2005). Влияние глипролинов на стрессогенные нарушения поведения крыс. Росс. Физиол. Журн. им. И.М. Сеченова 9.

4. Березов, Т.Т. и Коровкпн, Б.Ф. (1998). Биологическая химия. М.: Медицина.

5. Виленский, Б.С. и Яхно, Н.Н. (2006). Современное состояние проблемы инсульта. Вестник Российской АМН 9-10, 18-23.

6. Гусев, Е.И. и Скворцова, В.И. (2001). Ишемия головного мозга. Москва,1. Медицина.

7. Гусев, Е.И., Скворцова, В.И., и Стаховская, Л.В. (2007). Проблемы инсульта в Российской Федерации: время активных совместных действий. Журнал неврологии и психиатрии им. С.С. Корсакова 107, 4-10.

8. Джафаров, А.И., Магомедов, Н.М., и Кулиева, Э.М. (1985). Перекисное окисление липидов в наружных и внутренних мембранах митохондрий при аноксии. Бюл. экспер. биол. 10, 433-435. ,

9. Ю.Исаев, Н.К., Андреева, Н.А., Стельмашук, Е.В., и Зоров, Д.Б. (2005). Роль митохондрий в механизмах токсического действия глутамата. Биохимия 70, 241-780.

10. Плотников, ЕЛО. (2009). Митохондрии как центральное звеноповреждающих и защитных сигнальных путей при развитии почечной недостаточности. Дисс. Докт. Бпол. Наук.

11. Сафарова, Э.Р. (2003). Фармакологическое исследование цптопротекторного дествия нейротропных пептидов. Автореф. Дисс. Канд. Биол. Наук

12. Турпасв, К.Т. (2002). Активные формы кислорода и экспрессия генов. Биохимия 67, 339-352.

13. Н.Яковлева, Е.В. , Кузенцов, B.C., Федоров, В.Н., Скворцова, В.И., Кошелев, В.Б., Гусев, Б.И., и Ашмарин, И.П. (1999). Исследование эффективности семакса при глобальной ишемии мозга in vivo. Бюл. эксперим. биол. и мед. 128, 172-174.

14. Aarts, М.М., Arundine, М., and Tymianski, М. (2003). Novel concepts in excitotoxic neurodegeneration after stroke. Expert Rev Mol Ivied 5, 1-22.

15. Abraham, H., Somogyvari-Vigh, A., Maderdrul, J.L., Vigh, S., and Arimura, A. (2002). Filament size influences temperature changes and brain damage following middle cerebral artery occlusion in rats. Exp Brain Res 142, 131-8.

16. Adams, J.M. and Cory, S. (2002). Apoptosomes: engines for caspase activation. CurrOpin Cell Biol 14, 715-20.

17. Alderton, W.IC, Cooper, C.E., and Knowles, R.G. (2001). Nitric oxide synthases: structure, function and inhibition. Biochem J 357, 593-615.

18. Alkayed, N J., Harukuni, I., Kimes, A.S., London, E.D., Traystman, R.J., and Hum, P.D. (1998). Gender-linked brain injury in experimental stroke. Stroke 29, 159-65; disctission 166.

19. Alleva, E. and Francia, N. (2009). Psychiatric vulnerability: suggestions from animal models and role of neurotrophins. Neurosci Biobehav Rev 33, 525-36.

20. Alonso de Lecinana, M., Diez-Tejedor, E., Gutierrez, M., Guerrero, S., Carceller, F., and Roda, J.M. (2005). New goals in ischemic stroke therapy: the experimental approach—harmonizing science with practice. Cerebrovasc Dis 20 Suppl 2, 159-68.

21. Amaro, S., Soy, D., Obach, V., Cervera, A., Planas, A.M., and Chamorro, A. (2007). A pilot study of dual treatment with recombinant tissue plasminogen activator and uric acid in acute ischemic stroke. Stroke 38, 2173-5.

22. Aronowski, J., Strong, R., and Grotta, J.C. (1997). Reperfusion injury: demonstration of brain damage produced by reperfusion after transient focal ischemia in rats. J Cereb Blood Flow Metab 17, 1048-56.

23. Asher, P. and Nowak, L. (1987). Electrophysiological studies on NMDA receptors. Trends inNeurosci. 10, 284-288.

24. Ashkenazi, A. (2002). Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer 2, 420-30.

25. Astrup, J., Siesjo, B.K., and Symon, L. (1981). Thresholds in cerebral ischemia the ischemic penumbra. Stroke 12, 723-5.

26. Astrup, J., Symon, L., Branston, N.M., and Lassen, N.A. (1977). Cortical evoked potential and extracellular K+ and H+ at critical levels of brainischemia. Stroke 8, 51-7.

27. Back, Т., FLoehn, M., Mies, G., Busch, E., Schmitz, В., fCohno, K., and Hossmann, K.A. (2000). Penumbral tissue alkalosis in focal cerebral ischemia: relationship to energy metabolism, blood flow, and steady potential. Ann Neurol 47, 485-92.

28. Bardutzky, J., Shen, Q., Henninger. N., Schwab, S., Duong, T.Q., and Fisher, M. (2007). Characterizing tissue fate after transient cerebral ischemia of varying duration using quantitative diffusion and perfusion imaging. Stroke 38, 1336-44.

29. Вагопе, F.C., Clark, R.K., Feuerstein, G., Lenkinski, R.E., and Sarkar, S.K. (1991). Quantitative comparison of magnetic resonance imaging (MR1) and histologic analyses of focal ischemic damage in the rat. Brain Res Bull 26, 285-91.

30. Barth, T.M., Jones, T.A., and Schallert, T. (1990). Functional subdivisions of the rat somatic sensorimotor cortex. Behav Brain Res 39, 73-95.

31. Bederson, J.B., Pitts, L.H., Tsuji, M., Nishimura, M.C., Davis, R.L., and Bartkowski, H. (1986b). Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17, 472-6.

32. Beetsch, J.W., Park, T.S., Dugan, L.L., Shah, A.R., and Gidday, J.M. (1998).ч

33. Beray-Berthat, V., Croci, N„ Plotkine, M., and Margaill, I. (2003). Polymorphonuclear neutrophils contribute to infarction and oxidative stress in the cortex but not in the striatum after ischemia-reperfusion in rats. Brain Res 987, 32-8.

34. Berridge, M.J. (1998). Neuronal calcium signaling. Neuron 21, 13-26.

35. Besancon, E., Guo, S., Lok, J., Tymianski, M., and Lo, E.H. (2008). Beyond NMDA and AM PA glutamate receptors: emerging mechanisms for ionic imbalance and cell death in stroke. Trends Pharmacol Sci 29, 268-75.

36. Betz, A.L., Randall, J., and Martz, D. (1991). Xanthine oxidase is not a major source of free radicals in focal cerebral ischemia. Am J Physiol 260, H563-8.

37. Bielecka, A.M. and Obuchowicz, E. (2008). Antiapoptotic action of lithium and valproate. Pharmacol Rep 60 , 771-82.

38. В lake, J.F., Brown, M.W., and Collingridge, G.L. (1988). CNQX blocks acidic amino acid induced depolarizations and synaptic components mediated by non-NMDA receptors in rat hippocampal slices. Neurosci Lett 89, 182-6.

39. Bohlen, O. and Halbach R.D. (2002). Neurotransmitters and Neuromodulators. GmBH: John Wiley & Sons 291 (Abstract)

40. Bonventrc, J.V. (1997). Roles of phospholipases A2 in brain cell and tissue injury associated with ischemia and excitotoxieity. J Lipid Mediat Cell Signal 17, 71-9.

41. Bonventre, J.V., Huang, Z., Taheri, M.R., O'Leary, E., Li, E., Moskowitz, M.A., and Sapirstein, A. (1997). Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature 390, 622-5.

42. Brinker, G., Franke, C., Hoehn, M., Uhlenkuken, U., and Hossmann, K.A. (1999). Thrombolysis of cerebral clot embolism in rat: effect of treatment delay. Neuroreport 10, 3269-72.

43. Broughton, B.R., Reutens, D.C., and Sobey, C.G. (2009). Apoptotic mechanisms after cerebral ischemia. Stroke 40, e33 1-9.

44. Brustovetsky, N. and Dubinsky, J.iVl. (2000). Dual responses of CNS mitochondria to elevated calcium. J Neurosci 20, 103-13.

45. Brustovetsky, N., Brustovetsky, Т., Jemmerson, R., and Dubinsky, J.M. (2002). Calcium-induced cytochrome с release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane. J Neurochem 80, 207-18.

46. Buchan, A.M., Xue, D., and Slivka, A. (1992). A new model of temporary focal neocortical ischemia in the rat. Stroke 23, 273-9.

47. Busch, E., lCruger, 1С., and Hossmann, K.A. (1997). Improved model of thromboembolic stroke and rt-PA induced reperfusion in the rat. Brain Res 778, 16-24.i

48. Bustamante, J., Czerniczyniec, A., and Lores-Arnaiz, S. (2007). Brain nitric oxide synthases and mitochondrial function. Front Biosci 12, 1034-40.

49. Carafoli, E. (1991). Calcium pump of the plasma membrane. Physiol Rev 71, 129-53.

50. Carafoli, E. and Molinari, M. (1998). Calpain: a protease in search of a function? Biochem Biophys Res Commun 247, 193-203.

51. Carano, R.A., Li, F., Trie, K., Helmer, K.G., Silva, M.D., Fisher, M., and Sotak, C.H. (2000). Multispectral analysis of the temporal evolution of cerebral ischemia in the rat brain. J Magn Reson Imaging 12, 842-58.

52. Carbonell, T. and Rama, R. (2007). Iron, oxidative stress and early neurological deterioration in ischcmic stroke. Curr Med Chem 14, 857-74.

53. Carmichael, S.T. (2005). Rodent models of focal stroke: size, mechanism, and puipose. NeuroRx 2, 396-409.

54. Carroll, J.E., Howard, E.F., Hess, D.C., Wakade, C.G., Chen, Q., and Cheng, C. (1998). Nuclear factor-kappa В activation during cerebral reperfusion: effect of attenuation with N-acetylcysteine treatment. Brain Res Mol Brain Res 56, 18691.

55. Castro, A.J. (1972). Motor performance in rats. The effects of pyramidal tract section. Brain Res 44, 313-23.

56. Chance, В., Sies, H., and Boveris, A. (1979). Hydroperoxide metabolism in mammalian organs. Physiol Rev 59, 527-605.

57. Chen, J., Li, Y., Wang, L„ Zhang, Z., Lu, D., Lu, M., and Chopp, M. (2001). Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32, 1005-11.

58. Chen, J., Nagayama, Т., Jin, K., Stetlcr, R.A,, Zhu, R.L., Graham, S.H., and Simon, R.P. (1998). Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. J Neurosci 18, 4914-28.

59. Chen, S.T., Hsu, C.Y., Iiogan, E.L., Maricq, H., and Balentine, J.D. (1986). A model of focal ischemic stroke in the rat: reproducible extensive cortical infarction. Stroke 17, 738-43.

60. Chesler, M. (1990). The regulation and modulation of pH in the nervous system. Prog Neurobiol 34, 401-27.

61. Cho, B.B. and Toledo-Pereyra, L.H. (2008). Caspase-independent programmed cell death following ischemic stroke. J Invest Surg 27, 141-7.

62. Cho, S., Szeto, H.H., Kim, E., Kim, H., Tolhurst, A.T., and Pinto, J.T. (2007). A novel cell-permeable antioxidant peptide, SS31, attenuates ischemic brain injury by down-regulating CD36. J Biol Chem 282, 4634-42.

63. Choi, D.W. (1985). Glutamale neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett 58, 293-7.

64. Choi, D.W. (1987). Ionic dependence of glutamate neurotoxicity. J Neurosci 7, 369-79.

65. Choi, D.W. (1990). Cerebral hypoxia: some new approaches and unanswered questions. J Neurosci 10, 2493-501.

66. Claiborne, A., Yeh, J.I., Mallett, T.C. Luba, J., Crane, E.J. 3rd, Charrier, V., and Parsonage, D. (1999). Protein-sulfenic acids: diverse roles for an unlikely player in enzyme catalysis and redox regulation. Biochemistry 38, 15407-16.

67. Combs, D.J. and DAlecy, L.G. (1987). Motor performance in rats exposed to severe forebrain ischemia: effect of fasting and 1,3-butanediol. Stroke 18, 5031 1.

68. Coon, M.J., Ding, X., Pernecky, S.J., and Vaz, A.D.N. (1992). Cytochrome P450: Progress and predictions. FASEB J. 6, 669-673.(Abstract)

69. Corbett, D. and Nurse, S. (1998). The problem of assessing effective neuroprotection in experimental cerebral ischemia. Prog Neurobiol 54, 53 1-48.

70. Coyle, P. (1986). Different susceptibilities to cerebral infarction in spontaneously hypertensive (SHR) and normotensive Sprague-Dawley rats. Stroke 17, 520-5.

71. Davis, M., Mendelow, A.D., Репу, R.H., Chambers, I.R., and James, O.F.1995). Experimental stroke and neuroprotection in the aging rat brain. Stroke 26, 1072-8.92.de Erausquin, G.A., Manev, H., Guidotti, A., Costa, E., and Brooker, G. (1990).

72. De Ryclc, M., Van Reempts, J., Borgers, M., Wauquier, A., and Janssen, P.A. (1989). Photochcmical stroke model: flunarizine prevents sensorimotor deficits after neocortical infarcts in rats. Stroke 20, 1383-90.

73. Dietrich, W.D., Busto, R., Watson, B.D., Scheinberg, P., and Ginsberg, M.D. (1987a). Photochemically induced cerebral infarction. II. Edema and blood-brain barrier disruption. Acta Neuropathol 72, 326-34.

74. Dietrich, W.D., Watson, B.D., Busto, R., Ginsberg, M.D., and Bethea, J.R. (1987b). Photochemically induced cerebral infarction. I. Early microvascular alterations. Acta Neuropathol 72, 315-25.

75. Dirnagl, U. and Meisel, A. (2008). Endogenous neuroprotection: mitochondria as gateways to cerebral preconditioning? Neuropharmacology 55, 334-44.

76. Dirnagl, U., Iadecola, C., and Moskovvitz, M.A. (1999). Pathobiolog) of ischaemic stroke: an integrated view. Trends Neurosci 22, 391-7.

77. Dirnagl, U., Simon, R.P., and Hallenbeck, J.M. (2003). Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 26, 248-54.

78. Dittmar, M., Spruss, Т., Schuierer, G., and Horn, M. (2003). External carotid artery territory ischemia impairs outcome in the endovascular filament model of middle cerebral artery occlusion in rats. Stroke 34, 2252-7.

79. Dittmar, M.S., Vatankhah, В., Fehm, N.P., Schuicrcr, G., Bogdahn, U., Horn, M., and Schlachetzki, F. (2006). Fischer-344 rats are unsuitable for the MCAO filament model due to their cerebrovascular anatomy. J Neurosci Methods 156, 50-4.

80. Dodd, S., Dean, O., Copolov, D.L., Malhi, G.S., and Berk, M. (2008). N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility. Expert Opin Biol Ther 8. 1955-62.

81. Drejer, J., Frandsen, A., Honore, Т., and Schousboe, A. (1987). Adenosine inhibits glutamate stimulated 3H.D-aspartate release from cerebellar granule cells. Neurochem. Int. /7,77-81.

82. Dringen, R. (2000). Metabolism and functions of glutathione in brain. Prog Neurobiol 62, 649-71.

83. Durukan, A., Marinkovic, I., Strbian, D., Pitkonen, M., Pedrono, E., Soinne, L., Abo-Ramadan, U., and Tatlisumak, T. (2009). Post-ischemic blood-brain barrier leakage in rats: one-week follow-up by MRJ. Brain Res 1280, 158-65.

84. Duverger, D. and MacKenzie, E.T. (1988). The quantification of cerebral infarction following focal ischemia in the rat: influence of strain, arterial pressure, blood glucose concentration, and age. J Cereb Blood Flow Metab 8, 449-61.

85. Dykens, J.A. (1994). Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated CA2+ and Na+: implicationsfor neurodegeneration. J Neurochem 63, 584-91.

86. Eklof, B. and Siesjo, B.K. (1972). The effect of bilateral carotid artery ligation upon the blood flow and the energy state of the rat brain. Acta Physiol Scand 86, 155-65.

87. Erdo, F., Berzsenyi, P., Nemet, L., and Andrasi, F. (2006). Talampanel improves the functional deficit after transient focal cerebral ischemia in rats. A 30-day follow up study. Brain Res Bull 68, 269-76.

88. Evenden, J.L. and Robbins, T.W. (1984). Effects of unilateral 6-hydroxydopamine lesions of the caudate-putamen on skilled forepaw use in the rat. Behav Brain Res 14, 61-8.

89. Fabian, R.H. and Kent, T.A. (1999). Superoxide anion production during reperfusion is reduced by an antineutrophil antibody after prolonged cerebral ischemia. Free Radic Biol Med 26, 355-61.

90. Facci, L., Leon, A., and Skaper, S.D. (1990). Hypoglycemic neurotoxicity in vitro: involvement of excitatory amino acid receptors and attenuation by monosialoganglioside GM1. Neuroscience 37, 709-16.

91. Fletcher, E.J. and Lodge, D. (1988). Glycine reverses antagonism ofN-methyl-D-aspartate (NMDA) by l-hydroxy-3-aminopyrrolidone-2 (HA-966) but not by D-2-amino-5-phosphonovalerate (D-AP5) on rat cortical slices. Eur J Pharmacol 151, 161-2.

92. Fradc, J.M. and Barde, Y.A. (1998). Nerve growth factor: two receptors, multiple functions. Bioessays 20, 1 37-45.

93. Francis, J.W., Ren, J., Warren, L., Brown, R.FI. Jr, and Finklestein, S.P. (1997). Postischemic infusion of Cu/Zn superoxide dismutase or SOD:Tet45 1 reduces cerebral infarction following focal ischemia/reperfusion in rats. Exp Neurol 146, 435-43.

94. Fridovich, I. (1995). Superoxide radical and superoxide dismutases. Annu Rev Biochem 64, 97-1 12.

95. Fukuchi, K„ Kusuoka, H. Watanabe, Y., and Nishimura, T. (1999). Correlation of sequential MR images of microsphere-induced cerebral ischemia with histologic changes in rats. Invest Radiol 34, 698-703.

96. Fukumoto, Т., Morinobu, S., Okamoto, Y., Kagaya, A., and Yamawaki, S. (2001). Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology (Berl) 1j8, 100-6.

97. Fuxe, K., Bjelke, В., Andbjer, В., Grahn, H., Rimondini, R., and Agnati, L.F. (1997). Endothelin-1 induced lesions of the frontoparietal cortex of the rat. A possible model of focal cortical ischemia. Neuroreport 8, 2623-9.

98. Galio, V., Giovannini, C., and Levi, G. (1990). Modulation of non-N-methyl-D-aspartate receptors in cultured cerebellar granule cells. J Neurochem 54, 1619-25.

99. Garcia, J.H., Liu, K.F., and Ho, K.L. (1995). Neuronal necrosis after middle cerebral artery occlusion in Wistar rats progresses at different time intervals in the caudoputamen and the cortex. Stroke 26, 636-42; discussion 643.

100. Gharbawie, O.A. and Whishaw, l.Q. (2006). Parallel stages of learning and recovery of skilled reaching after motor cortex stroke: "oppositions" organize normal and compensatory movements. Behav Brain Res 175, 249-62.

101. Giffard, R.G., Monyer, H., and Choi, D.W. (1990). Selective vulnerability of cultured cortical glia to injury by extracellular acidosis. Brain Res 530, 138-41.

102. Gill, D.L., Ghosh, Т.К., and Mullaney, J.M. (1989). Calcium signalling mechanisms in endoplasmic reticulum activated by inositol 1,4,5-trisphosphate and GTP. Cell Calcium 10, 363-74.

103. Gill, R., Foster, A.C., and Woodruff, G.N. (1987). Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil. J Neurosci 7, 3343-9.

104. Ginsberg, M.D. and Busto, R. (1989). Rodent models of cerebral ischcmia. Stroke 20, 1627-42.

105. Giustarini, D., Rossi, R., Milzani, A., Colombo, R., and Dalle-Donne, I. (2004). S-glutathionylation: from redox regulation of protein functions to human diseases. J Cell Mol Med 8, 201-12.

106. Goldman, S.A., Pulsinelli, W.A., Clarke, W.Y., Kraig, R.P. and Plum, F. (1989). The effects of extracellular acidosis on neurons and glia in vitro. J Cereb Blood Flow Metab 9, 471-7.

107. Gonzalez, C.L. and Kolb, B. (2003). A comparison of different models of stroke on behaviour and brain morphology. Eur J Neurosci 18, 1950-62.

108. Gottlieb, R.A. (2000). Mitochondria: execution central. FEBS Lett 482, 6-12.

109. Grasso, G., Sfacteria, A., Meli, F., Fodale, V., Buemi, M., and lacopino, D.G. (2007). Neuroprotection by erythropoietin administration after experimental traumatic brain injury. Brain Res 1182, 99-105.

110. Gross, S.S. and Wolin, M.S. (1995). Nitric oxide: pathophysiological mechanisms. Annu Rex Physiol 57, 131-69.

111. Grotta, J. (1998). Stroke treatment in the human versus animal models. In Cerebrovascular disease: pathophysiology, diagnosis, and management. M, Ginsberg and J. Bogousslavsky, eds. (Blackwell Scientific Publications), pp. 1901-6.

112. Gunter, Т.Е. and Pfeiffer, D.R. (1990). Mechanisms by which mitochondria transport calcium. Am J Physiol 258, C755-86.

113. Gursoy-Ozdemir, Y., Can, A., and Dalkara, T. (2004). Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia. Stroke 35, 1449-53.

114. Haase, G., Pettmann, В., Raoul, C., and Henderson, C.E. (2008). Signaling by death receptors in the nervous system. Curr Opin Neurobiol 18, 284-91.

115. Halestrap, A.P. (2006). Calcium, mitochondria and reperfusion injury: aроге way to die. Biochem Soc Trans 34, 232-7.

116. Hamilton, M.H., Garcia-Mnnoz, M., and Arbuthnott, G.W. (1985). Separation of the motor consequences from other actions of unilateral 6-hydroxydopamine lesions in the nigrostriatal neurones of rat brain. Brain Res 348, 220-8.

117. Harada, H., Wang, Y., Mishima, Y., Uehara, N., Makaya, Т., and Kano, T. (2005). A novel method of detecting rCBF with laser-Doppler flowmetry without cranial window through the skull for a MCAO rat model. Brain Res Brain Res Protoc 14, 165-70.

118. Hard, R., Schurcr, L., Schmid-Schonbein, G. W., and del Zoppo, G.J. (1996). Experimental antileukocyte interventions in cerebral ischemia. J Cereb Blood Flow Metab 16, 1108-19.

119. Hartley, D.M., Monycr, H., Colamarino, S.A., and Choi, D. W. (1990). 7-Chlorokynurenate Blocks NMDA Receptor-Mediated Neurotoxicity in Murine Cortical Culture. Eur J Neurosci 2, 291-295.

120. ITatinen, S., Sairanen, M., Sirvio, J., and Jolkkonen. J. (2008). Improved sensorimotor function by rolipram following focal cerebral ischemia in rats. Restor Neurol Neurosci 26, 493-9.

121. Haunstetter, A. and Izumo, S. (2000). Future perspectives and potential implications of cardiac myocyte apoptosis. Cardiovasc Res 45, 795-801.

122. He, Y.Y., Hsu, C.Y., Ezrin, A.M., and Miller, M.S. (1993). Polyethylene glycol-conjugated superoxide dismutase in focal cerebral ischemia-rcperfusion. Am J Physiol265, H252-6.

123. He, Z., Yamawaki, Т., Yang, S., Day, A.L., Simpkins, J.W., and Naritomi, H. (1999). Experimental model of small deep infarcts involving the hypothalamus in rats: changes in body temperature and postural reflex. Stroke 30, 2743-51; discussion 2751.

124. Hefti, F. (1994). Neurotrophic factor therapy for nervous system degenerative diseases. J Neurobiol 25, 1418-35.

125. Heiss, W.D. and Rosner, G. (1983). Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol 14, 294301.

126. Hilger, Т., Blunk, J.A., Floehn, M., Mies, G., and Wester, P. (2004). Characterization of a novel chronic photothrombotic ring stroke model in rats by magnetic resonance imaging, biochemical imaging, and histology. J Cereb Blood Flow Metab 24, 789-97.

127. Hillered, L., Smith, M.L., and Siesjo, B.K. (1985). Lactic acidosis and recovery of mitochondrial function following fore bra in ischemia in the rat. J Cereb Blood Flow Metab 5, 259-66.

128. Hirakawa, M., Tamura, A., Nagashima, H., Nakayama, H., and Sano, K.1994). Disturbance of retention of memory after focal cerebral ischemia in rats. Stroke 25, 2471-5.

129. Hobbs, C.E., Murphy, M.P., Smith, R.A., and Oorschot, D.E. (2008). Neonatal rat hypoxia-ischemia: Effect of the anti-oxidant mitoquinol, and S-PBN. Pediatr Int 50, 481-8.

130. Hoelin, M., Nicolay, K., Franke, C., and van der Sanden, B. (2001). Application of magnetic resonance to animal models of cerebral ischemia. J Magn Reson Imaging 14, 491-509.

131. Hong, S.C., Goto, Y., Lanzino, G., Soleau, S., Kassell, N.F., and Lee, K.S. (1994). Neuroprotection with a calpain inhibitor in a model of focal cerebral ischemia. Stroke 25, 663-9.

132. Flood, W.F., Sun, E.T., Compton, R.P., and Monahan, J.B. (1989). 1-Aminocyclobutane-l-carboxylate (ACBC): a specific antagonist of the N-methyl-D-aspartate receptor coupled glycine receptor. Eur J Pharmacol 161, 281-2.

133. Hossmann, K.A. (1994). Viability thresholds and the penumbra of focal ischemia. Ann Neurol 36, 557-65.

134. Ноус, А.Т., Davoren, J.E., Wipf, P., Fink, M.P., and Kagan, V.E. (2008). Targeting mitochondria. Acc Chem Res 41, 87-97.

135. Huang, Z., Huang, P.L., Panahian, N., Dalkara, Т., Fishman, M.C., and Moskowitz, M.A. (1994). Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265, 1883-5.

136. Hudgins, W.R. and Garcia, J.H. (1970). Transorbital approach to the middle cerebral artery of the squirrel monkey: a technique for experimental cerebral infarction applicable to ultrastructural studies. Stroke /, 107-11.

137. Huettner, J.E. (1989). Indole-2-carboxylic acid: a competitive antagonist of potentiation by glycine at the NMDA receptor. Science 243, 1611-3.

138. Hunter, A.J., Green, A.R., and Cross, A.J. (1995). Animal models of acute ischaemic stroke: can they predict clinically successful neuroprotective drugs? Trends Pharmacol Sci 16, 123-8.

139. Hunter, A.J., Hatcher, J., Virley, D., Nelson, P., Irving, E., Hadingham, S.J., and Parsons, A.A. (2000). Functional assessments in mice and rats after focal stroke. Neuropharmacology 39, 806-16.

140. Iadecola, C. (1997). Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci 20, 132-9.

141. Iadecola, C., Zhang, F., Casey, R., Clark, H.B., and Ross, M.E. (1996). Inducible nitric oxide synthase gene expression in vascular cells after transient focal cerebral ischemia. Stroke 27, 1373-80.

142. Imai, H., Konno, K., Nakamura, M., Shimizu, Т., Kubota, C., Selci, K., Honda, F., Tomizawa, S., Tanaka, Y., Hata, H., and Saito, N. (2006). A new model of focal cerebral ischemia in the miniature pig. J Neurosurg 104, 12332.

143. Imaizumi, S„ Woolworth, V., Fishman, R.A., and Chan, P.H. (1990).1.posome-entrapped superoxide dismutase reduces cerebral infarction in cerebral ischemia in rats. Stroke 21, 1312-7.

144. Irwin, R.P., Lin, S.Z., Long, R.T., and Paul, S.M. (1994). N-methyl-D-aspartate induces a rapid, reversible, and calcium-dependent intracellular acidosis in cultured fetal rat hippocampal neurons. J Neurosci 14, 1352-7.

145. Jadhav, V. and Zhang, J.LI. (2008). Surgical brain injury: prevention is better than cure. Front Biosci 13 , 3793-7.

146. Jadhav, V., Solaroglu, 1., Obenaus, A., and Zhang, J.H. (2007). Neuroprotection against surgically induced brain injury. Surg Neurol 67, 1520; discussion 20.

147. Janaky, R., Varga, V., Hermann, A., Saransaari, P., and Oja, S.S. (2000). Mechanisms of L-cysteine neurotoxicity. Neurochem Res 25, 1397-405.

148. Jefls, G.J., Meloni, B.P., Bakker, A.J., and Knuckev, N.W. (2007). The role of the Na(+)/Ca(2+) exchanger (NCX) in neurons following ischaemia. J Clin Neurosci 14, 507-14.

149. Jiang, M.IT. and Llada, J. (2007). Early and sharp nitric oxide production and anoxic depolarization in the rat hippocampus during transient forebrain ischemia. Eur J Pharmacol 567, 83-8.

150. Jolkkonen, J., Puurunen, K., Rantakomi, S., Harkonen, A., Haapalinna, A., and Sivenius, J. (2000). Behavioral effects of the alpha(2)-adrenoceptor antagonist, atipamezole, after focal cerebral ischemia in rats. Eur J Pharmacol 400, 211-9.

151. Jones. T.A., Chu, C.J., Grande, L.A., and Gregory, A.D. (1999). Motor skills training enhances lesion-induced structural plasticity in the motor cortex of adult rats. J Neurosci 19, 10153-63.

152. Jope, R.S. and Bijur, G.N. (2002). Mood stabilizers, glycogen synthase kinase-3beta and cell survival. Mol Psychiatry 7 Suppl 1, S35-45.

153. Juhaszova, M., Zorov, D.B., Yaniv, Y., Nuss, H.B., Wang, S., and Sollott, S.J. (2009). Role of glycogen synthase kinase-3beta in cardioprotection. С ire Res 104, 1240-52.

154. Kalimo, H., Rehncrona, S., Soderfeldt, В., Olsson, Y., and Siesjo, B.K. (1981). Brain lactic acidosis and ischemic cell damage: 2. Histopathology. J Cereb Blood Flow Metab /, 313-27.

155. Kaneko, D., Nakamura, N., and Ogawa, T. (1985). Cerebral infarction in rats using homologous blood emboli: development of a new experimental model. Stroke 16, 76-84.

156. Kaplan, A.La., Koshelev, V.B., Nezavibat'ko, V.N., and Ashmarin, I.P. (1992). Increased resistance to hypoxia effected by the neuropeptide preparation SEMAX. Fiziol Cheloveka 18, 104-7.

157. Katsura, K., Ekholm, A., and Siesjo, B.K. (1992). Coupling among changes in energy metabolism, acid-base homeostasis, and ion fluxes in ischemia. Can J Physiol Pharmacol 70 Suppl, S170-5.

158. Kellenberger, S. and Schild, L. (2002). Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol Rev 82, 735-67.

159. Kessler, M., Baudry, M., and Lynch, G. (1989). Quinoxaline derivatives are high-affinity antagonists of the NMDA receptor-associated glycine sites. Brain Res 489, 377-82.

160. Khoo, C., Helm, J., Choi, H.B., Kim, S.U., and McLarnon, J.G. (2001). Inhibition of store-operated Ca(2+) influx by acidic extracellular pH in cultured human microglia. Glia 36, 22-30.

161. Kim, D.K., Rordorf, G., Nemenoff, R.A., Koroshetz, W.J., and Bonventre, J.V, (1995). Glutamate stably enhances the activity of two cytosolic forms of phospholipase A2 in brain cortical cultures. Biochem J 310 (Pt 1), 83-90.

162. Kimelberg, H.K. (2005). Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy. Glia 50, 389-97.

163. Kimelberg, H.K., Barron, K.D., Bourlce, R.S., Nelson, L.R., and Cragoe, E.J. (1990). Brain anti-cytoxic edema agents. Prog Clin Biol Res 361, 363-85.

164. Kirino, Т., Tamura, A., and Sano, K. (1984). Delayed neuronal death in the rat hippocampus following transient forebrain ischemia. Acta Neuropathol 64, 139-47.

165. Kirsch, J.R., Traystman, R.J., and Hum, P.D. (1996). Anesthetics and cerebroprotection: experimental aspects. Int Anesthesiol Clin 34, 73-93.

166. Kitagawa, K., Matsumoto, M., Tagaya, M., Hala, R., Ueda, H., Niinobe, M., Handa, N., Fukunaga, R., Kimura, K., Mikoshiba, K., and et, a.l. (1990). 'Ischemic tolerance' phenomenon found in the brain. Brain Res 528, 21-4.

167. Kleim, J.A., Bruneau, R., VandenBerg, P., MacDonald, E., Mulrooney, R., and Pocock, D. (2003). Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult. Neurol Res 25, 789-93.

168. Knowles, R.G. and Moncada, S. (1994). Nitric oxide synthases in mammals. Biochem J 298 (Pt 2), 249-58.

169. Koizumi, J., Yoshida, Y., Nakazawa, Т., and Ooneda, G. (1986). Experimental studies of ischemic brain edema. 1. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn J Stroke 8, 1-8.

170. Kong, L.Q. Xie, J.X., Han, H.B., and Liu, H.D. (2004). Improvements in the intraluminal thread technique to induce focal cerebral ischaemia in rabbits.

171. J Neurosci Methods 137,315-9.

172. Kontos, H.A. (2001). Oxygen radicals in cerebral ischemia: the 2001 Willis lecture. Stroke 32, 2712-6.

173. Kozlov, A.V., Sobhian, В., Duvigneau, C., Gemeiner, M., Nohl, H., Redl, IT., and Bahrami, S. (2001). Organ specific formation of nitrosyl complexes under intestinal ischemia/reperfusion in rats involves NOS-independent mechanism(s). Shock 15, 366-71.

174. Kukreja, R.C., Kontos, H.A., Hess, M.L., and Ellis, E.F. (1986). PGH synthase and lipoxygenase generate superoxide in the presence of NADH or NADPH. С ire Res 59, 612-9.

175. Kwak, S. and Weiss, J.H. (2006). Calcium-permeable AMPA channels in neurodegenerative disease and ischemia. Curr Opin Neurobiol 16, 281-7.

176. Laemmli, U.K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680-5.

177. Laing, R.J., Jakubowski, J., and Laing, R.W. (1993). Middle cerebral artery occlusion without craniectomy in rats. Which method works best? Stroke 24, 294-7; discussion 297-8.

178. Lauer, K.K., Shen, H., Stein, E.A., Но, K.C., Kampine, J.P., and Hudetz, A.G. (2002). Focal cerebral ischemia in rats produced by intracarotid embolization with viscous silicone. Neurol Res 24, 181-90.

179. Lee, B.I., Lee, D.J., Cho, K.J., and Kim, G.W. (2005). Early nuclear translocation of endonuclease G and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Neurosci Lett 386, 23-7.

180. Lee, K.S., Frank, S., Vanderklish, P., Arai, A., and Lynch, G. (1991). Inhibition of proteolysis protects hippocampal neurons from ischemia. Proc Natl Acad Sci U S A 88, 7233-7.

181. Lenhard, S.C., Strittmatter, R., Price, W.J., Chandra, S., White, R.F., and Barone, F.C. (2008). Brain MRI and neurological deficit measurements in focal stroke: rapid throughput validated with isradipine. Pharmacology 81, 1-10.

182. Lepore, D.A., Kozlov, A.V. Stewart, A.G., Hurley, J.V., Morrison, W.A., and Tomasi, A. (1999). Nitric oxide synthase-independent generation of nitric oxide in rat skeletal muscle ischemia-reperfusion injury. Nitric Oxide 3, 75-84.

183. LeSauteur, L., Wei, L., Gibbs, B.F., and Saragovi, H.U. (1995). Small peptide mimics of nerve growth factor bind TrkA receptors and affect biological responses. J Biol Chem 270, 6564-9.

184. Lessmann, V. (1998). Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS. Gen Pharmacol 31, 667-74.

185. Levi-Montalcini, R. (1987). The nerve growth factor 35 years later. Science 237, 1154-62.

186. Li, F. and Fisher, M. (2001). Animal modeling for developing stroke therapy. Woburn,MA: Butterworth-Heinemann 83-96.(Abstract)

187. Li, F., Omae, Т., and Fisher, M. (1999). Spontaneous hyperthermia and its mechanism in the intraluminal suture middle cerebral artery occlusion model of rats. Stroke 30, 2464-70; discussion 2470-1.

188. Li, F„ Silva, M.D., Sotak, C.H., and Fisher, M. (2000). Temporal evolution of ischemic injury evaluated with diffusion-, perfusion-, and T2-weighted MRI. Neurology 54, 689-96.

189. Li, L.Y., Luo, X., and Wang, X. (2001). Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412, 95-9.

190. Liebler, D.C., Kling, D.S., and Reed, D.J. (1986). Antioxidant protection of phospholipid bilayers by alpha-tocopherol. Control of alpha-tocopherol status and lipid peroxidation by ascorbic acid and glutathione. J Biol Chem 267, 12114-9.

191. Lin, Y. and Phillis, J.W. (1991). Oxypurinol reduces focal ischemic brain injury in the rat. Neurosci Lett 126, 187-90.

192. Lindsay, S., Liu, Т.Н., Xu, J.A., Marshall, P.A., Thompson, J.K., Parks, D.A., Freeman, B.A., Hsu, C.Y., and Beckman, J.S. (1991). Role of xanthine dehydrogenase and oxidase in focal cerebral ischemic injury to rat. Am J Physiol 261, H2051-7.

193. Lipton, P. (1999). Ischemic cell death in brain neurons. Physiol Rev 79, 1431-568.

194. Liu, H.T., Tashmukhamedov, B.A., Inoue, H., Okada, Y., and Sabirov, R.Z. (2006). Roles of two types of anion channels in glutamate release from mouse astrocytes under ischemic or osmotic stress. Glia 54, 343-57.

195. Loh, K.P., Huang, S.H., De Silva, R., Tan, B.K., and Zhu, Y.Z. (2006). Oxidative stress: apoptosis in neuronal injury. Curr Alzheimer Res 3, 327-37.

196. Longa, E.Z., Weinstein, P.R., Carlson, S., and Cummins, R. (1989). Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20, 84-91.

197. Longo, F.M., Manthorpe, M., Xie, Y.M., and Varon, S. (1997). Synthetic NGF peptide derivatives prevent neuronal death via a p75 receptor-dependent mechanism. J Neurosci Res 48, 1-17.

198. Lorez, H., Keller, F., Ruess, G., and Otten, U. (1989). Nerve growth factor increases in adult rat brain after hypoxic injury. Neurosci Lett 98, 33944.

199. Love, S. (2003). Apoptosis and brain ischaemia. Prog Neuropsychopharmacol Biol Psychiatry 27, 267-82.

200. Ly, J.V., Zavala, J.A., and Donnan, G.A. (2006). Neuroprotection and thrombolysis: combination therapy in acute ischaemic stroke. Expert Opin Pharmacother 7, 1571-81.

201. Lykissas, M.G., Batistatou, A.K., Charalabopoulos, K.A., and Beris, A.E. (2007). The role of neurotrophins in axonal growth, guidance, and regeneration. Cuit Neurovasc Res 4, L43-51.

202. Lythgoe, M.F., Sibson, N.R., and Harris, N.G. (2003). Neuroimaging of animal models of brain disease. Br Med Bull 65, 235-57.

203. Ma, J., Zhao, L., and Nowak, T.S. Jr (2006). Selective, reversible occlusion of the middle cerebral artery in rats by an intraluminal approach. Optimized filament design and methodology. J Neurosci Methods 156, 76-83.

204. MaeDonald, V.D., Sundt, T.M. Jr, and Winkelmann, R.K. (1972). Histochemical studies in the zone of ischemia following middle cerebral artery occlusion in cats. J Neurosurg 37, 45-54.

205. MacManus, J.P. and Linnik, M.D. (1997). Gene expression induced by cerebral ischemia: an apoptotic perspective. J Cereb Blood Flow Metab 17, 815-32.

206. Macrae, I.M., Robinson, M.J., Graham, D.I., Reid, J.L., and McCulloch,

207. J. (1993). Endothelin-1-induced reductions in cerebral blood flow: dose dependency, time course, and neuropathological consequences. J Cereb Blood Flow Metab 13, 276-84.

208. Mahadik, S. and Karpiak, S. (1988). Gangliosides in treatment of neuronal injury and disease. Drug Dev. Res. 15,

209. Maher, P. (2005). The effects of stress and aging on glutathione metabolism. Ageing Res Rev 4, 288-314.

210. Maier, C.M. and Chan, P.H. (2002). Role of superoxide dismutases in oxidative damage and neurodegenerative disorders. Neuroscientist 8, 323-34.

211. Manev, IT., Costa, E., Wroblewski, J.T., and Guidotti, A. (1990). Abusive stimulation of excitatory amino acid receptors: a strategy to limit neurotoxicity. FASEB J 4, 2789-97.

212. Manev, H., Favaron, M., Guidotti, A., and Costa, E. (1989). Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death. Mol Pharmacol 36, 106-12.

213. Margaill, I., Plotkine, M., and Lerouet, D. (2005). Antioxidant strategies in the treatment of stroke. Free Radic Biol Med 39, 429-43.

214. Markgraf, C.G., Green, E.J., Hurwitz, B.E., Morikawa, E., Dietrich, W.D., McCabe, P.M., Ginsberg, M.D., and Schneiderman, N. (1992). Sensorimotor and cognitive consequences of middle cerebral artery occlusion in rats. Brain Res 575, 238-46.

215. Markgraf, C.G., Green, E.J., Hurwitz, B.E., Morikawa, E., Dietrich, W.D., McCabe, P.M., Ginsberg, M.D., and Schneiderman, N. (1992). Sensorimotor and cognitive consequences of middle cerebral artery occlusion in rats. Brain Res 575, 238-46.

216. Mattson, M.P., Culmsee, C., and Yu, Z.F. (2000). Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res 301, 173-87.

217. Mayzel-Oreg, O., Omae, Т., Kazemi, M., Li, F., Fisher, M., Cohen, Y., and Sotak, C.H. (2004). Microsphere-induced embolic stroke: an MRI study. Magn Reson Med 51, 1232-8.

218. McDonald. J.W., Bhattacharyya, Т., Sensi, S.L., Lobner, D., Ying, H.S., Canzoniero, L.M., and Choi, D.W. (1998). Extracellular acidity potentiates AMPA receptor-mediated cortical neuronal death. J Neurosci 18, 6290-9.

219. McPherson, R.J. and Juul, S.E. (2008). Recent trends in erythropoietin-mediated neuroprotection. Int J Dev Neurosci 26, 103-11.

220. Mehta, S.H., Webb, R.C., Ergul, A., Tawfik, A., and Dorrance, A.M. (2004). Neuroprotection by tempol in a model of iron-induced oxidative stress in acute ischemic stroke. Am J Physiol Regul Integr Comp Physiol 286, R283-8.

221. Memezawa, IT., Minamisawa, IT., Smith, M.L., and Siesjo, B.K. (1992). Ischemic penumbra in a model of reversible middle cerebral artery occlusion in the rat. Exp Brain Res 89, 67-78.

222. Meng, X., Fisher, M., Shen, Q., Sotak, C.H., and Duong, T.Q. (2004). Characterizing the diffusion/perfusion mismatch in experimental focal cerebral ischemia. Ann Neurol 55, 207-12.

223. Menzies, S.A., Hoff, J.T., and Betz, A.L. (1992). Middle cerebral artery occlusion in rats: a neurological and pathological evaluation of a reproducible model. Neurosurgery 31, 100-6; discussion 106-7.

224. Merchenthaler, I., Dellovade, T.L., and Shughrue, P.J. (2003).

225. Neuroprotection by estrogen in animal models of global and focal ischemia. Ann N Y Acad Sci 1007, 89-1 00.

226. Mergenthaler, P., Dirnagl, U., and Meisel, A. (2004). Pathophysiology of stroke: lessons from animal models. Metab Brain Dis 19, 151-67.

227. Mhairi Macrae, I. (1992). New models of focal cerebral ischaemia. Br J Clin Pharmacol 34, 302-8.

228. Mizusawa, H., Ishii, Т., and Bannai, S. (2000). Peroxiredoxin I (macrophage 23 kDa stress protein) is highly and widely expressed in the rat nervous system. Neurosci Lett 283, 57-60.

229. Molnar, L., Hegedus, 1С., and Felcete, I. (1988). A new model for inducing transient cerebral ischemia and subsequent reperfusion in rabbits without craniectomy. Stroke 19, 1262-6.

230. Montoya, C.P., Campbell-Hope, L.J., Pemberton, K.D. and Dunnett, S.B. (1991). The "staircase test"; a measure of independent forelimb reaching and grasping abilities in rats. J Neurosci Methods 36, 219-28.

231. Moro, M.A., Almeida, A., Bolanos, J.P., and Lizasoain, I. (2005). Mitochondrial respiratory chain and free radical generation in stroke. Free Radic Biol Med 39, 1291-304.

232. Nagel, S., Wagner, S., Koziol, J., Kluge, В., and Heiland, S. (2004). Volumetric evaluation of the ischemic lesion size with serial MRI in a transient MCAO model of the rat: comparison of DWI and T1WI. Brain Res Brain Res1. Protoc 12, 172-9.

233. Namura, S., Zhu, J., Fink, K., Endres, M., Srinivasan, A., Tomaselli, K.J., Yuan, J., and Moskowitz, M.A. (1998). Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 18, 3659-68.

234. Napieralski, J.A., Banks, R.J., and Chesselet, M.F. (1998). Motor and somatosensory deficits following uni- and bilateral lesions of the cortex induced by aspiration or thermocoagulation in the adult rat. Exp Neurol 154, 80-8.

235. Nedospasov, A.A. (1998). Competition involving biogenic NO. Biochemistry (Mosc) 63, 744-65.

236. Nogawa, S„ Zhang, F., Ross, M.E., and Iadecola, C. (1997). Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 17, 2746-55.

237. Noguchi, C.T., Asavaritikrai, P., Teng, R., and Jia, Y. (2007). Role of erythropoietin in the brain. Crit Rev Oncol Hematol 64, 159-71.

238. Obrenovitch, T.P. (1995). The ischaemic penumbra: twenty years on. Cerebrovase Brain Metab Rev 7, 297-323.

239. O'Brien, M.D. and Waltz, A.G. (1973). Transorbital approach for occluding the middle cerebral artery without craniectomy. Stroke 4, 201-6.

240. Okada, M., Tamura, A., Urae, A., Nakagomi, Т., Kirino, Т., Mine, K.,and Fujiwara, M. (1995). Long-term spatial cognitive impairment following middle cerebral artery occlusion in rats. A behavioral study. J Cereb Blood Flow Metab 15, 505-12.

241. Oliff, H.S., Coyle, P., and Weber, E. (1997). Rat strain and vendor differences in collateral anastomoses. J Cereb Blood Flow Metab 17, 571-6.

242. Olney, J.W., de Gubareff, Т., and Labruyere, J. (1979). alpha-Aminoadipate blocks the neurotoxic action of N-methyl aspartate. Life Sci 25, 537-40.

243. Olney, J.W., Labruyere, J., and Price, M.T. (1989). Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244, 1360-2.

244. Ostrovskaya, R.U., Gudasheva, T.A., Zaplina, A.P., Vahitova, J.V., Salimgareeva, M.H., Jamidanov, R.S., and Seredenin, S.B. (2008). Noopept stimulates the expression of NGF and BDNF in rat hippocampus. Bull Exp Biol Med 146, 334-7.

245. Ostwald, K., Hagberg, H„ Andine, P., and Karlsson, J.O. (1993). Upregulation of calpain activity in neonatal rat brain after hypoxic-ischemia. Brain Res 630, 289-94.

246. Overgaard, К. (1994). Thrombolytic therapy in experimental embolic stroke. Cerebrovasc Brain Metab Rev 6, 257-86.

247. Pan, J., Konstas, A.A., Bateman, В., Ortolano, G.A., and Pile-Spellman, J. (2007). Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies. Neuroradiology 49, 93-102.

248. Papadopoulos, S.M., Chandler, W.F., Salamat, M.S., Topol, E.J., and Sackellares, J.C. (1987). Recombinant human tissue-type plasminogen activator therapy in acute thromboembolic stroke. J Neurosurg 67, 394-8.

249. Pattarawarapan, M. and Burgess, K. (2003). Molecular basis of neurotrophin-receptor interactions. J Med Chem 46, 5277-91.

250. Pellegrini-Giampietro, D.E. (2003). The distinct role of mGlul receptors in post-ischemic neuronal death. Trends Pharmacol Sci 24, 461-70.

251. PETERSON, G.M. and BARNETT, P.E. (1961). The cortical destruction necessary to produce a transfer of a forced-practice function. J Comp Physiol Psychol 54, 382-5.

252. Pignataro, G., Simon, R.P., and Xiong, Z.G. (2007). Prolonged activation of ASIC la and the time window for neuroprotection in cerebral ischaemia. Brain 130, 151-8.

253. Pilcher, H.R. (2003). Drug research: the ups and downs of lithium. Nature 425, 1 18-20.

254. Pisa, M. (1988). Motor functions of the striatum in the rat: critical role of the lateral region in tongue and forelimb reaching. Neuroscience 24, 453-63.

255. Prass, К., Braun, J.S., Dirnagl, U., Meisel, C., and Meisel, A. (2006). Stroke propagates bacterial aspiration to pneumonia in a model of cerebral ischemia. Stroke 37, 2607-12.

256. Prass, 1С., Scharff, A., Ruseher, 1С., Lowl, D., Muselmann, C., Victorov, I., ICapinya, ГС., Dirnagl, U., and Meisel. A. (2003). Ilypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin. Stroke 34, 1981-6.

257. Prast, H. and Philippu, A. (2001). Nitric oxide as modulator of neuronal function. Prog Neurobiol 64, 51-68.

258. Pulsinelli, W.A., Brierley, J.B., and Plum, F. (1982). Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11, 491-8.

259. Purdy, P.D., Devous, M.D. Sr, Batjer. H.H., White, C.L. 3rd, Meyer, Y., and Samson, D.S. (1989). Microfibrillar collagen model of canine cerebral infarction. Stroke 20, 1361-7.

260. Rak, R„ Chao, D.L., Pluta, R.M., Mitchell, J.В., Oldfield, E.H., and Watson, J.C. (2000). Neuroprotection by the stable nitroxide Tempol during reperlusion in a rat model of transient focal ischemia. J Neurosurg 92, 646-51.

261. Rami, A. and Krieglstein, J. (1993). Protective effects of calpain inhibitors against neuronal damage caused by cytotoxic hypoxia in vitro and ischemia in vivo. Brain Res 609, 67-70.

262. Rapp, .Т.Н., Pan, X.M., Yu, В., Swanson, R.A., Higashida, R.T., Simpson, P., and Saloner, D. (2003). Cerebral ischemia and infarction from atheroemboli <100 microm in Size. Stroke 34, 1976-80.

263. Rauca, C., Henrich-Noack, P., Schafer, K., Hollt, V., and Reymann, K.G. (1998). (S)-4C3ITPG reduces infarct size after focal cerebral ischemia. Neuropharmacology 37, 1649-52.

264. Regli, L., Anderson, R.E., and Meyer, F.B. (1995). Effects of intermittent reperfusion on brain pHi, rCBF, and NADH during rabbit focal cerebral ischemia. Stroke 26, 1444-51; discussion 1451-2.

265. Ren, M., Senatorov, V.V., Chen, R.W., and Chuang, D.M. (2003). Postinsult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia/reperfusion model. Proc Natl Acad Sci USA 100, 6210-5.

266. Ridder, D.A. and Schwaninger, M. (2009). NF-kappaB signaling in cerebral ischemia. Neuroscience 158, 995-1006.

267. Riobo, N.A., Melani, M., Sanjuan, N., Fiszman, M.L., Gravielle, M.C., Carreras, M.C., Cadenas, E., and Poderoso, J.J. (2002). The modulation of mitochondrial nitric-oxide synthase activity in rat brain development. J Biol Chem 277, 42447-55.

268. Robinson, M.J., Macrae, I.M., Todd, M., Reid, J.L., and McCulloch, J. (1990). Reduction of local cerebral blood flow to pathological levels by endothelin-1 applied to the middle cerebral artery in the rat. Neurosci Lett 118, 269-72.

269. Robinson, R.G., Shoemaker, W.J., Schlumpf, M., Valk, Т., and Bloom, F.E. (1975). Effect of experimental cerebral infarction in rat brain on catecholamines and behaviour. Nature 255, 332-4.

270. Rokitskaya, T.I., Klishin, S.S., Severina, 1.1., Skulachev, V.P. and Antonenko, Y.N. (2008). Kinetic analysis of permeation of mitochondria-targeted antioxidants across bilayer lipid membranes. J Membr Biol 224, 9-19.

271. Roos, A. and Boron, W.F. (1981). Intracellular pH. Physiol Rev 61, 296434.

272. Rosenbaum, D.M., Gupta, G., D'Amore, J., Singh, M., Weidenheim, K., Zhang, EI., and ICessler, J.A. (2000). Fas (CD95/APO-1) plays a role in the pathophysiology of focal cerebral ischemia. J Neurosci Res 61, 686-92.

273. Rosenbe rg, G.A. (2002). Matrix metalloproteinases in neuroinflammation. Glia 39, 279-91.

274. Rother, J. (2008). Neuroprotection does not work! Stroke 39, 523-4.

275. Rothman, S.M. and Olney, J.W. (1995). Excitotoxicity and the NMDA receptor—still lethal after eight years. Trends Neurosci 18, 57-8.

276. Rothman, S.M., Yamada, IC.A., and Lancaster, N. (1993). Nordihydroguaiaretic acid attenuates NMDA neurotoxicity—action beyond the receptor. Neuropharmacology 32, 1279-88.

277. Sabol, K.E., Neill, D.B., Wages, S.A., Church, W.H., and Justice, J.B. (1985). Dopamine depletion in a striatal subregion disrupts performance of a skilled motor task in the rat. Brain Res 335, 33-43.

278. Saluja, I., Song, D., O'Regan, M.H., and Phillis, J.W. (1997). Role ofphospholipase A2 in the release of free fatty acids during ischemia-reperfusion in the rat cerebral cortex. Neurosci Lett 233, 97-100.

279. Sambrook, J. and Gething, M.J. (1989). Protein structure. Chaperones, paperones. Nature 342, 224-5.

280. Sapirstein, A. and Bonventre, J.V. (2000). Phospholipases A2 in ischemic and toxic brain injury. Neurochem Res 25, 745-53.

281. Saragovi, H.U. and Gehring, K. (2000). Development of pharmacological agents for targeting neurotrophins and their receptors. Trends Pharmacol Sci 21, 93-8.

282. Schewe, T. (1995). Molecular actions of ebselen—an antiinflammatory antioxidant. Gen Pharmacol 26, 1 153-69.

283. Schoepp, D.D., Jane, D.E., and Monn, J.A. (1999). Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 38, 143 1-76.

284. Seeburg, P.H. (1993). The TINS/TiPS Lecture. The molecular biology of mammalian glutamate receptor channels. Trends Neurosci 16, 359-65.

285. Sengpiel, В., Preis, E., Krieglstein, J., and Prehn, J.H. (1998). NMDA-induced superoxide production and neurotoxicity in cultured rat hippocampal neurons: role of mitochondria. Eur J Neurosci 10, 1903-10.

286. Seubert, P., Larson, J., Oliver, M., Jung, M.W., Baudry, M., and Lynch,

287. G. (1988). Stimulation ofNMDA receptors induces proteolysis of spectrin in hippocampus. Brain Res 460, 189-94.

288. Shapira, S., Sapir, M., Wengier, A., Grauer, E., and Kadar, T. (2002). Aging has a complex effect on a rat model of ischemic stroke. Brain Res 925, 148-58.

289. Sharkey, J., Ritchie, 1.М., and Kelly, P.A. (1993). Perivascular microapplication of endothelin-1: a new model of focal cerebral ischaemia in the rat. J Cereb Blood Flow Metab 13, 865-71.

290. Sheardown, M.J., Nielsen, E.O., Hansen, A.J., Jacobsen, P., and Honore, T. (1990). 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline: a neuroprotectant for cerebral ischemia. Science 247, 571-4.

291. Shi, H. and Liu. K.J. (2007). Cerebral tissue oxygenation and oxidative brain injury during ischemia and reperfusion. Front Biosci 12, 1318-28.

292. Shigeno, Т., Mima, 'Г., Takakura, K., Graham, D.I., Kato, G., Hashimoto, Y., and Furukawa, S. (1991). Amelioration of delayed neuronal death in the hippocampus by nerve growth factor. J Neurosci 11, 2914-9.

293. Shigeno, Т., Teasdale, G.M., McCulloch, J., and Graham, D.I. (1985). Recirculation model following MCA occlusion in rats. Cerebral blood flow, cerebrovascular permeability, and brain edema. J Neurosurg 63, 212-1.

294. Shimamura, N., Matchett, G., Tsubokawa, Т., Ohkuma, H., and Zhang, J. (2006). Comparison of silicon-coated nylon suture to plain nylon suture in the rat middle cerebral artery occlusion model. J Neurosci Methods 156, 161-5.

295. Shimizu, K., Rajapakse, N., Horiguchi, Т., Payne, R.M., and Busija, D.W. (2003). Protective effect of a new nonpeptidyl mimetic of SOD, M4040I, against focal cerebral ischemia in the rat. Brain Res 963, 8-14.

296. Shpargel, K.B., Jalabi, W., Jin, Y., Dadabayev, A., Penn, M.S., and Trapp, B.D. (2008). Preconditioning paradigms and pathways in the brain. Cleve Clin J Med 75 Suppl 2, S77-82.

297. Siemkowicz, E. and Hansen, A.J. (1981). Brain extracellular ion composition and EEG activity following 10 minutes ischemia in normo- and hyperglycemic rats. Stroke 12, 236-40.

298. Siesjo, B.K. (1988). Acidosis and ischemic brain damage. Neurochem Pathol 9, 31-88.

299. Sicsjo, В.К., Katsura, К., Zhao, Q., Folbergrova, J., Pahlmark, K., Siesjo, P., and Smith, M.L. (1995). Mechanisms of secondary brain damage in global and focal ischemia: a speculative synthesis. J Neurotrauma 12, 943-56.

300. Simard, J.M., Tarasov, K.V., and Gerzanich, V. (2007). Non-selective cation channels, transient receptor potential channels and ischemic stroke. Biochim Biophys Acta /772, 947-57.

301. Simon, R.P., Swan, J.H., Griffiths, Т., and Meldrum, B.S. (1984). Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain. Science 226, 850-2.

302. Skaper, S.D. (2008). The biology of neurotrophins, signalling pathways, and functional peptide mimelics of neurotrophins and their receptors. CNS Neurol Disord Drug Targets 7, 46-62.

303. Skaper, S.D., Facci, L„ Milani, D„ and Leon. A. (1989). Monosialoganglioside GM1 protects against anoxia-induced neuronal death in vitro. Exp Neurol 106, 297-305.

304. Skulachcv, V.P. (2007). A biochemical approach to the problem of aging: "megaproject" on membrane-penetrating ions. The first results and prospects. Biochemistry (Mosc) 72, 1385-96.

305. Smith, P.K., Crohn, R.I., Hermanson, G.T., Mallia, A.K., Gartner, F.H., Provenzano, M.D., Fujimoto, E.K., Goeke, N.M. Olson, B.J., and Klenk, D.C. (1985). Measurement of protein using bicinchoninic acid. Anal Biochem 150, 76-85.

306. Soloniuk, D.S., Perkins, E., and Wilson, J.R. (1992). Use of allopurinol and deferoxamine in cellular protection during ischemia. Surg Neurol 38, 110n J.

307. Sorimachi, H., Ishiura, S., and Suzuki, K. (1997). Structure and physiological function of calpains. Biochem J 328 (Pt 3), 721-32.

308. Spedding, M. and Gressens, P. (2008). Neurotrophins and cytokines in neuronal plasticity. Novartis Found Symp 289, 222-33; discussion 233-40.

309. Spirduso, W.W., Gilliam, P.E., Schallert, Т., Upchurch, M., Vaughn, D.M., and Wilcox, R.E. (1985). Reactive capacity: a sensitive behavioral marker of movement initiation and nigrostriatal dopamine function. Brain Res 335, 45-54.

310. STAIR Stroke Therapy Academic Industry Roundtable (1999). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30, 2752-8.

311. Stover, J.F., Lowitzsch, K., and Kempski, O.S. (1997). Cerebrospinal fluid hypoxanthine, xanthine and uric acid levels may reflect glutamate-mediated exeitotoxicity in different neurological diseases. Neurosci Lett 238, 25-8.

312. Strauss. S., Otten, U., Joggerst, В., Pluss, K., and Volk, B. (1994). Increased levels of nerve growth factor (NGF) protein and mRNA and reactive gliosis following kainic acid injection into the rat striatum. Neurosci Lett 168, 193-6.

313. Sugawara, Т., Fujimura, M., Noshita, N., Kim, G.W., Saito, A., Hayashi, Т., Narasimhan, P., Maier, C.M., and Chan, P.FI. (2004). Neuronal death/survival signaling pathways in cerebral ischemia. NeuroRx 1, 17-25.

314. Sugawara, Т., Kawasc, M., Lewen, A., Noshita, N., Gasche, Y., Fujimura, M., and Chan, P.FI. (2000). Effect of hypotension severity on hippocampal CA1 neurons in a rat global ischemia model. Brain Res 877, 281 -7.

315. Sugimori, H., Yao, Fl., Ooboshi, H., Ibayashi, S., and lida, M. (2004). Krypton laser-induced photothrombotic distal middle cerebral artery occlusion without craniectomy in mice. Brain Res Brain Res Protoc 13, 189-96.

316. Sugimoto, K. and ladecola, C. (2003). Delayed effect of administrationof COX-2 inhibitor in mice with acute cerebral ischemia. Brain Res 960, 2736.

317. Suzuki, J., Yoshimoto, 'Г., Tnanka, S., and Sakamoto, T. (1980). Production of various models of cerebral infarction in the dog by means of occlusion of intracranial trunk arteries. Stroke 11, 337-41.

318. Swanson, R.A., Farrell, 1С, and Simon, R.P. (1995). Acidosis causes failure of astrocyte glutamate uptake during hypoxia. J Cereb Blood Flow Metab /5, 417-24.

319. Takagi, Y., Mitsui, A., Nishiyama, A., Nozaki, 1С., Sono, H., Gon, Y., Hashimoto, N., and Yodoi, J. (1999). Overexpression of thioredoxin in transgenic mice attenuates focal ischemic brain damage. Proc Natl Acad Sci U S A 96, 4131-6.

320. Takizawa, S., Hogan, M„ and Hakim, A.M. (1991). The effects of a competitive NMDA receptor antagonist (CGS-19755) on cerebral blood flow and pFI in focal ischemia. J Cereb Blood Flow Metab 11, 786-93.

321. Tan, C.C., Eckardt, ICU., and Ratcliffe, P.J. (1991). Organ distribution of erythropoietin messenger RNA in normal and uremic rats. Kidney Int 40, 6976.

322. Tatlisumak, Т. and Li, F. (2003). Use of diffusion- and perfusion-weighted magnetic resonance imaging in drug development for ischemic stroke. Curr Drug Targets CNS Neurol Disord 2, 131-41.

323. Tauskela, J.S. (2007). MitoQ—a mitochondria-targcted antioxidant. IDrugs 10, 399-412.

324. Thorne, R.G. and Frey, W.F1. 2nd (2001). Delivery of neurotrophic factors to the central nervous system: pharmacokinetic considerations. Clin Pharmacokinet 40, 907-46.

325. Tombaugh, G.C. and Sapolsky, R.M. (1993). Evolving concepts about the role of acidosis in ischemic neuropathology. J Neurochem 61, 793-803.

326. Tomita, M. and Fukuuchi, Y. (1996). Leukocytes, macrophages and secondary brain damage following cerebral ischemia. Acta Neurochir SuppI 66, 32-9.

327. Tomlinson, F.H., Anderson, R.E., and Meyer, F.B. (1993a). Brain pHi, cerebral blood flow, and NADH fluorescence during severe incomplete global ischemia in rabbits. Stroke 24, 435-43.

328. Tomlinson, F.H., Anderson, R.E., and Meyer, F.B. (1993b). Acidic foci within the ischemic penumbra of the New Zealand white rabbit. Stroke 24, 2030-9; discussion 2040.

329. Torriglia, A. and Lepretre, C. (2009). LEl/L-DNase II: interplay between caspase-dependent and independent pathways. Front Biosci 14, 4836-47.

330. Towbin, H,, Staehelin, Т., and Gordon, J. (1992). Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. 1979. Biotechnology 24, 145-9.

331. Tsukahara, Т., Yonekawa, Y., Tanaka, K., Ohara, O., Wantanabe, S.,

332. Kimura, Т., Nishijima, Т., and Taniguchi, Т. (1994). The role of brain-derived neurotrophic factor in transient forebrain ischemia in the rat brain. Neurosurgery 34, 323-3 1; discussion 331.

333. Varon, S. and Conner, J.M. (1994). Nerve growth factor in CNS repair. J Neurotrauma 11, 473-86.

334. Vignais, P.V. (2002). The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Cell Mol Life Sci 59, 1428-59.

335. Villoslada, P. and Genain, C.P. (2004). Role of nerve growth factor and other trophic factors in brain inflammation. Prog Brain Res 146, 403-14.

336. Vyas, Т.К., Shahiwala, A., Marathe, S., and Misra, A. (2005). Intranasal drug delivery for brain targeting. Curr Drug Deliv 2, 165-75.

337. Wahl, F., Allix, M„ Plotkine, M., and Boulu, R.G. (1992). Neurological and behavioral outcomes of focal cerebral ischemia in rats. Stroke 23, 267-72.

338. Walder, C.E., Green, S.P., Darbonne, W.C., Mathias, J., Rae, J., Dinauer, M.C., Curnutte, J.Т., and Thomas, G.R. (1997). Ischemic stroke injury is reduced in mice lacking a functional NADPH oxidase. Stroke 28, 2252-8.

339. Waldmann, R., Champigny, G., Bassilana, F., Heurteaux, C., and Lazdunski, M. (1997). A proton-gated cation channel involved in acid-sensing. Nature 386, 173-7.

340. Wang, G.J., Randall, R.D., and Thayer, S.A. (1994). Glutamate-induced intracellular acidification of cultured hippocampal neurons demonstrates altered energy metabolism resulting from Ca2+ loads. J Neurophysiol 72, 2563-9.

341. Wang, K.K. (2000). Calpain and caspasc: can you tell the difference? Trends Neurosci 23, 20-6.

342. Warnick, C.T. and Lazarus, H.M. (1 981). Recovery of nucleotide levels after cell injury. Can J Biochem 59 , 116-21.

343. Watkins, J. and Olverman, H. (1987b). Agonists and an tagonists for excitatory amino acid receptors. Trends in Neurosci. 10, 265-272.

344. Watkins, J.C. and Olverman, H.J. (1987a). Agonists and an tagonists for excitatory amino acid receptors. Trends in Neurosci. 10, 265-272.

345. Watson, B.D., Dietrich, W.D., Busto, R„ Wachtel, M.S., and Ginsberg, M.D. (1985). Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol /7,497-504.

346. Wei, G., Dawson, V.L., and Zweier, J.L. (1999). Role of neuronal andendothelial nitric oxide synthase in nitric oxide generation in the brain following cerebral ischemia. Biochim Biophys Acta 1455, 23-34.

347. Weiss, J., Goldberg, M.P., and Choi, D.W. (1986). Ketamine protects cultured neocortica! neurons from hypoxic injury. Brain Res 380, 186-90.

348. Wemmie, J.A., Askwith, C.C., Lamani, E., Cassell, M.D., Freeman, J.H. Jr, and Welsh, M.J. (2003). Acid-sensing ion channel 1 is localized in brain regions with high synaptic density and contributes to fear conditioning. J Neurosci 23, 5496-502.

349. Wester, P., Watson, B.D., Prado, R., and Dietrich, W.D. (1995). A photothrombotic 'ring' model of rat stroke-in-evolution displaying putative penumbral inversion. Stroke 26, 444-50.

350. Whishaw, I.Q., O'Connor, W.T., and Dunnett, S.B. (1986). The contributions of motor cortex, nigrostriatal dopamine and caudate-putamen to skilled fore limb use in the rat. Brain 109 ( Pt 5J, 805-43.

351. Wiebers, D.O., Adams, H.P. Jr, and Whisnant, J.P. (1990). Animal models of stroke: are they relevant to human disease? Stroke 27, 1-3.

352. Winterbourn, C.C. and Metodiewa, D. (1994). The reaction of superoxide with reduced glutathione. Arch Biochem Biophys 314, 284-90.

353. Woitzik, J. and Schilling, L. (2002). Control of completeness and immediate detection of bleeding by a single laser-Doppler flow probe during intravascular middle cerebral artery occlusion in rats. J Neurosci Methods 122, 75-8.

354. Woitzik, J., Schneider, U.C., Thome, C., Schroeck, H., and Schilling, L. (2006). Comparison of different intravascular thread occlusion models for experimental stroke in rats. J Neurosci Methods 151, 224-31.

355. Woodruff, G.N., Foster, A.C., Gill, R., Kemp, J.A., Wong, E.H., and1.erscn, L.L. (1987). The interaction between MK-801 and receptors forN-methyl-D-aspartate: functional consequences. Neuropharmacology 26, 903-9.

356. Wu, D. (2005). Neuroprotection in experimental stroke with targeted neurotrophins. NeuroRx 2, 120-8.

357. Wu, M.L. Chen, J.H., Chen, W.H., Chen, Y.J., and Chu, K.C. (1999). Novel role of the Ca(2+)-ATPase in NMDA-induced intracellular acidification. Am J Physiol 277, 01X1-21,

358. Xiong, Z.G., Chu, X.P., and Simon, R.P. (2006). Ca2+ -permeable acid-sensing ion channels and ischemic brain injury. J Membr Biol 209, 59-68.

359. Xiong. Z.G., Zhu, X.M., Chu, X.P., Minami, M., Hey, J., Wei, W.L., MacDonald, J.F., Wenunie, J.A., Price, M.P. Welsh, M.J., and Simon, R.P. (2004). Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 118, 687-98.

360. Xu, J., Culman, J., Blume, A., Brecht, S., and Gohlke, P. (2003). Chronic treatment with a low dose of lithium protects the brain against ischemic injuiy by reducing apoptolic death. Stroke 34. 1287-92.

361. Yagi, K., ICitazato, K.T., Uno, M., Tada, Y. Kinouchi, 'Г., Shimada, K., and Nagahiro, S. (2009). Edaravone. a free radical scavenger, inhibits MMP-9-related brain hemorrhage in rats treated with tissue plasminogen activator. Stroke 40, 626-31.

362. Yanamoto, H., Nagaia, I., Niitsu, Y., Xue, J.H., Zhang, Z., and Kikuchi, H. (2003). Evaluation of М С AO stroke models in normotensive rats: standardized neocortical infarction by the 3VO technique. Exp Neurol 182, 261-74.

363. Yang, Y., Yang, Т., Li, Q„ Wang, C.X., and Shuaib, A. (2002). A new reproducible focal cerebral ischemia model b> introduction of polyvinylsiloxane into the middle cerebral artery: a comparison study. J Neurosci Methods 118, 199-206.

364. Yermolaieva, O., Leonard, A.S., Schnizler, M.K., Abboud, P.M., and Welsh, M.J. (2004). Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel la. Proc Natl Acad Sci USA 101, 6752-7.

365. Ying, W., Han, S.K., Miller, J.W., and Swanson, R.A. (1999). Acidosis potentiates oxidative neuronal death by multiple mechanisms. J Neurochem 73, 1549-56.

366. Yonemori, F., Yamada, IT., Yamaguchi, Т., Uemura, A., and Tamura, A.1996). Spatial memory disturbance after focal cerebral ischemia in rats. J Cereb Blood Flow Metab 16, 973-80.

367. Yoon, K.W. and Rothman, S.M. (1991). Adenosine inhibits excitatory but not inhibitory synaptic transmission in the hippocampus. J Neurosci 11, 1375-80.

368. Yu, Z.F., Bruce-Keller, A.J., Goodman, Y., and Mattson, M.P. (1998). Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res 53, 613-25.

369. Zhai, J., Peoples, R.W., and Li, C. (1998). Proton inhibition of GABA-activated current in rat primary sensory neurons. Pflugers Arch 435, 539-45.

370. Zhang, L., Zhang, R.L., Wang, Y., Zhang, C., Zhang, Z.G., Meng, IT., and Chopp, M. (2005). Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor. Stroke 36, 847-52.

371. Zhang, R., Brennan, M.L., Shen, Z., MacPherson, J.C., Schmitt, D., Molenda, C.E., and Hazen, S.L. (2002). Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. J Biol Chem 277, 46116-22.

372. Zhao, K., Luo, G., Giannclli, S., and Szeto, H.H. (2005). Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell lines. Biochem Pharmacol 70,

373. Zweier, J.L., Wang, P., Samouilov, A., and Kuppusamy, P. (1995). Enz\ me-independent formation of nitric oxide in biological tissues. Nat Med1796-806.7, 804-9.

Обратите внимание, представленные выше научные тексты размещены для ознакомления и получены посредством распознавания оригинальных текстов диссертаций (OCR). В связи с чем, в них могут содержаться ошибки, связанные с несовершенством алгоритмов распознавания. В PDF файлах диссертаций и авторефератов, которые мы доставляем, подобных ошибок нет.