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 наук
• 2009

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.

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

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.

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