Особенности метаболизма глутамата при шизофрении тема диссертации и автореферата по ВАК РФ 03.00.04, доктор биологических наук Бокша, Ирина Сергеевна

• Бокша, Ирина Сергеевна
• доктор биологических наук
• 2008

Оглавление диссертации доктор биологических наук Бокша, Ирина Сергеевна

I. ВВЕДЕНИЕ

АКТУАЛЬНОСТЬ ИССЛЕДОВАНИЯ

ЦЕЛЬ И ОСНОВНЫЕ ЗАДА ЧИ ИССЛЕДОВАНИЯ

НА УЧНАЯ НОВИЗНА РАБОТЫ

НАУЧНО-ПРАКТИЧЕСКОЕ ЗНАЧЕНИЕ РАБОТЫ

ОСНОВНЫЕ ПОЛОЖЕНИЯ РАБОТЫ

II. ОБЗОР ЛИТЕРАТУРЫ. МЕТАБОЛИЗМ ГЛУТАМАТА В МОЗГЕ ЧЕЛОВЕКА

ВЗАИМОСВЯЗЬ НЕЙРОМЕДИА ТОРНЫХ СИСТЕМ

ГЛУТАМАТЕРГИЧЕСКАЯГИПОТЕЗА ШИЗОФРЕНИИ 16 МОЗГ ПСИХИЧЕСКИ ЗДОРОВЫХ ЛИЦ. СОПРЯЖЕННОСТЬ

ФУНКЦИИ НЕЙРОНОВ И ГЛИИ ЧЕРЕЗ МЕТАБОЛИЗМ ГЛУТАМАТА

ГЛУТАМАТ/ГЛУТАМИНОВЫЙ ЦИКЛ

СХЕМА МЕТАБОЛИЗМА ГЛУТАМАТА

СИНТЕЗ ГЛУТАМАТА В НЕЙРОНАХ

ДРУГИЕ ПУТИ БИОСИНТЕЗА ГЛУТАМАТА

УТИЛИЗАЦИЯ ГЛУТАМАТА В НЕРВНОЙ ТКАНИ 30 ВКЛЮЧЕНИЕ ГЛУТАМАТА В ПЕПТИДЫ

И ЕГО ОТЩЕПЛЕНИЕ ОТ ПЕПТИДОВ 32 ПОГЛОЩЕНИЕ ГЛУТАМАТА И СИНТЕЗ ГЛУТАМИНА

- ЭНЕРГОЗАВИСИМЫЕ ПРОЦЕССЫ

ВЛИЯНИЕ рН И ДЕФИЦИТА ЭНЕРГИИ НА МЕТАБОЛИЗМ ГЛУТАМАТА 36 ОТ ЧАСТНЫХ ВОПРОСОВ (ОТДЕЛЬНЫЕ ФЕРМЕНТЫ МЕТАБОЛИЗМА

ГЛУТАМАТА) К ОБЩЕМУ (СИСТЕМНЫЕ СВЯЗИ)

ГЛУТАМИНСИНТЕТАЗА МОЗГА ЧЕЛОВЕКА

СТРУКТУРА ГЛУТАМИНСИНТЕТАЗЫ МОЗГА ЧЕЛОВЕКА

ГЛУТАМАТДЕГИДРОГЕНАЗА МОЗГА ЧЕЛОВЕКА 42 НАРУШЕНИЯ МЕТАБОЛИЗМА ГЛУТАМАТА ПРИ ПАТОЛОГИЯХ

НЕРВНОЙ СИСТЕМЫ

ФЕРМЕНТЫ ОБМЕНА ГЛУТАМА ТА В МОЗГЕ ПРИ ШИЗОФРЕНИИ 47 ФАРМАКОЛОГИЧЕСКИЕ ПОДХОДЫ К ЛЕЧЕНИЮ ШИЗОФРЕНИИ

НА ОСНОВЕ «ГЛУТАМА ТНОЙ ГИПОТЕЗЫ» ЕЕ ПА ТОГЕНЕЗА 49 БИОХИМИЧЕСКИЕ ИССЛЕДОВАНИЯ ПЕРИФЕРИЧЕСКОЙ

КРОВИ ПРИ ШИЗОФРЕНИИ 5 0 КОМПОНЕНТЫ ГЛУТАМАТНОЙ СИСТЕМЫ

В ТРОМБОЦИТАХ ПЕРИФЕРИЧЕСКОЙ КРОВИ

III. МЕТОДЫ ИССЛЕДОВАНИЯ

КЛИНИКО-АНА ТОМИЧЕСКИЙ И КЛИНИЧЕСКИЙ МА ТЕРИАЛ

ХАРАКТЕРИСТИКА КЛИНИЧЕСКОГО МАТЕРИАЛА

МЕТОДЫ ЛАБОРАТОРНЫХ ИССЛЕДОВАНИЙ

ВЫДЕЛЕНИЕ И ОЧИСТКА ФЕРМЕНТОВ

ВЫДЕЛЕНИЕ ГС

ВЫДЕЛЕНИЕ И ОЧИСТКА ИЗОФЕРМЕНТОВ ГДГ

МЕТОДЫ ИССЛЕДОВАНИЯ ОЧИЩЕННЫХ БЕЛКОВ

ПРИГОТОВЛЕНИЕ ЭКСТРАКТОВ БЕЛКОВ ТКАНИ МОЗГА

ОПРЕДЕЛЕНИЕ ФЕРМЕНТАТИВНОЙ АКТИВНОСТИ 63 ВЕСТЕРН-ИММУНОБЛОТТИНГ С ХЕМИЛЮМИНЕСЦЕНТНЫМ

УСИЛЕНИЕМ СИГНАЛА

МЕТОДЫ ИССЛЕДОВАНИЯ ТРОМБОЦИТОВ

СТАТИСТИЧЕСКИЕ МЕТОДЫ

IV. РЕЗУЛЬТАТЫ.

ГЛУТАМИНСИНТЕТАЗА МОЗГА ЧЕЛОВЕКА

СТРУКТУРА ГС МОЗГА ЧЕЛОВЕКА

ОБНАРУЖЕНИЕ И ИЗУЧЕНИЕ ГСПБ

ГЛУТАМАТДЕГИДРОГЕНАЗА МОЗГА ЧЕЛОВЕКА

И30Ф0РМЫ ГДГ МОЗГА ЧЕЛОВЕКА

СВОЙСТВА ОЧИЩЕННЫХ ИЗОФОРМ ГДГ 102 ФЕРМЕНТЫ МЕТАБОЛИЗМА ГЛУТАМАТА

В МОЗГЕ В НОРМЕ И ПРИ ШИЗОФРЕНИИ

ГС, ГСПБ И ГДГ В ПРЕФРОНТАЛЬНОЙ КОРЕ 107 КОЛИЧЕСТВО ГС, ГСПБ, ГДГ И ГЛИАЛЬНЫХ БЕЛКОВ

В РАЗЛИЧНЫХ СТРУКТУРАХ МОЗГА 112 ГС, ГСПБ, ГДГ, КФК ВВ, ГФКБ И ОМБ: СРАВНЕНИЕ

ГРУППЫ КОНТРОЛЯ С БОЛЬНЫМИ ШИЗОФРЕНИЕЙ

КОМПЛЕКСНЫЙ ПОДХОД В ИССЛЕДОВАНИИ БЕЛКОВ МОЗГА

СВЯЗИ МЕЖДУ КОЛИЧЕСТВОМ БЕЛКОВ

В ТРЕХ СТРУКТУРАХ МОЗГА 117 СВЯЗИ МЕЖДУ КОЛИЧЕСТВОМ БЕЛКОВ

В КАЖДОЙ ОБСЛЕДУЕМОЙ ГРУППЕ (КОНТРОЛЬ, ШИЗОФРЕНИЯ)

КЛАСТЕРНЫЙ АНАЛИЗ НЕЙРОХИМИЧЕСКИХ ДАННЫХ 121 ИЗМЕРЕНИЯ КОЛИЧЕСТВА КОМПОНЕНТОВ ГЛУТАМАТНОЙ

СИСТЕМЫ В ПЕРИФЕРИЧЕСКОЙ КРОВИ

ТРОМБОЦИТАРНЫЕ ГСПБ И ГДГ В КОНТРОЛЬНОЙ ГРУППЕ И

У БОЛЬНЫХ ШИЗОФРЕНИЕЙ (ДО КУРСА ЛЕЧЕНИЯ) 125 ГСПБ И ГДГ ТРОМБОЦИТОВ ДО И В ХОДЕ

АНТИПСИХОТИЧЕСКОГО ЛЕЧЕНИЯ

V. ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ

Заключение диссертации по теме «Биохимия», Бокша, Ирина Сергеевна

9) Результаты работы подтверждают правомочность существования глутаматной гипотезы патогенеза шизофрении, которая может быть представлена следующим образом: в патогенезе шизофрении играют роль не только рецепторы и переносчики глутамата, но также ферменты обмена глутамата. При этом особенности метаболизма глутамата при шизофрении состоят в изменениях количества ключевых метаболических ферментов в мозге и крови больных по сравнению с психически здоровыми лицами, а также в изменениях корреляционных связей между концентрациями этих ферментов в мозге больных по сравнению с психически здоровыми лицами.

VI. Заключение

В настоящей работе для понимания закономерностей, регулирующих количества ферментов метаболизма Глу в нервной ткани, использован системный подход [1, 89]. Можно отметить положительные моменты применения такого подхода в изучении метаболизма глутамата при шизофрении:

1) обнаружены корреляции количеств ряда белков, включая ферменты метаболизма глутамата, в мозге психически здоровых лиц и изменения корреляций при шизофрении;

2) обнаружены корреляции между количествами ключевых ферментов Глу (ГСПБ, ГДГ) в тромбоцитах и психопатологическими проявлениями шизофрении (повышение количества ферментов метаболизма Глу у больных шизофренией по сравнению с контролем зарегистрированы не только в

153 мозге, но и крови - в тромбоцитах), выяснено, антипсихотическое лечение влияет на количество тромбоцитарных ферментов метаболизма Глу; (3) выяснено, что количество ГСПБ, определенное до лечения, позволяет предсказать скорость достижения положительного эффекта от лечения (т.е. момент, когда больной становится «респондером»).

Таким образом, особенности метаболизма глутамата в мозге при шизофрении заключаются не только в изменении количеств ключевых ферментов метаболизма глутамата, но также нарушении регуляторных связей, поддерживающих уровни этих ферментов, причем изменяется также картина связей между уровнями ферментов и количествами основных структурных глиальных белков. Кроме того, в мозге появляется (регистрируется) новая, по-видимому, компенсаторная связь между количеством ключевых ферментов метаболизма глутамата и энергетического метаболизма (ГС и КФК ВВ).

Можно также отметить больший разброс уровней ферментов метаболизма Глу (особенно количеств ГСПБ) у больных по сравнению с психически здоровыми лицами, и эта особенность обнаружена при изучении мозговых и тромбоцитарных ферментов (в отсутствие различий между группами в возрасте и при равном числе представителей каждого пола).

Исходя из результатов исследования, представляется перспективным определение количеств ГСПБ и ГДГ в тромбоцитах с целью поиска и выделения подгрупп больных шизофренией, для которых лечение атипичными нейролептиками может быть более эффективным.

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