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Заключение

Клеточные и молекулярные механизмы патогенеза БП активно изучаются в последние два десятилетия. Особое значение имеют результаты клинических исследований, проведенных с помощью неинвазивных нейровизуализационных методов и патоанатомических исследований, выполненных на аутопсийном материале, полученном в терминальной фазе клинической стадии (Угрюмов, 2010; Betarbet et al., 2000b; Bezard et al., 2001; Palfi et al., 2002; Sandmann-Keil, Braak, 2005; Ugrumov, 2008).

На основе данных клинических исследований создано два типа экспериментальных моделей БП: токсические и генетические, которые имитируют комплементарные механизмы патогенеза. Генетические модели воспроизводят протеинопатии и агрегацию патологических белков, а токсические модели - избирательную гибель ДА-ергических нейронов нигростриатной системы. Наиболее широко используются модели на основе применения нейротоксинов, специфических для ДА-ергических нейронов, 6-ГДА и МФТП. В подавляющем большинстве работ моделирование БП затрагивает только терминальную фазу симптомной стадии, когда подавляющее большинство ДА-ергических нейронов уже погибло и лечение крайне неэффективно (Tranzer, Thoenen, 1968; Ungerstedt, 1968; Gerlach, Riederer, 1996). Исследования, проведенные на таких моделях, позволили идентифицировать два типа качественно различающихся и включающихся последовательно компенсаторных процессов, которые направлены на поддержание межклеточной концентрации ДА и на повышение чувствительности клеток-мишеней к ДА. Однако до последнего времени остается неясной динамика и молекулярные механизмы дегенерации ДА-ергических нейронов и включающихся при этом компенсаторных процессов на ранних этапах заболевания (доклиническая стадия) - до появления нарушений двигательной функции. Более того, отсутствует информация о том, какие именно компенсаторные процессы включаются на доклинической стадии БП, и приводит ли именно их «истощение» к нарушению двигательной функции.
На эти вопросы в настоящее время невозможно ответить, используя клинический материал, т.к. до сих пор невозможно выявить больных на доклинической стадии. Приблизиться к пониманию механизмов начальных этапов развития БП пока можно, только используя экспериментальные модели доклинической и ранней клинической стадий БП, которые недавно были разработаны авторами статьи. Эти модели сейчас широко используются для выяснения клеточно-молекулярных механизмов нейродегенерации, пластичности нигростриатной системы мозга и поиска триггеров нарушения моторной функции, т.е. клеточно-молекулярных механизмов, ответственных за переход из доклинической стадии в клиническую. Более того, они воспроизводят не только локальную дегенерацию нигростриатных ДА-ергических нейронов, но и системные патологические изменения в нервной системе и как следствие - в функциональной активности внутренних органов и в составе физиологически активных веществ в крови. Эти исследования позволяют идентифицировать относительно специфичные периферические легкодоступные для анализа биомаркеры, на основе которых предполагается создать комплексную диагностику БП на доклинической стадии. Такой подход имеет большое значение и при поиске новых молекулярных мишеней для медикаментозной терапии, основанной на замедлении дегенерации нейронов и регуляции компенсаторных процессов с учетом их специфики на каждой стадии заболевания. Особый интерес представляет поиск молекулярных механизмов - триггеров нарушения моторного поведения, которые также могут служить мишенями для фармакотерапии нового поколения. Создание доклинической диагностики и превентивной нейропротекторной терапии, направленной на остановку или замедление нейродегенерации, позволит продлить неограниченно долго (до смерти по другой причине) доклиническую стадию заболевания и период комфортной жизни потенциального больного.

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Источник: М.В. Угрюмова. НЕЙРОДЕГЕНЕРАТИВНЫЕ ЗАБОЛЕВАНИЯ: от генома до целостного организма. В 2-х томах. Том 1 / Под ред. М.В. Угрюмова. - М.: Научный мир,2014. - 580 с.. 2014

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