Роль кинуренинов в регуляции поведения и процессов памяти у дрозофилы

  • Александр Владимирович Журавлев Институт физиологии им. И. П. Павлова РАН
  • Екатерина Александровна Никитина Институт физиологии им. И. П. Павлова РАН; Российский государственный педагогический университет им. А. И. Герцена https://orcid.org/0000-0003-1897-8392
  • Елена Владимировна Савватеева-Попова Институт физиологии им. И. П. Павлова РАН
Ключевые слова: кинуренины, дрозофила, 3-гидроксикинуренин, кинуреновая кислота, память

Аннотация

Метаболиты кинуренинового пути обмена триптофана (КПОТ), или кинуренины, обладают рядом нейроактивных свойств. Нарушения КПОТ наблюдаются при различных заболеваниях нервной системы, таких как болезни Хантингтона, Паркинсона и Альцгеймера, старческое слабоумие, шизофрения, депрессивные состояния и др. Известны два основных механизма воздействия кинуренинов на процессы в нервных клетках — модуляция активности клеточных рецепторов и модуляция окислительно-восстановительного потенциала. Так, кинуреновая кислота (KYNA) является неспецифическим антагонистом ионотропных рецепторов глутамата и ингибитором эксайтотоксических процессов. 3-гидроксикинуренин (3НОК) ингибирует перекисное окисление липидов, но в высокой концентрации вследствие окислительной аутодимеризации вызывает гиперпродукцию пероксида водорода, что приводит к гибели нервных клеток. Молекулярные механизмы нейроактивности кинуренинов удобно исследовать на простых модельных объектах, таких как пчела и дрозофила, мутации генов КПОТ у которых они специфически влияют на содержание кинуренинов. Удобство использования мутантов дрозофилы для изучения нейротропных свойств кинуренинов определяется рядом обстоятельств: 1) отсутствие пути синтеза NAD+ из 3HOK у насекомых и, следовательно, влияния дефектов КПОТ на энергетический метаболизм; 2) отсутствие у насекомых ряда метаболитов КПОТ, таких как хинолиновая кислота, потенциирующая нейротоксические свойства 3НОК; 3) высокий уровень 3НОК в организме в силу необходимости синтезировать в большом количестве пигмент ксантомматин; 4) методическая простота проведения генетических, физиологических и молекулярно-биологических исследований. Накопление 3НОК у мутанта cardinal (сd) дрозофилы вызывает нарушение брачной песни самца и развитие синаптической патологии на поздних сроках жизни имаго. Кроме того, у cd наблюдается возраст-зависимое нарушение среднесрочной памяти в парадигме условно-рефлекторного подавления ухаживания. Вышеуказанное позволяет рассматривать сd как модель сенильной деменции у человека. Напротив, у мутанта cinnabar (cn) с накоплением KYNA отмечено позитивное влияние данного нейропротектора на память и звукопродукцию. В целом продукты КПОТ оказывают активирующее действие на ЦНС и поведенческие процессы.

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Опубликован
2020-03-02
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