Толерантность к парадоксальному увеличению двигательной активности, вызванной ингибированием фосфодиэстеразы 10А, на модели гиподофаминергии

Введение: Фосфодиэстеразы (ФДЭ) – группа ферментов, гидролизующих фосфодиэфирную связь в циклических нуклеотидах. ФДЭ10A в основном представлена в среднеразмерных шипиковых нейронах стриатума. Функционально ингибирование ФДЭ10A имитирует действие агонистов D1-подобных и антагонистов D2-подобных дофаминовых рецепторов, одновременно модулируя «прямой» и «непрямой» стриато-таламо-кортикальные пути мозга. К настоящему моменту охарактеризованы преимущественно эффекты ингибирования ФДЭ10A, воспроизводящие угнетающее двигательную активность действие антагонистов D2-подобных дофаминовых рецепторов.

Цель работы: оценка стимулирующего двигательную активность действия ингибиторов ФДЭ10А, а также возможного развития толерантности к данным эффектам при их повторном введении.

Методы: Гиподофаминергическое состояние у самцов крыс стока Wistar моделировали введением ингибитора VMAT2 тетрабеназина (3 мг/кг). Эффекты селективных ингибиторов ФДЭ10А, MP-10 (0,3-5 мг/кг) и RO5545965 (0,1-0,9 мг/кг), на двигательную активность крыс оценивали при однократном и повторном введении (5 и 10 дней). 

Результаты: Выключение ФДЭ10А дозозависимо стимулировало двигательную активность крыс после введения тетрабеназина. Однако повторное введение ингибиторов ФДЭ10А сопровождалось развитием толерантности к их парадоксальному стимулирующему действию.

Заключение: Развитие толерантности может ограничивать потенциальное клиническое использование ингибиторов ФДЭ10А с целью коррекции гиподофаминергических симптомов у пациентов с болезнью Паркинсона. Необходимы исследования молекулярных механизмом данного явления.

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