Эпигенетическая регуляция транскрипционной активности генов, связанных с нейропротекторным действием цефтриаксона, в головном мозге у крыс на модели спорадической болезни Альцгеймера: участие гистоновой деацетилазы 1

Гистоновые деацетилазы (HDAC) – это ферменты, обеспечивающие подавление транскрипции генов, а ингибиторы HDAC рассматриваются как потенциальные лекарственные средства для лечения болезни Альцгеймера (БА). Ранее мы обнаружили, что цефтриаксон, антибиотик с нейропротекторной активностью, повышает уровни мРНК генов Ide и Mme, кодирующих ферменты, которые участвуют в катаболизме амилоидабета, в миндалине мозга у крыс линии OXYS, модели спорадической БА. С другой стороны, нарушения нейротрофических факторов (в частности, BDNF) играют важную роль в патогенезе БА. Более того, HDAC класса I (HDAC1) участвуют в регуляции транскрипционной активности Bdnf. Целью данного исследования было оценить влияние цефтриаксона на обогащение HDAC1 в промоторах генов Mme, Ide и Bdnf в миндалине у крыс OXYS и на уровни мРНК Bdnf в миндалине крыс OXYS и Вистар. Для эпигенетического анализа и определения уровней мРНК Bdnf использовали хроматин-иммунопреципитацию и количественную ПЦР, соответственно. Не выявлено значимого обогащения HDAC1 или его изменений под действием цефтриаксона в промоторах Mme и Ide. В то же время цефтриаксон ослаблял связывание HDAC1 с промотором IV Bdnf. Это новый механизм регуляции транскрипции в головном мозге цефтриаксоном, который может быть задействован в его нейропротекторной активности. У 5-месячных крыс OXYS он, по-видимому, играет минорную роль, поскольку цефтриаксон не изменял уровни транскрипта 5 Bdnf, содержащего экзоны IV и IX. Мы также впервые продемонстрировали транскриптспецифическую регуляцию транскрипции Bdnf с помощью цефтриаксона. Цефтриаксон значительно повысил уровни транскрипта 6 Bdnf, содержащего экзоны VII, VIII и IX. Результаты исследования могут быть учтены при терапии БА.

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