Аннотация
При некоторых патологических состояниях, например, фармакорезистентной эпилепсии, эпилептическом статусе или определённых формах генетических аномалий спайковая активность ГАМКергических интернейронов может усиливать процессы возбуждения в нервной ткани и провоцировать генерацию иктального разряда. В результате противосудорожные средства, действующие на ГАМКергическую систему, могут оказаться неэффективными или даже усиливать судорожную активность. Этот парадоксальный эффект работы тормозной системы обусловлен нарушением ионного баланса в нервной ткани. В данном обзоре рассмотрены механизмы инициации иктального разряда в нейронных сетях из-за нарушения баланса хлорид-ионов и ионов калия, а также возможные методы воздействия на регуляцию ионных концентраций. Для подавления эпилептической активности, вызванной дисбалансом ионов, эффективным может оказаться как усиление (или ослабление) активности определенных транспортеров ионов и ионных насосов в нейронах, так и их дополнительная экспрессия с помощью генной терапии. В поддержании необходимых концентраций ионов калия и хлора в нервной ткани важное значение имеют NaK-помпа, NKCC1- и KCC2-котранспортеры, которые ранее неоднократно рассматривались в качестве фармакологических мишеней для противоэпилептического воздействия. Препятствием для работы в этом направлении является отсутствие достаточно селективных фармакологических инструментов для воздействия на них, а также методов доставки препаратов к эпилептическому очагу. Более перспективным направлением представляется использование методов генной терапии, таких как гиперэкспрессия транспортера KCC2 в эпилептическом очаге. Другим возможным направлением может стать применение оптогенетических инструментов: специально сконструированных светочувствительных ионных помп или каналов. В этом случае энергия фотонов может быть использована для создания требуемых градиентов хлорид-ионов и ионов калия, однако и у этих методов пока есть существенные ограничения, которые затрудняют их быстрое введение в практику.
Литература
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