Antiviral Drug Ivermectin at Nanomolar Concentrations Inhibits Glycine-Induced Chloride Current in Rat Hippocampal Neurons.

Ivermectin (IVM) belongs to the class of macrocyclic lactones, which is used as an antiparasitic agent. At present, the researchers focus on possibility to use IVM in treatment of certain forms of cancer and viral diseases such as COVID-19. The mechanisms of IVM action are not clear. It is assumed that IVM affects chloride channels and increases cytoplasmic concentration of chloride. This study examines the effect of IVM on chloride currents induced by glycine (IGly). Experiments were carried out on isolated pyramidal neurons of the rat hippocampus with whole-cell patch clamp. A short-term (600 msec) application of IVM in a concentration of 10 µM induced a slow inward current, which persisted after washing the neurons. The low concentrations (0.1-1000 nM) of IVM did not induce any novel current, but it rapidly and reversibly reduced the peak amplitude and accelerated desensitization of IGly in a dose-dependent manner. The threshold concentrations of IVM sufficient to reduce peak amplitude of IGly and to accelerate desensitization of IGly were 100 nM and 0.1 nM, respectively. The study revealed a high sensitivity of neuronal glycine receptors to IVM.

Antiviral drug ivermectin in nanomolar concentrations inhibits glycine-induced chloride current in rat hippocampal neurons

Ivermectin (IVM) belongs to the class of macrocyclic lactones and is used as an antiparasitic agent. The possibility of using IVM for the treatment of certain forms of cancer, as well as an antiviral agent, in particular for the treatment of COVID-19, is discussed. The mechanisms of action of IVM are not fully understood. It is assumed that IVM changes the functioning of the chloride channels and increases the concentration of chloride in the cytoplasm. In this work, we studied the effect of IVM on the chloride current induced by glycine ( I _Gly). The work was carried out on isolated pyramidal neurons of the rat hippocampus using the patch clamp method. It was found that a short application (600 ms) of an IVM at a concentration of 10 muM causes the generation of a slow and irreversible incoming current. At low concentrations (0.1-1000 nM), the IVM did not induce its own current, but rapidly, reversibly, and in a dose-dependent manner reduced the peak amplitude and accelerated the desensitization of the I _Gly. The threshold concentration of the IVM to reduce the peak amplitude of I _Gly was 100 nM, and to accelerate the desensitization of I _Gly, it was 0.1 nM. So, a high sensitivity of neuronal glycine receptors to ivermectin has been firstly shown. Ивермектин принадлежит к классу макроциклических лактонов и используется как антипаразитарное средство. Обсуждается возможность использования препарата для лечения некоторых форм онкологических заболеваний, а также в качестве антивирусного средства, в частности, для лечения COVID-19. Механизмы действия ивермектина до конца не изучены. Предполагается, что он меняет работу хлорных каналов и увеличивает концентрацию хлора в цитоплазме. Изучали влияние ивермектина на хлорный ток, индуцированный глицином ( I _Gly) на изолированных пирамидных нейронах гиппокампа крысы методом patch-clamp. Короткая аппликация (600 мс) ивермектина в концентрации 10 мкМ вызывала генерацию медленного и необратимого при отмывании входящего тока. При низких концентрациях (0.1-1000 нМ) ивермектин не индуцировал собственный ток и при этом быстро, обратимо и дозозависимо уменьшал пиковую амплитуду и ускорял десенситизацию I _Gly. Пороговая концентрация ивермектина для уменьшения пиковой амплитуды I _Gly составляла 100 нМ, а для ускорения десенситизации I _Gly - 0.1 нМ. Показана высокая чувствительность нейрональных глициновых рецепторов к ивермектину.