Laboratory of Psychopharmacology, FSBI Zakusov Institute of Pharmacology, 125315, Moscow, Russia.
Laboratory of Radioisotope Research Methods, FSBI Zakusov Institute of Pharmacology, 125315, Moscow, Russia.
Eur J Pharmacol. 2021 Jul 15;903:174150. doi: 10.1016/j.ejphar.2021.174150. Epub 2021 May 5.
Inhibition of the activity of extracellular signal-regulated kinases (ERK1/2) induced by the activation of the dopamine D2 receptor signalling cascade may be a promising pharmacological target. The aim of this work was to study the involvement of ERK1/2 and dopamine D2 receptor in the mechanism of the anticonvulsant action of valproic acid (VA) and a new benzoylpyridine oxime derivative (GIZH-298), which showed antiepileptic activity in different models of epilepsy. We showed that subchronic exposure to maximal electroshock seizures (MES) for 5 days reduced the density of dopamine D2 receptors in the striatum of mice. GIZH-298 counteracted the decrease in the number of dopamine D2 receptors associated with MES and increased the number of ligand binding sites of dopamine D2 receptors in mice without MES. The affinity of dopamine D2 receptors to the ligand was not changed by GIZH-298. MES caused an increase in ERK1/2 and synapsin I phosphorylation in the striatum while GIZH-298, similar to VA, reduced the levels of both phospho-ERK1/2 and phosphosynapsin I after MES, which correlated with the decrease in the intensity of seizure in mice. In addition, GIZH-298 suppressed ERK1/2 phosphorylation in SH-SY5Y human neuroblastoma cells at therapeutic concentrations, while VA inhibited ERK1/2 phosphorylation in vivo but not in vitro. The data obtained expand the understanding of the mechanisms of action of VA and GIZH-298, which involve regulating the activity of ERK1/2 kinases, probably by modulating dopamine D2 receptors in limbic structures, as well as (in the case of GIZH-298) directly inhibiting of the ERK1/2 cascade.
抑制细胞外信号调节激酶（ERK1/2）的活性，ERK1/2 的活性由多巴胺 D2 受体信号级联的激活所诱导，这可能是一个有前途的药理学靶点。本工作的目的是研究 ERK1/2 和多巴胺 D2 受体在丙戊酸（VA）和一种新的苯甲酰基吡啶肟衍生物（GIZH-298）抗惊厥作用机制中的作用，GIZH-298 在不同的癫痫模型中显示出抗癫痫活性。我们表明，慢性电休克（MES）5 天暴露会降低小鼠纹状体中多巴胺 D2 受体的密度。GIZH-298 对抗与 MES 相关的多巴胺 D2 受体数量减少，并增加无 MES 的小鼠中多巴胺 D2 受体配体结合位点的数量。GIZH-298 不改变多巴胺 D2 受体对配体的亲和力。MES 导致纹状体中 ERK1/2 和突触蛋白 I 磷酸化增加，而 GIZH-298 与 VA 相似，可降低 MES 后磷酸化 ERK1/2 和磷酸化突触蛋白 I 的水平，这与小鼠癫痫发作强度降低相关。此外，GIZH-298 以治疗浓度抑制 SH-SY5Y 人神经母细胞瘤细胞中 ERK1/2 的磷酸化，而 VA 抑制体内 ERK1/2 的磷酸化，但不在体外。所获得的数据扩展了对 VA 和 GIZH-298 作用机制的理解，这些机制涉及调节 ERK1/2 激酶的活性，可能通过调节边缘结构中的多巴胺 D2 受体，以及（在 GIZH-298 的情况下）直接抑制 ERK1/2 级联反应。
