<b>Small molecule ion channel agonist/antagonist screen</b> <b>DATA</b>

The neurogenetic disorder duplication 15q syndrome (Dup15q) is characterized by a high incidence of autism spectrum disorder (ASD) and pharmacoresistant epilepsy. Standard-of-care broad-spectrum anti-epileptic drugs (AED) often fail to control seizures in Dup15q, emphasizing the need for the identification of new therapeutic compounds. Previously, we generated a model of Dup15q in <i>Drosophila melanogaster</i> by overexpressing <i>Dube3a</i> in glial cells, instead of neurons. This model recapitulates the spontaneous seizures present in Dup15q patients. Here, we screened a set of FDA-approved compounds for their ability to suppress seizures in <i>repo&gt;Dube3a</i> flies. We used 72 compounds from the Enzo SCREEN-WELL Ion Channel Library for primary screening of seizure suppression. Six compounds were identified that significantly reduced seizure duration. Furthermore, the compounds that passed the primary and secondary screenings were associated with K⁺ channels. Glial-specific knockdown of the inward rectifying potassium (<i>Irk</i>) 2 channel exacerbated the seizure phenotype in these animals indicating a mechanism of action for drugs that bind irk2, like minoxidil, and are able to suppress seizures through the rebalancing of K+ extracellularly. This pharmacological and molecular investigation further supports the role of extracellular K⁺ content in Dup15q seizure activation and provides a putative target for therapeutic intervention.<br>

神经遗传性15号染色体区域重复综合征（duplication 15q syndrome, Dup15q）以自闭症谱系障碍（autism spectrum disorder, ASD）高发以及耐药性癫痫为主要特征。临床标准治疗方案中的广谱抗癫痫药物（anti-epileptic drugs, AED）往往无法有效控制Dup15q患者的癫痫发作，凸显了开发新型治疗化合物的迫切需求。此前，我们通过在黑腹果蝇（Drosophila melanogaster）的胶质细胞而非神经元中过表达Dube3a基因，构建了Dup15q疾病模型，该模型能够重现Dup15q患者的自发性癫痫发作表型。本研究中，我们针对repo驱动Dube3a过表达的果蝇（repo>Dube3a果蝇），筛选了可抑制癫痫发作的FDA批准化合物。我们采用恩佐（Enzo）SCREEN-WELL离子通道文库中的72种化合物开展癫痫抑制活性初筛，最终鉴定出6种可显著缩短癫痫发作持续时间的化合物。此外，通过初筛与复筛的化合物均与钾离子（K+）通道相关。对内向整流钾（Irk）2通道进行胶质细胞特异性敲低后，果蝇的癫痫表型显著加剧，这提示了米诺地尔等结合Irk2通道的药物的作用机制：通过重新平衡细胞外钾离子水平来抑制癫痫发作。本项药理学与分子生物学研究进一步证实了细胞外钾离子浓度在Dup15q癫痫发作激活过程中的作用，并为该疾病的治疗干预提供了潜在靶点。

搜集汇总

背景与挑战

背景概述

该数据集包含针对复制15q综合征（Dup15q）相关癫痫的小分子离子通道激动剂/拮抗剂筛选数据，使用果蝇模型过表达Dube3a模拟疾病发作，并筛选了72种FDA批准化合物，发现六种化合物能显著减少癫痫持续时间且与钾离子通道相关。研究揭示了通过调节细胞外钾离子平衡抑制癫痫的机制，为Dup15q的治疗提供了潜在药物靶点。