Maeda Kazuma, Tanimura Miki, Masago Yusaku, Horiyama Tsukasa, Takemoto Hiroshi, Sasaki Takuya, Koyama Ryuta, Ikegaya Yuji, Ogawa Koichi
Laboratory for Drug Discovery and Disease Research, Shionogi Pharmaceutical Research Center, Shionogi and Co., Ltd., Osaka, Japan.
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Front Pharmacol. 2024 Aug 29;15:1455812. doi: 10.3389/fphar.2024.1455812. eCollection 2024.
Autism Spectrum Disorder (ASD) is a developmental condition characterized by core symptoms including social difficulties, repetitive behaviors, and sensory abnormalities. Aberrant morphology of dendritic spines within the cortex has been documented in genetic disorders associated with ASD and ASD-like traits. We hypothesized that compounds that ameliorate abnormalities in spine dynamics might have the potential to ameliorate core symptoms of ASD. Because the morphology of the spine is influenced by signal inputs from other neurons and various molecular interactions, conventional single-molecule targeted drug discovery methods may not suffice in identifying compounds capable of ameliorating spine morphology abnormalities. In this study, we focused on spine phenotypes in the cortex using BTBR /J (BTBR) mice, which have been used as a model for idiopathic ASD in various studies. We established an compound screening system using primary cultured neurons from BTBR mice to faithfully represent the spine phenotype. The compound library mainly comprised substances with known target molecules and established safety profiles, including those approved or validated through human safety studies. Following screening of this specialized library containing 181 compounds, we identified 15 confirmed hit compounds. The molecular targets of these hit compounds were largely focused on the 5-hydroxytryptamine receptor (5-HTR). Furthermore, both 5-HTR agonist and 5-HTR antagonist were common functional profiles in hit compounds. Vortioxetine, possessing dual attributes as a 5-HTR agonist and 5-HTR antagonist, was administered to BTBR mice once daily for a period of 7 days. This intervention not only ameliorated their spine phenotype but also alleviated their social behavior abnormality. These results of vortioxetine supports the usefulness of a spine phenotype-based assay system as a potent drug discovery platform targeting ASD core symptoms.
自闭症谱系障碍（ASD）是一种发育性疾病，其特征在于核心症状，包括社交困难、重复行为和感觉异常。在与ASD和ASD样特征相关的遗传疾病中，已记录到皮质内树突棘的异常形态。我们假设，能够改善脊柱动力学异常的化合物可能具有改善ASD核心症状的潜力。由于脊柱的形态受来自其他神经元的信号输入和各种分子相互作用的影响，传统的单分子靶向药物发现方法可能不足以识别能够改善脊柱形态异常的化合物。在本研究中，我们使用BTBR /J（BTBR）小鼠研究皮质中的脊柱表型，该小鼠在各种研究中被用作特发性ASD的模型。我们建立了一个使用来自BTBR小鼠的原代培养神经元的化合物筛选系统，以忠实地呈现脊柱表型。化合物库主要包含具有已知靶分子和既定安全性的物质，包括那些通过人体安全性研究批准或验证的物质。在筛选了这个包含181种化合物的专门文库后，我们鉴定出15种确认的活性化合物。这些活性化合物的分子靶点主要集中在5-羟色胺受体（5-HTR）上。此外，5-HTR激动剂和5-HTR拮抗剂都是活性化合物中的常见功能特征。伏硫西汀具有5-HTR激动剂和5-HTR拮抗剂的双重属性，每天给BTBR小鼠给药一次，持续7天。这种干预不仅改善了它们的脊柱表型，还减轻了它们的社交行为异常。伏硫西汀的这些结果支持了基于脊柱表型的检测系统作为靶向ASD核心症状的有效药物发现平台的有用性。
