一种新型Tankyrase抑制剂乙酰化衍生物改善孤独症小鼠社交障碍的作用

A novel acetylated derivative of Tankyrase inhibitor ameliorates social deficits in a mouse model of autism spectrum disorder

摘要

目的 探讨一种新型Tankyrase抑制剂 (TNKI) 的酯化衍生物对孤独症谱系障碍 (ASD) 小鼠社交功能障碍的改善作用。方法 采用酯化修饰的策略合成一种TNKI的乙酰化衍生物 (命名为TNKI-Ac), 在293T细胞及ASD小鼠 (Shank3b^-/-小鼠) 原代皮层神经元中, 通过Western blotting、TOPflash荧光素酶报告基因、细胞外酸化率、胞内乳酸检测等方法评估其对Wnt信号和糖酵解的作用。并进一步经尾静脉注射给予Shank3b^-/-小鼠TNKI-Ac处理, 通过三箱社交实验、居住入侵实验、超声发声检测其对小鼠社交功能的影响。结果 TNKI-Ac在293T细胞和Shank3b^-/-小鼠原代皮层神经元中均表现出与TNKI原药类似的Wnt信号/糖酵解双抑制作用 (P<0.05)。比TNKI更优的是, 尾静脉注射TNKI-Ac可显著改善Shank3b^-/-小鼠的社交偏好性、社交互动和超声交流能力 (P<0.05)。结论 酯化修饰可在一定程度上改善TNKI的药效学特征, 其乙酰化衍生物TNKI-Ac对ASD小鼠社交功能障碍具有明确的改善作用, 具有做为前药分子进一步开发的潜能。

Abstract

Objective To investigate the effects of a novel esterified Tankyrase inhibitor (TNKI) on the social deficits in mice with autism spectrum disorder (ASD). Methods Esterification modification strategy was adopted to design and synthesize an acetylated TNKI (named as TNKI-Ac). Its inhibitory effects on Wnt signaling and glycolysis were evaluated using 293T cells and primary cortical neurons isolated from ASD mice (Shank3b^-/- mice) through Western blotting, TOPflash assay, extracellular acidification rate, and intracellular lactate levels. The TNKI-Ac was administered to Shank3b^-/- mice via tail vein injection, and its effects on social deficits were assessed by the three-chamber test, resident-intruder test and ultrasonic vocalization. Results Similar to the original TNKI, TNKI-Ac exhibited a dual inhibitory effect on Wnt signaling and glycolysis in both 293T cells and primary Shank3b^-/- cortical neurons (P<0.05). Superior to TNKI, tail vein injection of TNKI-Ac significantly ameliorated the social deficits (including social preference, social interaction and social communication) in Shank3b^-/- mice (P<0.05). Conclusion Esterification modification may improve the pharmacodynamic properties of TNKI to some extent. The acetylated derivative of TNKI can ameliorate the social deficits in ASD mice and may serve as a potential prodrug for further development.

关键词

孤独症谱系障碍 / 社交障碍 / Wnt信号 / 糖酵解 / Tankyrase抑制剂 / 小分子化合物 / 酯化 / Shank3b突变

Key words

autism spectrum disorder / social deficits / Wnt signaling / glycolysis / Tankyrase inhibitor / small-molecule compound / esterification / Shank3b mutation

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基金资助

科技部科技创新2030“脑科学与类脑研究”重大项目(2021ZD0201005)

陕西省重点研发计划项目(2025SF-YBXM-393)

陕西省自然科学基础研究计划项目(2025JC-YBMS-1027)