Vorinostat Corrects Cognitive and Non-Cognitive Symptoms in a Mouse Model of Fragile X Syndrome.
Vorinostat Corrects Cognitive and Non-Cognitive Symptoms in a Mouse Model of Fragile X Syndrome.
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Vorinostat在脆弱X综合征的小鼠模型中纠正了认知和非认知症状。
DOI：
10.1093/ijnp/pyab081
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发表时间：
2022-02-11
期刊：
影响因子：
--
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Ding Q;Wu X;Li X;Wang H
脆性X综合征（FXS）是由FMR1基因突变引起的。这是一种遗传性智力残疾和自闭症。尽管最近在阐明疾病机制方面取得了进展，但没有有效的药物。由于新药开发是一个漫长的过程，重新利用现有的fda批准的药物为FXS的临床干预提供了一个机会。我们之前的研究通过转录组分析预测了伏立诺他对FXS的潜在治疗作用。我们分析了伏立诺他诱导的转录组变化，并证实其与三氟拉嗪诱导的转录组变化相似，三氟拉嗪先前被证明可以纠正与FXS相关的病理结果。为了验证治疗效果，我们在FXS小鼠模型中检测了伏立诺他对纠正关键行为和细胞症状的作用。我们发现伏立他能恢复Fmr1基因敲除小鼠的物体定位记忆和被动回避记忆。对于非认知行为症状，伏立诺他纠正了自闭症相关的改变，包括重复行为和社会互动缺陷。在露天场地试验中，伏立诺他抑制了竞技场中心区域的过度活跃。令人惊讶的是，vorinostat并没有纠正培养的Fmr1敲除海马神经元中异常升高的蛋白质合成，这表明不同方面的病理结果可能对特定治疗干预有不同的反应。我们使用药物诱导的转录组标记来预测现有药物的新应用。我们的数据揭示了fda批准的药物伏立诺他对FXS小鼠模型的治疗效果。
Fragile X syndrome (FXS) is caused by mutations in the FMR1 gene. It is a form of heritable intellectual disability and autism. Despite recent advance in elucidating disease mechanisms, there is no efficacious medication. Because de novo drug development is a lengthy process, repurposing the existing FDA-approved drugs offers an opportunity to advance clinical intervention for FXS. Our previous study with transcriptome analysis predicts potential therapeutic effects of vorinostat on FXS. We analyzed the vorinostat-induced transcriptome changes and confirmed its similarity to that induced by trifluoperazine, which was previously shown to correct pathological outcomes associated with FXS. To validate the therapeutic efficacy, we examined vorinostat’s effect on correcting the key behavioral and cellular symptoms in a mouse model of FXS. We found that vorinostat restores object location memory and passive avoidance memory in the Fmr1 knockout mice. For the non-cognitive behavioral symptoms, vorinostat corrected the autism-associated alterations, including repetitive behavior and social interaction deficits. In the open field test, vorinostat dampened hyperactivity in the center area of the arena. Surprisingly, vorinostat did not correct the abnormally elevated protein synthesis in cultured Fmr1 knockout hippocampal neurons, suggesting that different aspects of pathological outcomes may respond differently to a specific therapeutic intervention. We used the drug-induced transcriptome signature to predict new application of existing drugs. Our data reveal the therapeutic effects of the FDA-approved drug vorinostat in a mouse model of FXS.
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