Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects
Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects
复制标题
全转录组计算机筛选表明心血管和传染病与非典型抗精神病药物副作用的作用机制有关
DOI：
10.1101/2020.04.09.033472
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Malekizadeh Y
中科院分区：
文献类型：
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作者：
Malekizadeh Y
背景：痴呆患者服用抗精神病药物后卒中/血栓栓塞事件、感染和死亡都显著增加，但人们对其有害的原因知之甚少。使用药物再利用范式的新应用，我们旨在确定潜在的不良事件机制。方法采用RNA测序方法对经氨硫pride、利培酮和volinanserin处理的SH‐SY5Y细胞进行全转录组测序。进行生物信息学分析，对来自国家生物技术信息中心基因表达综合库（NCBI GEO）中415,252个样本的抗精神病药物特征和表达数据之间的关联进行评分。结果：动脉硬化、静脉血栓栓塞和流感NCBI GEO衍生样本对抗精神病药物特征评分为阳性。富含抗精神病信号的途径与心血管和免疫系统有关（例如，脑源性神经营养因子[BDNF]、血小板源性生长因子受体[PDGFR]‐β、肿瘤坏死因子[TNF]、转化生长因子[TGF]‐β、硒氨基酸代谢和流感感染）。结论这些发现首次将抗精神病药物与特定心血管和感染性疾病的已知副作用联系起来，为解释相关不良事件提供了新的信息。
BackgroundStroke/thromboembolic events, infections, and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events.MethodsWhole transcriptome signatures were generated for SH‐SY5Y cells treated with amisulpride, risperidone, and volinanserin using RNA sequencing. Bioinformatic analysis was performed that scored the association between antipsychotic signatures and expression data from 415,252 samples in the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) repository.ResultsAtherosclerosis, venous thromboembolism, and influenza NCBI GEO‐derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (eg, brain derived neurotrophic factor [BDNF], platelet derived growth factor receptor [PDGFR]‐beta, tumor necrosis factor [TNF], transforming growth factor [TGF]‐beta, selenoamino acid metabolism, and influenza infection).ConclusionsThese findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events.