Characterization of the Molecular Mechanisms Underlying Lurasidone-Induced Acute Manic Episodes in Bipolar Depression: A Network Pharmacology and Molecular Docking Approach

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-04-09 DOI:10.1111/cns.70383

Chao Li, Lei Yang, Qiuyu Zhang, Ying Zhang, Ranli Li, Feng Jia, Lina Wang, Xiaoyan Ma, Hongjun Tian, Chuanjun Zhuo

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引用次数: 0

Abstract

Background

Lurasidone monotherapy has been approved for the treatment of bipolar depression. However, several case reports have indicated treatment with lurasidone-induced acute mania in people with bipolar depression. The mechanism by which this occurs remains to be elucidated.

Objective

In this study, we systematically explored the mechanism of action of lurasidone-induced acute mania in bipolar depression using network pharmacology and molecular docking.

Methods

Putative target genes for lurasidone were obtained from the GeneCards, PharmMapper, SwissTargetPrediction, and DrugBank databases. Targets for bipolar depression and acute mania were collected from the DisGeNET and GeneCards databases. A protein–protein interaction (PPI) network was built to screen the hub targets. The Bioinformatics platform and Database for Annotation, Visualization, and Integrated Discovery were used for the visualization of the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of the top 20 core targets. The drug-pathway-target-disease network was constructed using Cytoscape. Finally, molecular docking was performed to evaluate the binding affinity between lurasidone and potential targets.

Results

In total, 327, 1253, and 429 targets of lurasidone, bipolar depression, and acute mania were identified, respectively. A topological analysis of the PPI network revealed the top 20 hub targets. Based on PPI, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the top 20 hub targets, lurasidone was found to induce acute manic episodes in people with bipolar depression by targeting the serotonergic synapse signaling pathway via MAOB, HTR1A, HTR2A, HTR3A, SLC18A2, HTR1B, and HTR7. Molecular docking revealed good binding affinities between lurasidone and these potential targets.

Conclusions

This study revealed that lurasidone may regulate the serotonergic synapse signaling pathway by interacting with the identified core targets MAOB, HTR1A, HTR2A, HTR3A, SLC18A2, HTR1B, and HTR7 to induce treatment-emergent mania in people with bipolar depression. Our work provides a theoretical basis for the pharmacology of lurasidone-induced acute mania in bipolar depression and further basic research.

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鲁拉西酮诱导双相抑郁症急性躁狂发作的分子机制表征：网络药理学和分子对接方法

鲁拉西酮单药疗法已被批准用于治疗双相抑郁症。然而，一些病例报告表明，鲁拉西酮诱导的急性躁狂症治疗双相抑郁症患者。这种现象发生的机制还有待阐明。目的利用网络药理学和分子对接技术，系统探讨鲁拉西酮诱导急性躁狂症治疗双相抑郁症的作用机制。方法从GeneCards、PharmMapper、SwissTargetPrediction和DrugBank数据库中获取鲁拉西酮的推定靶基因。双相抑郁和急性躁狂症的目标从DisGeNET和GeneCards数据库中收集。构建蛋白-蛋白相互作用（PPI）网络筛选枢纽靶点。利用生物信息学平台和Database for Annotation， Visualization， and Integrated Discovery对前20个核心靶点进行基因本体可视化和京都基因与基因组百科全书分析。利用Cytoscape构建了药物通路-靶点-疾病网络。最后进行分子对接，评估鲁拉西酮与潜在靶点的结合亲和力。结果鲁拉西酮、双相抑郁和急性躁狂症的治疗靶点分别为327、1253和429个。对PPI网络的拓扑分析揭示了前20个枢纽目标。基于PPI、Gene Ontology和京都基因与基因组百科全书对前20个枢纽靶点的通路分析，我们发现鲁拉西酮通过MAOB、HTR1A、HTR2A、HTR3A、SLC18A2、HTR1B和HTR7靶向5 -羟色胺能突触信号通路，诱导双相抑郁症患者急性躁狂发作。分子对接显示鲁拉西酮与这些潜在靶点具有良好的结合亲和力。结论鲁拉西酮可能通过与MAOB、HTR1A、HTR2A、HTR3A、SLC18A2、HTR1B、HTR7等核心靶点相互作用，调控5 -羟色胺能突触信号通路，诱导双相抑郁症患者治疗性躁狂。本研究为鲁拉西酮诱导双相抑郁症急性躁狂的药理学及进一步的基础研究提供了理论依据。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.