Aripiprazole intestinal side effects in flies

IF 5.9 3区农林科学 Q1 VETERINARY SCIENCES

Lab Animal Pub Date : 2025-05-02 DOI:10.1038/s41684-025-01555-y

Jorge Ferreira

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Abstract

Aripiprazole, a third-generation antipsychotic, acts as a dopamine partial agonist and is generally better tolerated than older antipsychotics by humans. However, many patients report gastrointestinal side effects, the mechanisms of which remain unclear. A study in Disease Models & Mechanisms used Drosophila melanogaster to model the potential gut toxicity of aripiprazole, exploring the conserved drug metabolism pathways and well-characterized intestinal system. Oral aripiprazole exposure in flies caused mitochondrial dysfunction, leading to elevated reactive oxygen species (ROS) and activation of the JNK (c-Jun N-terminal kinase) signaling pathway, linked to cellular stress and death, specifically via the fly orthologue basket (bsk). Chronic JNK activation disrupted intestinal homeostasis, triggered apoptosis and led to gut tissue degeneration. Here, the gene puckered, a negative regulator of JNK signaling, was upregulated, confirming pathway engagement. Notably, supplementation with antioxidants mitigated these toxic effects. These findings link aripiprazole-induced gut toxicity to mitochondrial dysfunction and ROS-dependent JNK activation and suggest a mechanistic basis for the drug’s gastrointestinal side effects observed in patients.

Original reference: Hurcomb, J.D. et al. Dis. Model. & Mech. 18, dmm052180 (2025)

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阿立哌唑对果蝇肠道的副作用

阿立哌唑是第三代抗精神病药，作为多巴胺部分激动剂，通常比人类较老的抗精神病药耐受性更好。然而，许多患者报告了胃肠道副作用，其机制尚不清楚。疾病模型研究& &；机制利用黑腹果蝇模拟阿立哌唑的潜在肠道毒性，探索保守的药物代谢途径和具有良好特征的肠道系统。口服阿利哌唑会导致果蝇线粒体功能障碍，导致活性氧（ROS）升高和JNK （c-Jun n -末端激酶）信号通路的激活，这与细胞应激和死亡有关，特别是通过果蝇同源物篮（bsk）。慢性JNK激活破坏肠道稳态，引发细胞凋亡，导致肠道组织变性。在这里，基因褶皱，JNK信号的负调节因子，被上调，确认通路参与。值得注意的是，补充抗氧化剂可以减轻这些毒性作用。这些发现将阿立哌唑诱导的肠道毒性与线粒体功能障碍和ros依赖性JNK激活联系起来，并提示了该药物在患者中观察到的胃肠道副作用的机制基础。原始参考文献：Hurcomb， J.D.等。分离模型。,机械18，dmm052180 （2025）

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来源期刊

Lab Animal 农林科学-兽医学

CiteScore

0.60

自引率

2.90%

发文量

181

审稿时长

>36 weeks

期刊介绍： LabAnimal is a Nature Research journal dedicated to in vivo science and technology that improves our basic understanding and use of model organisms of human health and disease. In addition to basic research, methods and technologies, LabAnimal also covers important news, business and regulatory matters that impact the development and application of model organisms for preclinical research. LabAnimal's focus is on innovative in vivo methods, research and technology covering a wide range of model organisms. Our broad scope ensures that the work we publish reaches the widest possible audience. LabAnimal provides a rigorous and fair peer review of manuscripts, high standards for copyediting and production, and efficient publication.