A Drosophila model of chemotherapy-related cognitive impairment.
A Drosophila model of chemotherapy-related cognitive impairment.
复制标题
化疗相关认知障碍的果蝇模型。
DOI：
10.1101/2023.06.01.543297
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Feany,MelB
中科院分区：
文献类型：
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作者：
Torre,Matthew;Bukhari,Hassan;Nithianandam,Vanitha;Zanella,CamilaA;Mata,DouglasA;Feany,MelB
化疗相关认知障碍（CRCI）是一种常见的治疗不良反应，其特点是涉及包括记忆在内的多个认知领域的缺陷。尽管 CRCI 的发病率很高，并且预计未来几十年癌症幸存者会增加，但 CRCI 的病理生理学仍未完全了解，这凸显了需要新的模型系统来研究 CRCI。鉴于果蝇中强大的遗传方法和简便的高通量筛选能力，我们的目标是验证 CRCI 的果蝇模型。我们对成年果蝇施用化疗药物顺铂、环磷酰胺和阿霉素。所有测试的化疗药物（尤其是顺铂）均观察到神经认知缺陷。然后，我们对顺铂处理的果蝇组织进行了组织学和免疫组织化学分析，证明了神经变性、DNA 损伤和氧化应激增加的神经病理学证据。因此，我们的 CRCI 果蝇模型概括了化疗患者报告的临床、放射学和组织学改变。我们的新果蝇模型可用于对 CRCI 通路进行机械剖析和药理学筛选，以确定改善 CRCI 的新疗法。
Chemotherapy-related cognitive impairment (CRCI) is a common adverse effect of treatment and is characterized by deficits involving multiple cognitive domains including memory. Despite the significant morbidity of CRCI and the expected increase in cancer survivors over the coming decades, the pathophysiology of CRCI remains incompletely understood, highlighting the need for new model systems to study CRCI. Given the powerful array of genetic approaches and facile high throughput screening ability in Drosophila, our goal was to validate a Drosophila model of CRCI. We administered the chemotherapeutic agents cisplatin, cyclophosphamide, and doxorubicin to adult Drosophila. Neurocognitive deficits were observed with all tested chemotherapies, especially cisplatin. We then performed histologic and immunohistochemical analysis of cisplatin-treated Drosophila tissue, demonstrating neuropathologic evidence of increased neurodegeneration, DNA damage, and oxidative stress. Thus, our Drosophila model of CRCI recapitulates clinical, radiologic, and histologic alterations reported in chemotherapy patients. Our new Drosophila model can be used for mechanistic dissection of pathways contributing to CRCI and pharmacologic screens to identify novel therapies to ameliorate CRCI.