Torre Matthew, Bukhari Hassan, Nithianandam Vanitha, Zanella Camila A, Mata Douglas A, Feany Mel B
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Foundation Medicine, Inc., Cambridge, MA.
bioRxiv. 2023 Jun 5:2023.06.01.543297. doi: 10.1101/2023.06.01.543297.
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 , our goal was to validate a model of CRCI. We administered the chemotherapeutic agents cisplatin, cyclophosphamide, and doxorubicin to adult . Neurocognitive deficits were observed with all tested chemotherapies, especially cisplatin. We then performed histologic and immunohistochemical analysis of cisplatin-treated tissue, demonstrating neuropathologic evidence of increased neurodegeneration, DNA damage, and oxidative stress. Thus, our model of CRCI recapitulates clinical, radiologic, and histologic alterations reported in chemotherapy patients. Our new model can be used for mechanistic dissection of pathways contributing to CRCI and pharmacologic screens to identify novel therapies to ameliorate CRCI.
化疗相关认知障碍（CRCI）是治疗中常见的不良反应，其特征是涉及包括记忆在内的多个认知领域的功能缺陷。尽管CRCI发病率高，且预计未来几十年癌症幸存者数量会增加，但CRCI的病理生理学仍未完全明确，这凸显了研究CRCI新模型系统的必要性。鉴于在[具体生物模型]中强大的一系列基因方法和便捷的高通量筛选能力，我们的目标是验证一个CRCI模型。我们给成年[具体生物模型]施用了化疗药物顺铂、环磷酰胺和阿霉素。所有测试的化疗药物均观察到神经认知缺陷，尤其是顺铂。然后我们对顺铂处理的[具体生物模型]组织进行了组织学和免疫组织化学分析，证明了神经退行性变增加、DNA损伤和氧化应激的神经病理学证据。因此，我们的CRCI模型概括了化疗患者中报道的临床、放射学和组织学改变。我们的新模型可用于对导致CRCI的途径进行机制剖析，并进行药物筛选以识别改善CRCI的新疗法。
