C5aR1 inhibition alleviates cranial radiation-induced cognitive decline.

IF 16.6 1区医学 Q1 ONCOLOGY

Cancer research Pub Date : 2025-10-14 DOI:10.1158/0008-5472.can-24-4869

Robert P Krattli,An H Do,Sanad M El-Khatib,Leila Alikhani,Mineh Markarian,Arya R Vagadia,Manal T Usmani,Shreya Madan,Janet E Baulch,Richard J Clark,Trent M Woodruff,Andrea J Tenner,Munjal M Acharya

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引用次数: 0

Abstract

Cranial radiation therapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive decline (RICD) is a particularly pressing problem for brain cancer survivors who live long post-RT lives. Radiation-induced neuroinflammation and gliosis lead to excessive loss of synaptic integrity and cognitive dysfunction. Using intact and brain cancer-bearing mouse models, we showed here that inhibiting anaphylatoxin complement C5a receptor (C5aR1) signaling is neuroprotective against RICD. Both genetic loss in a C5ar1 knockout mouse and pharmacological inhibition using the orally active, brain-penetrant C5aR1 antagonist PMX205 reversed RICD, leading to neurocognitive improvements in object recognition memory and memory consolidation tasks. Inhibiting the C5a/C5aR1 axis reduced microglial activation, astrogliosis, and synaptic loss in the irradiated brain. Importantly, C5aR1 blockade in two syngeneic, orthotopic glioblastoma-bearing mouse models protected against RICD and elevated gene signatures associated with neuroprotection without interfering with the therapeutic efficacy of RT in reducing tumor volume in vivo. As PMX205 has been found to be safe in clinical trials with healthy individuals, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need.

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C5aR1抑制可减轻颅脑辐射引起的认知能力下降。

脑癌的颅放射治疗（RT）导致认知功能不可逆转的下降，没有可用的补救措施。辐射引起的认知能力下降（RICD）是脑癌幸存者在放射治疗后长期生存的一个特别紧迫的问题。辐射引起的神经炎症和神经胶质瘤导致突触完整性的过度丧失和认知功能障碍。通过完整的和脑癌小鼠模型，我们发现抑制过敏毒素补体C5a受体（C5aR1）信号传导对RICD具有神经保护作用。C5ar1基因敲除小鼠的基因缺失和口服C5ar1脑渗透拮抗剂PMX205的药理学抑制都逆转了RICD，导致物体识别记忆和记忆巩固任务的神经认知改善。抑制C5a/C5aR1轴可减少受辐射脑中的小胶质细胞活化、星形胶质细胞形成和突触丧失。重要的是，C5aR1阻断在两种同基因的原位胶质母细胞瘤小鼠模型中可以防止RICD和与神经保护相关的基因特征升高，而不会干扰RT在体内减少肿瘤体积的治疗效果。由于PMX205在健康个体的临床试验中被发现是安全的，C5aR1抑制是解决RICD的一种翻译可行的方法，这是一种未满足的医疗需求。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer research 医学-肿瘤学

CiteScore

16.10

自引率

0.90%

发文量

7677

审稿时长

2.5 months

期刊介绍： Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.