Krattli Robert P, Do An H, El-Khatib Sanad M, Alikhani Leila, Markarian Mineh, Vagadia Arya R, Usmani Manal T, Madan Shreya, Baulch Janet E, Clark Richard J, Woodruff Trent M, Tenner Andrea J, Acharya Munjal M
bioRxiv. 2024 Dec 21:2024.07.02.601806. doi: 10.1101/2024.07.02.601806.
Cranial radiation therapy (RT) for brain cancers leads to an irreversible decline in cognitive function without an available remedy. Radiation-induced cognitive deficits (RICD) are a particularly pressing problem for the survivors of pediatric and low grade glioma (LGG) cancers who often live long post-RT lives. Radiation-induced elevated neuroinflammation and gliosis, triggered by the detrimental CNS complement cascade, lead to excessive synaptic and cognitive loss. Using intact and brain cancer-bearing mouse models, we now show that targeting anaphylatoxin complement C5a receptor (C5aR1) is neuroprotective against RICD. We used a genetic knockout, C5aR1 KO mouse, and a pharmacologic approach, employing the orally active, brain penetrant C5aR1 antagonist PMX205 to reverse RICD. Irradiated C5aR1 KO and WT mice receiving PMX205 showed significant neurocognitive improvements in object recognition memory and memory consolidation tasks. Inhibiting C5a/C5aR1 axis reduced microglial activation, astrogliosis, and synaptic loss in the irradiated brain. Importantly, C5aR1 blockage in two syngeneic, orthotopic glioblastoma-bearing mice protected against RICD without interfering with the therapeutic efficacy of RT to reduce tumor volume . PMX205 clinical trials with healthy individuals and amyotrophic lateral sclerosis (ALS) patients showed no toxicity, drug-related adverse events, or infections. Thus, C5aR1 inhibition is a translationally feasible approach to address RICD, an unmet medical need.
Cranial radiotherapy for brain cancers activates CNS complement cascade, leading to cognitive decline. Ablation of the complement C5a/C5aR1 axis alleviates radiation-induced neuroinflammation, synaptic loss, and cognitive dysfunction, providing a novel tractable approach.
脑癌的颅脑放射治疗（RT）会导致认知功能不可逆转地下降，且尚无有效治疗方法。对于小儿和低级别胶质瘤（LGG）癌症幸存者而言，放射诱导的认知缺陷（RICD）是一个尤为紧迫的问题，因为他们在放疗后通常能存活很长时间。由有害的中枢神经系统补体级联反应引发的放射诱导的神经炎症和胶质增生会导致过度的突触和认知丧失。利用完整的和患脑癌的小鼠模型，我们现在表明靶向过敏毒素补体C5a受体（C5aR1）对RICD具有神经保护作用。我们使用了基因敲除的C5aR1 KO小鼠以及药理学方法，采用口服活性、可穿透大脑的C5aR1拮抗剂PMX205来逆转RICD。接受PMX205的照射后的C5aR1 KO和野生型小鼠在物体识别记忆和记忆巩固任务中显示出显著的神经认知改善。抑制C5a/C5aR1轴可减少照射后大脑中的小胶质细胞激活、星形胶质增生和突触丧失。重要的是，在两只同基因、原位携带胶质母细胞瘤的小鼠中阻断C5aR1可预防RICD，而不会干扰放疗减少肿瘤体积的治疗效果。对健康个体和肌萎缩侧索硬化症（ALS）患者进行的PMX205临床试验显示没有毒性、药物相关不良事件或感染。因此，抑制C5aR1是一种在临床上可行的方法，可解决RICD这一未满足的医疗需求。
脑癌的颅脑放疗会激活中枢神经系统补体级联反应，导致认知能力下降。消除补体C5a/C5aR1轴可减轻放射诱导神经炎症、突触丧失和认知功能障碍，提供了一种新的可处理方法。
