PO.CL11.01 · 临床研究
利用PARP抑制剂对抗化疗诱导的认知障碍的神经保护作用
Leveraging a PARP inhibitor as neuroprotection against chemotherapy induced cognitive impairments
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
基于铂（Pt）的化疗对许多癌症而言是挽救生命的，但它们会诱导持续性DNA损伤和神经炎症，可深刻改变认知功能，统称为化疗诱导的认知障碍（CICI）。这些持久效应的分子驱动因素在很大程度上仍不明确，但症状包括注意力受损、记忆缺陷以及言语和运动功能下降，这提示海马存在显著的易损性。顺铂是一种广泛使用的Pt药物，可引起广泛的DNA交联和强烈的促炎信号。新出现的证据提示聚（ADP-核糖）聚合酶1（PARP1）参与此过程；当被顺铂诱导的DNA损伤持续激活时，PARP1驱动代谢功能障碍、炎症放大和神经元修复受损。PARP1抑制剂在其他神经退行性疾病中已显示神经保护作用，可减少神经炎症并延缓功能衰退。我们假设过度的PARP1激活对顺铂诱导的海马功能障碍有显著贡献，而靶向PARP抑制可减轻这些神经毒性级联反应并保护神经元健康。为确定PARP抑制剂尼拉帕利是作为神经保护剂还是挽救剂发挥作用，我们使用来自C57BL/6小鼠的小鼠神经干细胞（MNSCs）在体外评估了多个治疗时间窗口。细胞暴露于顺铂（IC50：0.4 μM），并在暴露前、暴露后或同时给予尼拉帕利（1 μM）。与单用顺铂相比，尼拉帕利在所有时间点均显著改善细胞活力（p<0.0001）。在原代海马神经元中（顺铂IC50：0.6 μM），联合治疗显著增加PSD95斑点和树突分支（p<0.0001），表明突触结构得到保护。为确保尼拉帕利的神经保护作用不减弱顺铂的抗癌疗效，我们在ID8/MOSEC和SKOV3.ip1（IC50分别为34.11 μM和13.5 μM）卵巢癌细胞系中测试了相同的低剂量联合。相对于单用顺铂未观察到细胞活力增加，证实尼拉帕利不干扰顺铂的细胞毒性。综上所述，这些发现提示尼拉帕利在维持抗癌活性的同时减轻顺铂诱导的神经毒性。我们的下一阶段将在C57BL/6小鼠中评估尼拉帕利与临床相关顺铂剂量联用，以评估体内认知结局。本研究旨在阐明CICI背后的机制，并确定改善接受治疗患者生活质量和生存的策略。
查看英文原文 English abstract
Platinum-based (Pt) chemotherapies are lifesaving for many cancers, yet they induce persistent DNA damage and neuroinflammation that can profoundly alter cognitive function, collectively known as chemotherapy-induced cognitive impairments (CICI). The molecular drivers of these long-lasting effects remain mostly unknown, but symptoms include impaired concentration, memory deficits, and declines in speech and motor function this suggesting significant hippocampal vulnerability. Cisplatin, a widely used Pt agent causes extensive DNA crosslinking and robust proinflammatory signaling. Emerging evidence implicates poly (ADP-ribose) polymerase 1 (PARP1) in this process; when persistently activated by cisplatin-induced DNA damage- PARP1 drives metabolic dysfunction, inflammatory amplification, and impaired neuronal repair. PARP1 inhibitors have shown neuroprotective effects in other neurodegenerative disorders, reducing neuroinflammation and delaying functional decline. We hypothesized that excessive PARP1 activation contributes significantly to cisplatin-induced hippocampal dysfunction, and that targeted PARP inhibition could mitigate these neurotoxic cascades and preserve neuronal health. To determine whether the PARP inhibitor niraparib acts as a neuroprotective or rescue agent, we evaluated multiple treatment windows in vitro using mouse neural stem cells (MNSCs) from C57BL/6 mice. Cells were exposed to cisplatin (IC 50 : 0.4 µM) with niraparib (1 µM) administered pre-, post-, or concurrently. Niraparib significantly improved viability across all time points compared to cisplatin alone (p<0.0001). In primary hippocampal neurons (cisplatin IC 50 : 0.6 µM), combination treatment markedly increased PSD95 puncta and dendritic branching (p<0.0001), indicating preserved synaptic structure. To ensure that niraparib's neuroprotection did not dimmish cisplatin's anticancer efficacy, we tested the same low-dose combination in ID8/MOSEC and SKOV3.ip1 (IC 50 : 34.11 µM and IC 50 : 13.5 µM) ovarian cancer cell lines. No increase in viability was observed relative to cisplatin alone, confirming that niraparib did not interfere with cisplatin cytotoxicity. Together, these findings suggest that niraparib mitigates cisplatin-induced neurotoxicity while maintaining anti-cancer activity. Our next phase will evaluate niraparib alongside clinically relevant cisplatin dosing in C57BL/6 mice to assess cognitive outcomes in vivo. This works aims to clarify the mechanisms underlying CICI and identify strategies to improve quality of life and survivorship patients undergoing treatment.
利益披露 Disclosure
D. A. Ordaz, None..
S. Jain, None..
D. A. Bota, None.