Astrocytic NLRP3 cKO Mitigates Cognitive Impairment Induced by Paclitaxel in Mice

IF 4.5 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemical Research Pub Date : 2026-10-13 DOI:10.1007/s11064-026-04919-z

Jing Cao, Meng-Meng Li, Qing-Tao Liu, Jing-Yu Hui, Jian-Kai Sun, Zi-Yuan Wang, Zhi-Hui Gao, Yong Yang, Yi Hu, Hui-Tao Miao, Xing-Liao Luo

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引用次数: 0

Abstract

Chemotherapy-induced cognitive impairment (CICI) is a prevalent and debilitating sequela in cancer patients receiving paclitaxel. Our previous study revealed that glial cells, particularly astrocytes, regulate NLRP3-mediated neuroinflammation, which is crucial to the pathophysiology of cognitive deficits. However, the therapeutic potential of targeting astrocytic NLRP3 for CICI remains largely unexplored. This study sought to determine whether astrocyte-specific NLRP3 knockout (KO) could mitigate paclitaxel-induced cognitive impairment. A mouse model of CICI was established via intraperitoneal injection of paclitaxel. Cognitive function was assessed using the Morris water maze and novel object recognition tests. Immunofluorescence labelling and local field potential (LFP) recordings in the medial prefrontal cortex (mPFC) were used to analyze pathological changes. Astrocyte-specific NLRP3 KO reduced intensities of GFAP, decreased colocalization of cleaved caspase-1 and IL-18 with astrocytes. Besides, the deletion approach significantly mitigated paclitaxel-induced cognitive deficits and increased the expression of synaptic markers, including synaptophysin and postsynaptic density protein 95 (PSD95). Electrophysiologically, astrocytic NLRP3 deletion improved the power of β- and γ-band oscillations and enhanced β-γ phase-amplitude coupling during novel object exploration. Astrocyte-specific NLRP3 knockout confers a protective effect against paclitaxel-induced cognitive dysfunction, potentially through inhibition of NLRP3 inflammasome-mediated pyroptotic signaling in astrocytes and preservation of synaptic integrity within the mPFC.

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星形细胞NLRP3 cKO减轻紫杉醇诱导的小鼠认知损伤。

化疗引起的认知障碍（CICI）是接受紫杉醇治疗的癌症患者普遍存在的衰弱性后遗症。我们之前的研究表明，神经胶质细胞，特别是星形胶质细胞，调节nlrp3介导的神经炎症，这对认知缺陷的病理生理至关重要。然而，靶向星形细胞NLRP3治疗CICI的潜力在很大程度上仍未被探索。这项研究试图确定星形胶质细胞特异性NLRP3敲除（KO）是否可以减轻紫杉醇诱导的认知障碍。通过腹腔注射紫杉醇建立小鼠CICI模型。认知功能评估采用莫里斯水迷宫和新的目标识别测试。应用免疫荧光标记和局部场电位（LFP）记录分析内侧前额叶皮层（mPFC）的病理变化。星形胶质细胞特异性NLRP3 KO降低了GFAP的强度，减少了cleaved caspase-1和IL-18与星形胶质细胞的共定位。此外，删除方法显著减轻了紫杉醇诱导的认知缺陷，并增加了突触标记物的表达，包括突触素和突触后密度蛋白95 （PSD95）。在电生理上，星形细胞NLRP3缺失提高了β-和γ波段振荡的能力，增强了β-γ相振幅耦合。星形胶质细胞特异性NLRP3敲除对紫杉醇诱导的认知功能障碍具有保护作用，可能通过抑制星形胶质细胞中NLRP3炎症小体介导的热凋亡信号和保存mPFC内突触完整性来实现。

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

Neurochemical Research 医学-神经科学

CiteScore

7.70

自引率

2.30%

发文量

320

审稿时长

6 months

期刊介绍： Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.