中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (6): 2425-2432.doi: 10.4103/NRR.NRR-D-24-01055

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

NLRP3炎性体：脑小血管病发病或进展的关键因素

  

  • 出版日期:2026-06-15 发布日期:2026-04-17
  • 基金资助:
    国家自然科学基金青年基金项目（82201626），辽宁省自然科学基金面上项目（2022-MS-442），大连理工大学附属中心医院登峰计划项目（2024ZZ040）

MCC950 suppresses NLRP3-dependent neuroinflammation and ameliorates cognitive decline in a rat model of cerebral small vessel disease

Meiyan Zhang1, #, Xiaoyan Lan1, #, Yue Gao1, Shen Li2, Guanda Qiao3, Yajie Liang3, Miroslaw Janowski3, Piotr Walczak3, Chengyan Chu1, 3, *   

  1. 1Department of Neurology, Central Hospital of Dalian University of Technology, Dalian, Liaoning Province, China; 
    2Department of Neurology and Psychiatry, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; 
    3Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
  • Online:2026-06-15 Published:2026-04-17
  • Contact: Chengyan Chu, MD, Chengyan.Chu@som.umaryland.edu.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 82201626 (to CC); the Natural Science Foundation of Liaoning Province, No. 2022-MS-442 (to CC); and the Dalian Municipal Medical Key Specialty Climbing Project, No. 2024ZZ040 (to MZ).

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摘要：

 脑小血管病（CSVD）是导致认知障碍和痴呆的主要原因。然而，目前仍缺乏针对 CSVD 的有效预防或治疗方案。实验以自发性高血压（SHR）大鼠为研究对象，探讨了选择性NOD样受体家族含吡啶结构域蛋白3（NLRP3）抑制剂MCC950对CSVD发病机制和认知功能下降的潜在治疗作用。实验结果显示，自发性高血压大鼠长期给予MCC950（10mg/kg）干预能够抑制NLRP3炎性体的激活，从而抑制了热休克执行蛋白gasdermin D和促炎因子（包括IL（白细胞介素）-1β和IL-18）的产生。实验还观察到星形胶质细胞和小胶质细胞活化的减少；MCC950 能显著抑制自噬。更重要的是，行为评估结果显示，服用MCC950能改善受损的神经认知功能，这与CSVD大脑神经病理学特征（如血脑屏障破坏、白质损伤和内皮功能障碍）的改善有关。因此，实验揭示了NLRP3炎性体是导致CSVD发病或进展的关键因素，并表明基于NLRP3的疗法有望成为治疗CSVD的潜在新策略。


https://orcid.org/0000-0002-4486-1051 (Chengyan Chu)
 

关键词: 星形胶质细胞, 自噬, 血脑屏障, 脑小血管疾病, 认知功能, 内皮细胞, 小胶质细胞, 神经炎症, NLRP3炎性体, 白质

Abstract: Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia. However, there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel disease. In this study, we investigated the potential therapeutic effects of MCC950, a selective NOD-like receptor family pyrin domain-containing protein 3 inhibitor, on cerebral small vessel disease pathogenesis and cognitive decline in spontaneously hypertensive rats. Our results showed that chronic administration of MCC950 (10 mg/kg) to spontaneously hypertensive rats inhibited NOD-like receptor family pyrin domain-containing protein 3 inflammasome activation, thereby considerably suppressing the production of pyroptosis executive protein gasdermin D and pro-inflammatory factors, including interleukin-1β and -18. A decrease in astrocytic and microglial activation was also observed. We also found that MCC950 significantly inhibited autophagy. More importantly, behavioral assessment indicated that MCC950 administration ameliorated impaired neurocognitive function, which was associated with improvements in neuropathological hallmarks in the cerebral small vessel disease brain, such as blood‒brain barrier breakdown, white matter damage, and endothelial dysfunction. Thus, our findings revealed that the NOD-like receptor family pyrin domain-containing protein 3 inflammasome is a key contributor to the onset or progression of cerebral small vessel disease and suggested the potential of NOD-like receptor family pyrin domain-containing protein 3-based therapy as a potential novel strategy for treating cerebral small vessel disease.

Key words: astrocyte, autophagy, blood–brain barrier, cerebral small vessel disease, cognitive function, endothelial cells, microglia, neuroinflammation, NLRP3 inflammasome, white matter