中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (9): 2007-2013.doi: 10.4103/1673-5374.335163

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

尿石素A可减轻创伤性脑损伤后血脑屏障破坏及神经元凋亡

  

  • 出版日期:2022-09-15 发布日期:2022-03-05

Urolithin A alleviates blood-brain barrier disruption and attenuates neuronal apoptosis following traumatic brain injury in mice

Qiu-Yuan Gong#, Lin Cai#, Yao Jing, Wei Wang, Dian-Xu Yang, Shi-Wen Chen*, Heng-Li Tian*   

  1. Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
  • Online:2022-09-15 Published:2022-03-05
  • Contact: Shi-Wen Chen, MD, PhD, chenshiwen@126.com; Heng‐Li Tian, MD, PhD, tianhlsh@126.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 81974189 (to HLT), 81801236 (to QYG and LC), 82001310 (to DXY).

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摘要：

尿石素A是一种天然代谢物，由石榴、浆果和坚果等食物中的多酚类物质产生。最近有研究表明，尿石素A对帕金森病、阿尔茨海默病和脑出血等具有神经保护作用，但其对创伤性脑损伤的作用仍然未知。实验以控制性脑皮质撞击建立成年C57BL/6小鼠创伤性脑损伤模型，而后立即腹腔注射尿石素A进行治疗。结果发现尿石素A可明显减轻创伤性脑损伤小鼠的脑水肿，增加损伤皮质中紧密连接蛋白的表达以及皮质神经元自噬标志物LC3和p62的阳性反应，降低PI3K/Akt/mTOR信号通路调节因子Akt和mTOR以及神经炎症相关的Akt/IKK/NFκB信号通路调节因子IKKα和NFκB的磷酸化水平，减轻血脑屏障通透性，减少损伤皮质中神经元凋亡，且改善小鼠的神经功能。结果显示，尿石素A可能成为治疗创伤性脑损伤的候选药物，其神经保护作用可能与抑制PI3K/Akt/mTOR和Akt/IKK/NFκB信号通路减弱神经炎症以及增强自噬有关。

https://orcid.org/0000-0001-5461-8445 (Qiu-Yuan Gong); https://orcid.org/0000-0002-7087-4948 (Lin Cai); 
https://orcid.org/0000-0003-0525-503X (Heng-Li Tian); https://orcid.org/0000-0002-1088-8352 (Shi-Wei Chen)

关键词: 尿石素A, 创伤性脑损伤, 控制性脑皮质撞击, 血脑屏障, 紧密连接蛋白, 脑水肿, 神经元凋亡, 自噬, 神经保护, 神经药理学

Abstract: Urolithin A (UA) is a natural metabolite produced from polyphenolics in foods such as pomegranates, berries, and nuts. UA is neuroprotective against Parkinson’s disease, Alzheimer’s disease, and cerebral hemorrhage. However, its effect against traumatic brain injury remains unknown. In this study, we established adult C57BL/6J mouse models of traumatic brain injury by controlled cortical impact and then intraperitoneally administered UA. We found that UA greatly reduced brain edema; increased the expression of tight junction proteins in injured cortex; increased the immunopositivity of two neuronal autophagy markers, microtubule-associated protein 1A/B light chain 3A/B (LC3) and p62; downregulated protein kinase B (Akt) and mammalian target of rapamycin (mTOR), two regulators of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway; decreased the phosphorylation levels of inhibitor of NFκB (IκB) kinase alpha (IKKα) and nuclear factor kappa B (NFκB), two regulators of the neuroinflammation-related Akt/IKK/NFκB signaling pathway; reduced blood-brain barrier permeability and neuronal apoptosis in injured cortex; and improved mouse neurological function. These findings suggest that UA may be a candidate drug for the treatment of traumatic brain injury, and its neuroprotective effects may be mediated by inhibition of the PI3K/Akt/mTOR and Akt/IKK/NFκB signaling pathways, thus reducing neuroinflammation and enhancing autophagy. 

Key words: autophagy, blood-brain barrier, cerebral edema, controlled cortical impact model, neuronal apoptosis, neuropharmacology, neuroprotection, tight junction protein, traumatic brain injury, urolithin A