Urolithin A alleviates blood-brain barrier disruption and attenuates neuronal apoptosis following traumatic brain injury in mice.
Urolithin A alleviates blood-brain barrier disruption and attenuates neuronal apoptosis following traumatic brain injury in mice.
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尿石素 A 可减轻小鼠脑外伤后的血脑屏障破坏并减弱神经元凋亡
DOI：
10.4103/1673-5374.335163
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发表时间：
2022-09
影响因子：
6.1
通讯作者：
Tian HL
中科院分区：
文献类型：
--
作者：
Gong QY;Cai L;Jing Y;Wang W;Yang DX;Chen SW;Tian HL
尿石素A（UA）是一种天然代谢产物，由石榴、浆果和坚果等食物中的多酚类物质生成。UA对帕金森病、阿尔茨海默病和脑出血具有神经保护作用。然而，其对创伤性脑损伤的作用仍不明确。在本研究中，我们通过控制性皮质撞击法建立成年C57BL/6J小鼠创伤性脑损伤模型，随后腹腔注射UA。我们发现，UA显著减轻了脑水肿；增加了损伤皮质中紧密连接蛋白的表达；提高了两种神经元自噬标志物——微管相关蛋白1A/B轻链3A/B（LC3）和p62的免疫阳性率；下调了蛋白激酶B（Akt）和雷帕霉素靶蛋白（mTOR）的表达，这两者是磷脂酰肌醇3-激酶（PI3K）/Akt/mTOR信号通路的调节因子；降低了核因子κB抑制蛋白（IκB）激酶α（IKKα）和核因子κB（NFκB）的磷酸化水平，这两者是神经炎症相关的Akt/IKK/NFκB信号通路的调节因子；降低了损伤皮质的血脑屏障通透性和神经元凋亡；并改善了小鼠的神经功能。这些研究结果表明，UA可能是治疗创伤性脑损伤的候选药物，其神经保护作用可能是通过抑制PI3K/Akt/mTOR和Akt/IKK/NFκB信号通路来介导的，从而减轻神经炎症并增强自噬。
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.