NAAA inhibitor F96 attenuates BBB disruption and secondary injury after traumatic brain injury (TBI)
NAAA inhibitor F96 attenuates BBB disruption and secondary injury after traumatic brain injury (TBI)
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DOI：
10.1016/j.ejphar.2021.174561
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发表时间：
2021-10-19
影响因子：
5
通讯作者：
Li, Yuhang
中科院分区：
文献类型：
--
作者：
Li, Yitian;Zhou, Pan;Li, Yuhang
创伤性脑损伤（TBI）是世界范围内死亡的主要原因，目前还没有全面的治疗方法。防止血脑屏障（BBB）破坏对于TBI治疗至关重要。酰基乙醇胺酸酰胺酶（NAAA）调节的棕榈酰乙醇胺（PEA）信号在炎症控制中起重要作用。然而，NAAA在TBI后BBB功能障碍中的作用仍不清楚。在本研究中，我们发现TBI诱导损伤皮层中PEA水平的增加，从而防止TBI后BBB的破坏。TBI还诱导含有NAAA的中性粒细胞的浸润，增加NAAA对PEA降解的贡献。中性粒细胞来源的NAAA削弱了TBI后PEA/PPAR α介导的BBB保护作用，促进了免疫细胞的积聚，导致组织损伤的继发性扩大。NAAA的失活增加了损伤部位的PEA水平，防止了早期BBB损伤并改善了继发性损伤，从而引发了TBI后的长期功能改善。本研究发现了NAAA在TBI中的新作用，提示NAAA是BBB功能障碍相关CNS疾病的新的重要靶点。
Traumatic brain injury (TBI) is a leading cause of death worldwide, for which there is currently no comprehensive treatment available. Preventing blood-brain barrier (BBB) disruption is crucial for TBI treatment. Nacylethanolamine acid amidase (NAAA)-regulated palmitoylethanolamide (PEA) signaling play an important role in the control of inflammation. However, the role of NAAA in BBB dysfunction following TBI remains unclear. In the present study, we found that TBI induces the increase of PEA levels in the injured cortex, which prevent the disruption of BBB after TBI. TBI also induces the infiltration of NAAA-contained neutrophils, increasing the contribution of NAAA to the PEA degradation. Neutrophil-derived NAAA weakens PEA/PPAR alpha-mediated BBB protective effects after TBI, facilitates the accumulation of immune cells, leading to secondary expansion of tissue injury. Inactivation of NAAA increased PEA levels in injured site, prevents early BBB damage and improves secondary injury, thereby eliciting long-term functional improvements after TBI. This study identified a new role of NAAA in TBI, suggesting that NAAA is a new important target for BBB dysfunction related CNS diseases.