Department of Neurobiology, MOE Key Laboratory of Molecular Neurobiology, Ministry of Education, Neuroscience Research Centre of Changzheng Hospital, Second Military Medical University, Shanghai, 200433, People's Republic of China.
Department of Neurology, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University Shanghai, Yangpu Qu, People's Republic of China.
Purinergic Signal. 2017 Dec;13(4):529-544. doi: 10.1007/s11302-017-9579-y. Epub 2017 Aug 19.
Traumatic brain injury (TBI) is the leading cause of death and disability for people under the age of 45 years worldwide. Neuropathology after TBI is the result of both the immediate impact injury and secondary injury mechanisms. Secondary injury is the result of cascade events, including glutamate excitotoxicity, calcium overloading, free radical generation, and neuroinflammation, ultimately leading to brain cell death. In this study, the P2X7 receptor (P2X7R) was detected predominately in microglia of the cerebral cortex and was up-regulated on microglial cells after TBI. The microglia transformed into amoeba-like and discharged many microvesicle (MV)-like particles in the injured and adjacent regions. A P2X7R antagonist (A804598) and an immune inhibitor (FTY720) reduced significantly the number of MV-like particles in the injured/adjacent regions and in cerebrospinal fluid, reduced the number of neurons undergoing apoptotic cell death, and increased the survival of neurons in the cerebral cortex injured and adjacent regions. Blockade of the P2X7R and FTY720 reduced interleukin-1βexpression, P38 phosphorylation, and glial activation in the cerebral cortex and improved neurobehavioral outcomes after TBI. These data indicate that MV-like particles discharged by microglia after TBI may be involved in the development of local inflammation and secondary nerve cell injury.
创伤性脑损伤（TBI）是全球 45 岁以下人群死亡和残疾的主要原因。TBI 后的神经病理学是直接冲击损伤和继发性损伤机制的结果。继发性损伤是级联事件的结果，包括谷氨酸兴奋性毒性、钙超载、自由基生成和神经炎症，最终导致脑细胞死亡。在这项研究中，P2X7 受体（P2X7R）主要在大脑皮层的小胶质细胞中被检测到，并在 TBI 后小胶质细胞上上调。小胶质细胞转化为阿米巴样，并在损伤和相邻区域释放许多微囊泡（MV）样颗粒。P2X7R 拮抗剂（A804598）和免疫抑制剂（FTY720）显著减少了损伤/相邻区域和脑脊液中 MV 样颗粒的数量，减少了凋亡细胞死亡的神经元数量，并增加了大脑皮质损伤和相邻区域神经元的存活。P2X7R 和 FTY720 的阻断减少了大脑皮质中白细胞介素-1β的表达、P38 磷酸化和神经胶质的激活，并改善了 TBI 后的神经行为结果。这些数据表明，TBI 后小胶质细胞释放的 MV 样颗粒可能参与了局部炎症和继发性神经细胞损伤的发展。
