Department of Neurosurgery, The General Hospital of Western Theater Command, College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan, China; Mini-Invasive Neurosurgery and Translational Medical Center, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an 710003, China.
Department of Gastroenterology, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an 710003, China.
Exp Neurol. 2024 Oct;380:114912. doi: 10.1016/j.expneurol.2024.114912. Epub 2024 Aug 2.
Traumatic brain injury impairs brain function through various mechanisms. Recent studies have shown that alterations in pericytes in various diseases affect neurovascular function, but the effects of TBI on hippocampal pericytes remain unclear. Here, we investigated the effects of RAGE activation on pericytes after TBI using male C57BL/6 J mice. Hippocampal samples were collected at different time points within 7 days after TBI, the expression of PDGFR-β, NG2 and the HMGB1-S100B/RAGE signaling pathway was assessed by Western blotting, and the integrity of the hippocampal BBB at different time points was measured by immunofluorescence. RAGE-associated BBB damage in hippocampal pericytes occurred early after cortical impact. By culturing primary mouse brain microvascular pericytes, we determined the different effects of HMGB1-S100B on pericyte RAGE. To investigate whether RAGE blockade could protect neurological function after TBI, we reproduced the process of CCI by administering FPS-ZM1 to RAGE mice. TEM images and BBB damage-related assays showed that inhibition of RAGE resulted in a significant improvement in the number of hippocampal vascular basement membranes and tight junctions and a reduction in perivascular oedema compared with those in the untreated group. In contrast, mouse behavioural testing and doublecortin staining indicated that targeting the HMGB1-S100B/RAGE axis after CCI could protect neurological function by reducing pericyte-associated BBB damage. In conclusion, the present study provides experimental evidence for the strong correlation between the pericyte HMGB1-S100B/RAGE axis and NVU damage in the hippocampus at the early stage of TBI and further demonstrates that pericyte RAGE serves as an important target for the protection of neurological function after TBI.
创伤性脑损伤通过多种机制损害脑功能。最近的研究表明，各种疾病中周细胞的改变会影响神经血管功能，但 TBI 对海马周细胞的影响尚不清楚。在这里，我们使用雄性 C57BL/6J 小鼠研究了 RAGE 激活对 TBI 后周细胞的影响。在 TBI 后 7 天内的不同时间点采集海马样本，通过 Western blot 评估 PDGFR-β、NG2 和 HMGB1-S100B/RAGE 信号通路的表达，通过免疫荧光测量不同时间点海马 BBB 的完整性。皮质撞击后早期，RAGE 相关的 BBB 损伤发生在海马周细胞中。通过培养原代小鼠脑微血管周细胞，我们确定了 HMGB1-S100B 对周细胞 RAGE 的不同影响。为了研究 RAGE 阻断是否可以保护 TBI 后的神经功能，我们通过向 RAGE 小鼠给予 FPS-ZM1 来重现 CCI 过程。TEM 图像和 BBB 损伤相关检测表明，与未处理组相比，RAGE 抑制导致海马血管基底膜和紧密连接的数量显著增加，血管周围水肿减少。相比之下，小鼠行为测试和双皮质素染色表明，CCI 后靶向 HMGB1-S100B/RAGE 轴可以通过减少周细胞相关 BBB 损伤来保护神经功能。总之，本研究为 TBI 早期海马 NVU 损伤中周细胞 HMGB1-S100B/RAGE 轴与 NVU 损伤之间的强相关性提供了实验证据，并进一步表明周细胞 RAGE 是保护 TBI 后神经功能的重要靶点。
