Omega-3 PUFA调节小胶质细胞极化对小鼠颅脑外伤后白质损伤修复的作用及分子机制

Extensive white matter injury (WMI) has been documented in patients with traumatic brain injury (TBI). WMI is correlated with the long-term neurological deficits following TBI. Ignorance of TBI-induced white matter injury may attribute to the limitation of clinical treatment of TBI patients. Traumatic brain injury leads to the tremendous death or degeneration of oligodendrocytes and the demyelination of axons. It’s critical to promote the oligodendrogenesis and remyelination process in order to improve the neurological outcomes after TBI. Our previous research has demonstrated that dietary supplementary of omega-3 polyunsaturated fatty acids enriched fish oil significantly suppressed microglia activation and production of pro-inflammatory factors after stroke, attenuated white matter injury and neurological disorders after experimental traumatic brain injury. ω-3 PUFAs are promising therapeutic reagent for TBI treatment. Herein, we will investigate whether post insult application of ω-3 PUFA could alleviate WMI, enhance the differentiation and maturation of oligodendrocyte progenitor cells and remyelination procedure to improve the neurofunctional outcomes after TBI. Whether ω-3 PUFA facilitate microglia M2 polarization via regulating PPARγ/HDAC3/NF-κB pathway to protect oligodendrocytes and improve the recovery of myelin structure after TBI.

创伤性脑损伤（TBI）常引起严重的白质损伤，造成患者长期感觉运动和认知功能障碍。 临床上，对于TBI引起的白质损伤的关注度不高可能是治疗效果不佳的重要原因。TBI造成脑损伤周边区小胶质细胞的大量激活、少突胶质细胞急性死亡或退行性变，导致髓鞘脱失、轴突退化，引起长期的神经功能缺陷。促进损伤后少突胶质细胞的恢复和髓鞘结构修复成为TBI治疗的关键。我们的前期研究证实预先给予富含ω-3 PUFA的鱼油可以抑制脑卒中后小胶质细胞激活和促炎因子过度表达，显著减轻TBI引起的白质损伤，促进神经功能的恢复，其机制尚不清楚。本课题将研究TBI后给予ω-3 PUFA腹腔注射是否能够减轻TBI引起的白质损伤，促进髓鞘结构修复，其机制是否是通过促进激活小胶质细胞M2极化实现的？进一步阐明小胶质细胞中PPARγ/HDAC3/NF-κB信号通路可能是ω-3 PUFA调节小胶质细胞极化的关键分子靶点。

急性脑损伤，包括创伤性脑损伤（TBI）和脑缺血缺氧性损伤均引起严重的血脑屏障破坏、白质损伤，造成患者长期感觉运动和认知功能障碍。 临床上，对于白质损伤的关注度不高可能是治疗效果不佳的重要原因。急性脑损伤造成脑损伤周边区小胶质细胞的大量激活、血脑屏障破坏，外周免疫细胞的中枢浸润，少突胶质细胞急性死亡或退行性变，最终导致髓鞘脱失、轴突退化，引起长期的神经功能缺陷。抑制急性脑损伤后的炎症反应，保护血脑屏障的完整性，促进损伤后少突胶质细胞的恢复和髓鞘结构修复成为治疗急性脑损伤的关键。本项目研究初步证实了富含OMEGA-3 PUFA的鱼油可以抑制脑外伤后小胶质细胞激活和促炎因子过度表达，显著减轻TBI引起的白质损伤，促进神经功能的恢复，我们还对缺氧预处理对新生大鼠脑缺血缺氧所致的白质损伤的保护作用及机制，摄能限制对缺血性脑卒中的神经保护作用及机制，虫草素对脑外伤后白质损伤保护作用及机制以及Salvinorin A 对急性脑缺血引起的血脑屏障破坏的保护作用的探讨。