Abstract：
Increasing evidence suggests that endoplasmic reticulum stress (ER stress) and neuroinflammation are involved in the complex pathological process of traumatic brain injury (TBI). However, the pathological mechanisms of their interactions in TBI remain incompletely elucidated. Therefore, investigating and ameliorating neuroinflammation and ER stress post-TBI may represent effective strategies for treating secondary brain injury. Astragaloside IV (AS-IV) has been reported as a potential neuroprotective and anti-inflammatory agent in neurological diseases. This study utilized a mouse TBI model to investigate the pathological mechanisms and crosstalk of ER stress, neuroinflammation, and microglial cell morphology in TBI, as well as the mechanisms and potential of AS-IV in improving TBI. The research revealed that post-TBI, inflammatory factors IL-6, IL-1β, and TNF-α increased, microglial cells were activated, and the specific inhibitor of PERK phosphorylation, GSK2656157, intervened to alleviate neuroinflammation and inhibit microglial cell activation. Post-TBI, levels of ER stress-related proteins (p-PERK, p-eIF2a, ATF4, ATF6, and p-IRE1a) increased. Following AS-IV treatment, neurological dysfunction in TBI mice improved. Levels of p-PERK, p-eIF2a, and ATF4 decreased, along with reductions in inflammatory factors IL-6, IL-1β, and TNF-α. Changes in microglial/macrophage M1/M2 polarization were observed. Additionally, the PERK activator CCT020312 intervention eliminated the impact of AS-IV on post-TBI inflammation and ER stress-related proteins p-PERK, p-eIF2a, and ATF4. These results indicate that AS-IV alleviates neuroinflammation and brain damage post-TBI through the PERK pathway, offering new directions and theoretical insights for TBI treatment.
摘要：
越来越多的证据表明，内质网应激（ER应激）和神经炎症参与了创伤性脑损伤（TBI）的复杂病理过程。然而,TBI中它们相互作用的病理机制仍未完全阐明。因此,研究和改善TBI后的神经炎症和ER应激可能是治疗继发性脑损伤的有效策略。黄芪甲苷(AS-IV)已被报道为神经系统疾病中潜在的神经保护和抗炎剂。本研究利用小鼠TBI模型研究内质网应激的病理机制和串扰，神经炎症，TBI中的小胶质细胞形态，以及AS-IV改善TBI的机制和潜力。研究显示TBI后,炎症因子IL-6,IL-1β,TNF-α升高,小胶质细胞被激活，和PERK磷酸化的特异性抑制剂，GSK2656157，干预以减轻神经炎症并抑制小胶质细胞活化。TBI后,内质网应激相关蛋白的水平(p-PERK，p-eIF2a,ATF4、ATF6和p-IRE1a)增加。AS-IV治疗后，TBI小鼠的神经功能障碍得到改善。p-PERK的水平,p-eIF2a,ATF4下降，随着炎症因子IL-6，IL-1β的减少，和TNF-α。观察到小胶质细胞/巨噬细胞M1/M2极化的变化。此外,PERK激活剂CCT020312干预消除了AS-IV对TBI后炎症和ER应激相关蛋白p-PERK的影响，p-eIF2a,ATF4这些结果表明，AS-IV通过PERK途径减轻TBI后的神经炎症和脑损伤，为TBI治疗提供新的方向和理论见解。
