Lai Yichen, Hickey Robert W, Chen Yaming, Bayir Hülya, Sullivan Mara L, Chu Charleen T, Kochanek Patrick M, Dixon C Edward, Jenkins Larry W, Graham Steven H, Watkins Simon C, Clark Robert S B
Department of Critical Care Medicine, The Safar Center for Resuscitation Research and the Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, PA 15260, USA.
J Cereb Blood Flow Metab. 2008 Mar;28(3):540-50. doi: 10.1038/sj.jcbfm.9600551. Epub 2007 Sep 5.
Autophagy is a homeostatic process for recycling of proteins and organelles, induced by nutrient deprivation and regulated by oxygen radicals. Whether autophagy is induced after traumatic brain injury (TBI) is not established. We show that TBI in mice results in increased ultrastructural and biochemical evidence of autophagy. Specifically, autophagosomal vacuoles and secondary lysosomes were frequently observed in cell processes and axons in ipsilateral brain regions by electron microscopy, and lipidated microtubule-associated protein light chain 3, a biochemical footprint of autophagy referred to as LC3 II, was increased at 2 and 24 h after TBI versus controls. Since oxygen radicals are believed to be important in the pathogenesis of TBI and are essential for the process of starvation-induced autophagy in vitro, we also sought to determine if treatment with the antioxidant gamma-glutamylcysteinyl ethyl ester (GCEE) reduced autophagy and influenced neurologic outcome after TBI in mice. Treatment with GCEE reduced oxidative stress and partially reduced LC3 II formation in injured brain at 24 h after TBI versus vehicle. Treatment with GCEE also led to partial improvement in behavioral and histologic outcome versus vehicle. Taken together, these data show that autophagy occurs after experimental TBI, and that oxidative stress contributes to overall neuropathology, in part by initiating or influencing autophagy.
自噬是一种用于蛋白质和细胞器循环利用的稳态过程，由营养缺乏诱导并受氧自由基调节。创伤性脑损伤（TBI）后是否会诱导自噬尚未明确。我们发现，小鼠的TBI会导致自噬的超微结构和生化证据增加。具体而言，通过电子显微镜观察到，在同侧脑区的细胞突起和轴突中经常出现自噬体空泡和次级溶酶体，并且与自噬生化印记相关的脂化微管相关蛋白轻链3（称为LC3 II）在TBI后2小时和24小时相对于对照组有所增加。由于氧自由基被认为在TBI的发病机制中起重要作用，并且在体外饥饿诱导的自噬过程中是必不可少的，我们还试图确定用抗氧化剂γ-谷氨酰半胱氨酰乙酯（GCEE）治疗是否能减少自噬并影响小鼠TBI后的神经学结果。与载体相比，GCEE治疗在TBI后24小时降低了氧化应激并部分减少了损伤脑中LC3 II的形成。与载体相比，GCEE治疗还使行为和组织学结果得到部分改善。综上所述，这些数据表明实验性TBI后会发生自噬，并且氧化应激部分通过启动或影响自噬而导致整体神经病理学变化。
