title: Autophagy is increased after traumatic brain injury in mice and is partially inhibited by the antioxidant gamma-glutamylcysteinyl ethyl ester.
abstract: 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.
authors.affiliation: Department of Critical Care Medicine, The Safar Center for Resuscitation Research and the Brain Trauma Research Center, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Yichen
authors.initials: Y
authors.lastname: Lai
authors.forename: Robert W
authors.initials: RW
authors.lastname: Hickey
authors.forename: Yaming
authors.initials: Y
authors.lastname: Chen
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayir
authors.forename: Mara L
authors.initials: ML
authors.lastname: Sullivan
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.forename: Larry W
authors.initials: LW
authors.lastname: Jenkins
authors.forename: Steven H
authors.initials: SH
authors.lastname: Graham
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Robert S B
authors.initials: RS
authors.lastname: Clark
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D001930:Brain Injuries / Q000473:pathology*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress; D014916:Whole-Body Irradiation / Q000009:adverse effects