title: Autophagy is involved in traumatic brain injury-induced cell death and contributes to functional outcome deficits in mice.
abstract: Previous data demonstrate that traumatic brain injury (TBI) activates autophagy, and increases microtubule-associated protein 1 light chain 3 (LC3) immunostaining mainly in neurons. However, the role of autophagy in traumatic brain damage remains elusive. The aim of the present study was to investigate the autophagic mechanisms participating in traumatic brain injury. The autophagy inhibitors 3-methyladenine (3-MA) and bafliomycin A1 (BFA) were administered with a single i.c.v. injection before TBI. We first examined the protein levels of Beclin-1 and LC3 II, which have been found to promote autophagy previously. Immunoblotting analysis showed that 3-MA pretreatment reduced post-TBI Beclin-1 and LC3-II levels, and maintained p62/SQSTM1 (p62) levels. In addition, double immunolabeling showed that the increased punctate LC3-II dots colocalizing with Propidium Iodide (PI)-stained nuclei at 24 h after injury, were partially inhibited by 3-MA pretreatment. Furthermore, inhibition of autophagy could reduce TBI-induced cell injury assessed with i.p. injection of PI and lesion volume, and attenuate behavioral outcome evaluated by motor test and Morris water maze. The neuroprotective effects were associated with an inhibition on TBI-induced up-regulation of LC3, Beclin-1, cathepsin B, caspase-3 and the Beclin-1/Bcl-2 ratio. Taken together, these data imply that the autophagy pathway is involved in the pathophysiologic responses after TBI, and inhibition of this pathway may help attenuate traumatic damage and functional outcome deficits.
authors.affiliation: Department of Forensic Medicine, Shanghai Medical College, Fudan University, 138 Yi Xue Yuan Road, Xuhui District, Shanghai 200032, PR China.
authors.forename: C-L
authors.initials: CL
authors.lastname: Luo
authors.forename: B-X
authors.initials: BX
authors.lastname: Li
authors.forename: Q-Q
authors.initials: QQ
authors.lastname: Li
authors.forename: X-P
authors.initials: XP
authors.lastname: Chen
authors.forename: Y-X
authors.initials: YX
authors.lastname: Sun
authors.forename: H-J
authors.initials: HJ
authors.lastname: Bao
authors.forename: D-K
authors.initials: DK
authors.lastname: Dai
authors.forename: Y-W
authors.initials: YW
authors.lastname: Shen
authors.forename: H-F
authors.initials: HF
authors.lastname: Xu
authors.forename: H
authors.initials: H
authors.lastname: Ni
authors.forename: L
authors.initials: L
authors.lastname: Wan
authors.forename: Z-H
authors.initials: ZH
authors.lastname: Qin
authors.forename: L-Y
authors.initials: LY
authors.lastname: Tao
authors.forename: Z-Q
authors.initials: ZQ
authors.lastname: Zhao
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016923:Cell Death / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins