title: Cathepsin B contributes to traumatic brain injury-induced cell death through a mitochondria-mediated apoptotic pathway.
abstract: It has been reported that lysosomal proteases play important roles in ischemic and excitotoxic neuronal cell death. We have previously reported that cathepsin B expression increased remarkably after traumatic brain injury (TBI). The present study sought to investigate the effects of a selective cathepsin B inhibitor (CBI) [N-L-3-trans-prolcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-proline] on cell death and behavioral deficits in our model. We examined the levels of cathepsin B enzymatic activity and its expression by double labelling damaged cells in the brain slice with propidium iodide (PI) and anticathepsin B. The results showed an elevated enzymatic activity associated with TBI-induced increase in a mature form of cathepsin B, suggesting that cathepsin B may play a role in TBI-induced cell injury. PI was found to label cells positive for the neuronal-specific nuclear marker NeuN, whereas fewer GFAP-positive cells were labelled by PI, suggesting that neurons are more sensitive to cell death induced by TBI. Additionally, we found that pretreatment with CBI remarkably attenuated TBI-induced cell death, lesion volume, and motor and cognitive dysfunction. To analyze the mechanism of action of cathepsin B in the cell death signaling pathway, we assessed DNA fragmentation by electrophoresis, Bcl-2/Bax protein expression levels, Bid cleavage, cytochrome c release, and caspase-3 activation. The results imply that cathepsin B contributes to TBI-induced cell death through the present programmed cell necrosis and mitochondria-mediated apoptotic pathways.
authors.affiliation: Department of Forensic Medicine, Soochow University, Suzhou, China.
authors.forename: Cheng-Liang
authors.initials: CL
authors.lastname: Luo
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.forename: Yu-Xia
authors.initials: YX
authors.lastname: Sun
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Li
authors.forename: Hai-Jun
authors.initials: HJ
authors.lastname: Bao
authors.forename: Qiang-Qiang
authors.initials: QQ
authors.lastname: Cao
authors.forename: Hong
authors.initials: H
authors.lastname: Ni
authors.forename: Zheng-Hong
authors.initials: ZH
authors.lastname: Qin
authors.forename: Lu-Yang
authors.initials: LY
authors.lastname: Tao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018834:Chaperonin 60 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D018834:Chaperonin 60; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051546:Cyclooxygenase 2; D002401:Cathepsin B