Cathepsin B contributes to traumatic brain injury-induced cell death through a mitochondria-mediated apoptotic pathway

• Published in: Journal of neuroscience research 2010-10, Vol.88 (13), p.2847-2858
• Main Authors: Luo, Cheng-Liang, Chen, Xi-Ping, Yang, Rui, Sun, Yu-Xia, Li, Qian-Qian, Bao, Hai-Jun, Cao, Qiang-Qiang, Ni, Hong, Qin, Zheng-Hong, Tao, Lu-Yang
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Brain Injuries - drug therapy; Brain Injuries - metabolism; Brain Injuries - physiopathology; caspase-3; cathepsin B; Cathepsin B - antagonists & inhibitors; Cathepsin B - metabolism; Chaperonin 60 - metabolism; Cyclooxygenase 2 - metabolism; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Glial Fibrillary Acidic Protein - metabolism; Maze Learning - drug effects; Mice; Mitochondria - drug effects; Mitochondria - physiology; Motor Activity - drug effects; Motor Activity - physiology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Statistics, Nonparametric; tBid; Time Factors; traumatic brain injury; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 0360-4012; 1097-4547; 1097-4547
• DOI: 10.1002/jnr.22453

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. © 2010 Wiley‐Liss, Inc.