title: Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate.
abstract: There is currently no therapeutic drug treatment for traumatic brain injury (TBI) despite decades of experimental clinical trials. This may be because the mechanistic pathways for improving TBI outcomes have yet to be identified and exploited. As such, there remains a need to seek out new molecular targets and their drug candidates to find new treatments for TBI. This review presents supporting evidence for cathepsin B, a cysteine protease, as a potentially important drug target for TBI. Cathepsin B expression is greatly up-regulated in TBI animal models, as well as in trauma patients. Importantly, knockout of the cathepsin B gene in TBI mice results in substantial improvements of TBI-caused deficits in behavior, pathology, and biomarkers, as well as improvements in related injury models. During the process of TBI-induced injury, cathepsin B likely escapes the lysosome, its normal subcellular location, into the cytoplasm or extracellular matrix (ECM) where the unleashed proteolytic power causes destruction via necrotic, apoptotic, autophagic, and activated glia-induced cell death, together with ECM breakdown and inflammation. Significantly, chemical inhibitors of cathepsin B are effective for improving deficits in TBI and related injuries including ischemia, cerebral bleeding, cerebral aneurysm, edema, pain, infection, rheumatoid arthritis, epilepsy, Huntington's disease, multiple sclerosis, and Alzheimer's disease. The inhibitor E64d is unique among cathepsin B inhibitors in being the only compound to have demonstrated oral efficacy in a TBI model and prior safe use in man and as such it is an excellent tool compound for preclinical testing and clinical compound development. These data support the conclusion that drug development of cathepsin B inhibitors for TBI treatment should be accelerated.
authors.affiliation: American Life Science Pharmaceuticals, Inc. , San Diego, CA , USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Hook
authors.affiliation: AstraZeneca Neuroscience iMed , Cambridge, MA , USA.
authors.forename: J Steven
authors.initials: JS
authors.lastname: Jacobsen
authors.affiliation: Department of Chemical Engineering, University of Washington , Seattle, WA , USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Grabstein
authors.affiliation: Department of Neurosciences, Medical University of South Carolina , Charleston, SC , USA ; Ralph H. Johnson Veterans Administration Medical Center , Charleston, SC , USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Kindy
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego , La Jolla, CA , USA ; Department of Neurosciences, Department of Pharmacology, University of California San Diego , La Jolla, CA , USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Hook
keywords: E64d; cathepsin B; drug; protease; therapeutics; traumatic brain injury