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.