The cysteine protease cathepsin B is a key drug target and cysteine protease inhibitors are potential therapeutics for traumatic brain injury.

There are currently no effective therapeutic agents for traumatic brain injury (TBI), but drug treatments for TBI can be developed by validation of new drug targets and demonstration that compounds directed to such targets are efficacious in TBI animal models using a clinically relevant route of drug administration. The cysteine protease, cathepsin B, has been implicated in mediating TBI, but it has not been validated by gene knockout (KO) studies. Therefore, this investigation evaluated mice with deletion of the cathepsin B gene receiving controlled cortical impact TBI trauma. Results indicated that KO of the cathepsin B gene resulted in amelioration of TBI, shown by significant improvement in motor dysfunction, reduced brain lesion volume, greater neuronal density in brain, and lack of increased proapoptotic Bax levels. Notably, oral administration of the small-molecule cysteine protease inhibitor, E64d, immediately after TBI resulted in recovery of TBI-mediated motor dysfunction and reduced the increase in cathepsin B activity induced by TBI. E64d outcomes were as effective as cathepsin B gene deletion for improving TBI. E64d treatment was effective even when administered 8 h after injury, indicating a clinically plausible time period for acute therapeutic intervention. These data demonstrate that a cysteine protease inhibitor can be orally efficacious in a TBI animal model when administered at a clinically relevant time point post-trauma, and that E64d-mediated improvement of TBI is primarily the result of inhibition of cathepsin B activity. These results validate cathepsin B as a new TBI therapeutic target.

Deletion of the cathepsin B gene improves memory deficits in a transgenic ALZHeimer's disease mouse model expressing AßPP containing the wild-type ß-secretase site sequence.

Therapeutic agents that improve the memory loss of Alzheimer's disease (AD) may eventually be developed if drug targets are identified that improve memory deficits in appropriate AD animal models. One such target is ß-secretase which, in most AD patients, cleaves the wild-type (WT) ß-secretase site sequence of the amyloid-ß protein precursor (AßPP) to produce neurotoxic amyloid-ß (Aß). Thus, an animal model representing most AD patients for evaluating ß-secretase effects on memory deficits is one that expresses human AßPP containing the WT ß-secretase site sequence. BACE1 and cathepsin B (CatB) proteases have ß-secretase activity, but gene knockout studies have not yet validated that the absence of these proteases improves memory deficits in such an animal model. This study assessed the effects of deleting these protease genes on memory deficits in the AD mouse model expressing human AßPP containing the WT ß-secretase site sequence and the London γ-secretase site (AßPPWT/Lon mice). Knockout of the CatB gene in the AßPPWT/Lon mice improved memory deficits and altered the pattern of Aß-related biomarkers in a manner consistent with CatB having WT ß-secretase activity. But deletion of the BACE1 gene had no effect on these parameters in the AßPPWT/Lon mice. These data are the first to show that knockout of a putative ß-secretase gene results in improved memory in an AD animal model expressing the WT ß-secretase site sequence of AßPP, present in the majority of AD patients. CatB may be an effective drug target for improving memory deficits in most AD patients.