The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury

Abstract

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.

Brain Pyroglutamate Amyloid-β is Produced by Cathepsin B and is Reduced by the Cysteine Protease Inhibitor E64d, Representing a Potential Alzheimer's Disease Therapeutic

“…As shown here, CatB inhibitors reduced both flAβ and pGlu-Aβ and, thus, will likely be effective if either of these Aβ species cause the disease. Moreover, CatB inhibitors are potent neuroprotectants in models of traumatic brain injury and ischemia, which are risk factors for AD [101, 102]. And CatB knockout studies show that the absence of CatB prevents tumor necrosis factor (TNF) induced cell death and interleukin-1β (IL1β) inflammation, both of which occur in AD [103-107].…”

Potential Alzheimer’s Disease Therapeutics Among Weak Cysteine Protease Inhibitors Exhibit Mechanistic Differences Regarding Extent of Cathepsin B Up-Regulation and Ability to Block Calpain

“…First, selective calpain inhibitors have been widely reported to protect against ischemic insults and TBI (see Vanderklish & Bahr, 2000; Saatman et al, 2010; Ono et al, 2016). Second, E64d completely protected against the TBI-induced neuronal loss measured in CatB knockout mice (Hook et al, 2014b). Third, intracellular and hydrolyzed E64d, having a 0.04-μM IC 50 for blocking calpain (Huang et al, 1992), is 350 times more potent towards calpain vs. CatB and has been shown to lower Aβ peptide levels and improve memory in APP transgenic mice (Hook et al, 2007, 2011, 2014a).…”

Novel Insight into the Aetiology of Autism Spectrum Disorder Gained by Integrating Expression Data with Genome-wide Association Statistics

“…This TWAS found evidence that CTSB is upregulated in ASD across multiple brain tissues. CTSB encodes Cathepsin B, a cysteine protease that has been reported as a mediator of exercise enhanced hippocampal neurogenesis and spatial memory (36), and inhibitors of Cathepsin B have therapeutic potential for traumatic brain injury (37). Furthermore, treating rodent neuroprogenitor cells with exogenous Cathepsin B is associated with differential expression of multiple neurogenesis-related genes (36).…”