Inhibition of Cathepsin S Produces Neuroprotective Effects after Traumatic Brain Injury in Mice

Abstract

Cathepsin S (CatS) is a cysteine protease normally present in lysosomes. It has long been regarded as an enzyme that is primarily involved in general protein degradation. More recently, mounting evidence has shown that it is involved in Alzheimer disease, seizures, age-related inflammatory processes, and neuropathic pain. In this study, we investigated the time course of CatS protein and mRNA expression and the cellular distribution of CatS in a mouse model of traumatic brain injury (TBI). To clarify the roles of CatS in TBI, we injected the mice intraventricularly with LHVS, a nonbrain penetrant, irreversible CatS inhibitor, and examined the effect on inflammation and neurobehavioral function. We found that expression of CatS was increased as early as 1 h after TBI at both protein and mRNA levels. The increased expression was detected in microglia and neurons. Inhibition of CatS significantly reduced the level of TBI-induced inflammatory factors in brain tissue and alleviated brain edema. Additionally, administration of LHVS led to a decrease in neuronal degeneration and improved neurobehavioral function. These results imply that CatS is involved in the secondary injury after TBI and provide a new perspective for preventing secondary injury after TBI.

Cathepsin S Contributes to the Pathogenesis of Muscular Dystrophy in Mice

“…In vitro and in vivo studies using LHVS have shown promising therapeutic effects such as decreased ECM remodeling in hypertension-induced heart failure (37) and increased neuroprotection following traumatic brain injury (38) or peripheral nerve trauma (39, 40). These results confirm the specificity and efficacy of LHVS in targeting Ctss for a biologic effect in vivo that is consistent with its presumed function.…”

Alpha lipoic acid inhibits neural apoptosis via a mitochondrial pathway in rats following traumatic brain injury

“…Western blotting was performed as previously described (Xu et al, 2013). Briefly, equal amounts of protein were resolved by sodium dodecyl sulfate polyacrylamide gel electrophoresis on a 10%-12% Bis-Tris gel, then transferred to polyvinylidene difluoride membranes, which were blocked with nonfat dry milk buffer for 2 h and then incubated overnight at 4°C with primary antibodies against cleaved caspase-3 at 1:1000 (#9661, rabbit; Cell Signaling Technology), Caspase-3 at 1:200 (#sc-7148, rabbit; Santa Cruz Biotechnology), Bax at 1:400 (#ab32503, rabbit; Abcam, Cambridge, MA, USA), cytochrome c at 1:10,000 (#ab133504, rabbit; Abcam), COX IV at 1:1000 (#11967s, mouse; Cell Signaling Technology), and β-actin at 1:5000 (AP0060, Bioworld Technology, Inc.).…”

The Neuroprotection of Lysosomotropic Agents in Experimental Subarachnoid Hemorrhage Probably Involving the Apoptosis Pathway Triggering by Cathepsins via Chelating Intralysosomal Iron

“…It is noteworthy that ROS was regarded as a pivotal factor destabilizing the lysosomal membranes within lysosomes, where the acidic condition and the labile iron facilitated a Fenton-type reaction, particularly intralysosomal hydroxyl radicals HO• production [27]. More and more evidence have demonstrated that the cathepsins may play important roles in different diseases of the CNS, such as intracerebral hemorrhage (ICH), focal cerebral ischemia, and traumatic brain injury (TBI) [28][29][30]. Inhibition of cathepsin S provided a neuroprotective effect resulting from alleviating cerebral edema and suppressing neuronal degeneration [30].…”

“…More and more evidence have demonstrated that the cathepsins may play important roles in different diseases of the CNS, such as intracerebral hemorrhage (ICH), focal cerebral ischemia, and traumatic brain injury (TBI) [28][29][30]. Inhibition of cathepsin S provided a neuroprotective effect resulting from alleviating cerebral edema and suppressing neuronal degeneration [30]. Another study performed in TBI experiments of mice showed the knockout of the cathepsin B gene contributed to significant improvement of motor dysfunction, neuronal density in brain, and the reduction of pro-apoptotic Bax expression levels compared to wild-type (WT) mice [31].…”