Ruxolitinib, a promising therapeutic candidate for traumatic brain injury through maintaining the homeostasis of cathepsin B

Abstract

Traumatic brain injury (TBI) is one of the main causes of death and disability in the world. Owing to the heterogeneity and complexity of TBI pathogenesis, there is still no specific drug. Our previous studies have proved the neuroprotective effect of Ruxolitinib (Ruxo) on TBI, but further are needed to explore the potent mechanisms and potential translational application. Compelling evidence indicates that Cathepsin B (CTSB) plays an important role in TBI. However, the relationships between Ruxo and CTSB upon TBI remain non-elucidated. In this study, we established a mouse model of moderate TBI to clarify it. The neurological deficit in the behavioral test was alleviated when Ruxo administrated at 6 h post-TBI. Additionally, Ruxo significantly reduced the lesion volume. As for the pathological process of acute phase, Ruxo remarkably reduced the expression of proteins associated with cell demise, neuroinflammation, and neurodegeneration. Then the expression and location of CTSB were detected respectively. We found that the expression of CTSB exhibits a transient decrease and then persistent increase following TBI. The distribution of CTSB, mainly located at NeuN-positive neurons was unchanged. Importantly, the dysregulation of CTSB expression was reversed with the treatment of Ruxo. The timepoint was chosen when CTSB decreased, to further analyze its change in the extracted organelles; and Ruxo maintained the homeostasis of it in sub-cellular. In summary, our results demonstrate that Ruxo plays neuroprotection through maintaining the homeostasis of CTSB, and will be a promising therapeutic candidate for TBI in clinic.