Therapeutic potential of inhibition of the neuroinflammation induced cathepsin X:in vivoevidence

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder with unknown cause, but it has been postulated that chronic neuroinflammation may play a role in its pathogenesis. Microglia-derived lysosomal cathepsins have been increasingly recognized as important inflammatory mediators. Here, we analyzed the regional distribution and cellular localization of the cathepsin X in the rat brain with neuroinflammation-induced neurodegeneration. Unilateral injection of lipopolysaccharide (LPS) into the striatum induced strong upregulation of cathepsin X expression and its activity in the ipsilateral striatum.In addition to the striatum, cathepsin X overexpression was detected in other areas such as cerebral cortex, corpus callosum, subventricular zone and external globus pallidus mainly restricted to glial cells.Moreover, continuous administration of the cathepsin X specific inhibitor AMS36 showed protective effects against LPS-induced striatal degeneration, as seen by the decreased extent of striatal lesion and decreased expression of neuroinflammation marker. These results demonstrate that glial upregulated cathepsin X may play a role as a potential pathogenic factor in PD. Inhibition of cathepsin X enzymatic activity thus may be useful in preventing neuroinflammation-induced neurodegeneration.

Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

“…In addition, CatL inhibition alleviates the microglia-mediated neuroinflammatory responses through caspase-8 and NF-jB pathways [338]. Furthermore, cathepsins B [339], L [338], H [340], C [341], and X [342] are upregulated in different brain regions following LPS-induced neuroinflammation.…”

“…1B). Moreover, administration of a CatX inhibitor along with LPS injection revealed the potentially protective role of such inhibitors in neuroinflammation-induced striatal lesions [342]. Additionally, dendritic cells in the aging brains of mice have increased CatX protein levels, indicating on its role in neuroinflammation [351].…”