Cathepsin B inhibition by Z-FA.FMK blocks TNF-a/D-GalN-induced oxidative damage through increasing antioxidant defence in the brain of mice

Abstract

Cathepsin B is a cysteine lysosomal protease which takes place in many inflammatory diseases. Inflammatory processes within the brain represent a potential pathogenetic factor in neurodegenerative diseases and inhibiton of cathepsin B, which is an inflammation-related enzyme, can be a potential therapeutic utility in neuroinflammatory diseases. Thus, we researched the effect of benzyloxycarbonyl-phenilalaninealanine fluoromethylketone (Z-FA.FMK), which is a pharmacological inhibitor of cathepsin B, on tumour necrosis factor-I± (TNF-I±) and D-galactosamine (D-GalN)-induced brain damage. Because oxidative damage accompanies inflammatory processes we aimed to research the alteration in some markers of oxidative damage and antioxidant defence system. For this investigation mice were treated with 700 mg/kg D-GalN and 15 I¼g/kg TNF-I± one hour after administration with 8 mg/kg Z-FA.FMK. Treatment with Z-FA.FMK before TNF-I±/D-GalN injection resulted in decreased lipid peroxidation levels, while catalase, superoxide dismutase, glutathione peroxidase, paraoxonase 1 activities and glutathione levels were increased in the brain tissue of mice. These results showed that cathepsin B inhibition by Z-FA. FMK could be a potential therapeutic utility in neuroinflammatory diseases because of its ability to block TNF-I±/D-GalN-induced oxidative damage by increasing antioxidant defence in the brain of mice. Keywords: Benzyloxycarbonyl-Phenyl-Alanine-fluoromethylketone (Z-FA.FMK), Cathepsin B, Dgalactosamine, Oxidative damage, Tumour necrosis factor-I± (TNF-I±).