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

Year 2012, Volume: 71 Issue: 2, 85 - 93, 25.12.2012

Selda Gezginci-oktayoglu İsmet Burcu Turkyilmaz Refiye Yanardag Sehnaz Bolkent

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-α (TNF-α) 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 μg/kg TNF-α one hour after administration with 8 mg/kg Z-FA.FMK. Treatment
with Z-FA.FMK before TNF-α/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-α/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-α (TNF-α).

Keywords

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Z-FA.FMK aracılığı ile katepsin B inhibisyonu fare beyninde TNF- α/D-GalN ile oluşturulan oksidatif hasarı antioksidan savunmayı artırarak engeller

Abstract

Katepsin B birçok inflamatuvar hastalığın patolojisinde rol alan bir sistein proteazdır. Nörodejeneratif hastalıklarda beyindeki inflamatuvar süreçler potansiyel bir patojenik faktör olarak kabul edildiğinden, inflamasyon ile ilişkili bir enzim olan katepsin B’nin inhibisyonu nöroinflamatuvar hastalıklarda potansiyel bir tedavi yaklaşımı olabilir. Bu nedenle, katepsin B’nin farmakolojik bir inhibitörü olan olan benziloksikarbonil-fenilalanin-alanin-fluorometilketon (Z-FA.FMK)’un tümor nekroz faktor-α (TNF-α) ve D-galaktozamin (D-GalN) ile uyarılan beyin hasarı üzerine olan etkilerini araştırdık. Oksidatif hasar inflamatuvar süreçlere katıldığından, bazı oksidatif hasar ve antioksidan savunma göstergelerindeki değişimleri araştırmayı amaçladık. Bu araştırma için farelere 8 mg/kg Z-FA.FMK uygulanmasından 1 saat sonra 700 mg/kg D-GalN ve 15 µg/kg TNF-α enjekte edildi. TNF-α/D-GalN enjeksiyonundan önce Z-FA.FMK uygulanması fare beyin dokularında lipid peroksidasyon seviylerinin azalmasına karşın katalaz, superoksit dismutaz, glutatyon peroksidaz ve paraoksonaz 1 aktiviteleri ve glutatyon seviyelerinde artış ile sonuçlandı. Bu bulgular, Z-FA.FMK aracılığıyla katepsin B inhibisyonunun, fare beyninde TNF-α/D-GalN ile uyarılan oksidatif hasarı antioksidan savunmayı artırarak engellemesinden dolayı, nöroinflamatuvar hastalıklarda bir tedavi yaklaşımı olabileceğini göstermektedir.

Keywords

Benziloksikarbonil-fenilalanin-alanin-fluorometilketon (Z-FA.FMK), Katepsin B, D-galaktozamin, Oksidatif hasar, Tümor nekroz faktör-α (TNF-α)

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