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

S. Gezginci-Oktayoglu, Ismet Burcu Turkyilmaz, R. Yanardag, Ş. Bolkent
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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±).
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Z-FA抑制组织蛋白酶B。FMK通过增加小鼠大脑的抗氧化防御来阻断TNF-a/ d - galn诱导的氧化损伤
组织蛋白酶B是一种半胱氨酸溶酶体蛋白酶,在许多炎症性疾病中都有发生。脑内的炎症过程是神经退行性疾病的潜在致病因素,而组织蛋白酶B是一种与炎症相关的酶,抑制组织蛋白酶B可能是神经炎症疾病的潜在治疗工具。因此,我们研究了组织蛋白酶B的药理抑制剂苯氧羰基苯丙氨酸丙氨酸氟甲基酮(Z-FA.FMK)对肿瘤坏死因子- 1±(TNF-I±)和d -半乳糖胺(D-GalN)诱导的脑损伤的影响。由于氧化损伤伴随着炎症过程,我们旨在研究氧化损伤和抗氧化防御系统的一些标志物的改变。在给药1小时后,小鼠分别给予700 mg/kg D-GalN和15 μ g/kg TNF-I。Z-FA治疗。TNF-I±/D-GalN注射前FMK使小鼠脑组织脂质过氧化水平降低,过氧化氢酶、超氧化物歧化酶、谷胱甘肽过氧化物酶、对氧磷酶1活性和谷胱甘肽水平升高。结果表明Z-FA对组织蛋白酶B有抑制作用。FMK可能是神经炎症疾病的潜在治疗工具,因为它能够通过增加小鼠大脑中的抗氧化防御来阻断TNF-I±/ d - galn诱导的氧化损伤。关键词:苯氧羰基苯基丙氨酸氟甲基酮(Z-FA.FMK),组织蛋白酶B,半乳糖胺,氧化损伤,肿瘤坏死因子- 1±(TNF-I±)
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