The Synthetic Myeloperoxidase Inhibitor AZD3241 Ameliorates Dextran Sodium Sulfate Stimulated Experimental Colitis.

Autor:	Ahmad G; Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia., Chami B; Discipline of Oral Pathology, Faculty of Medicine and Health, School of Dentistry, The University of Sydney, Sydney, NSW, Australia., Liu Y; Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia., Schroder AL; Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia., San Gabriel PT; Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia., Gao A; Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia., Fong G; Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia., Wang X; Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia., Witting PK; Discipline of Pathology, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2020 Sep 15; Vol. 11, pp. 556020. Date of Electronic Publication: 2020 Sep 15 (Print Publication: 2020).
DOI:	10.3389/fphar.2020.556020
Abstrakt:	Chronic inflammatory bowel disease (IBD) is a condition with multifactorial pathophysiology. To date, there is no permanent cure and the disease is primarily managed by immunosuppressive drugs; long-term use promotes serious side effects including increased risk malignancies. The current study aimed to target neutrophil-myeloperoxidase, a key contributor to the pathogenesis of IBD, through the use of AZD3241that inhibits extracellular myeloperoxidase. Experimental colitis was induced in C57BL/6 male mice by 2% dextran sodium sulfate in drinking water ad libitum over 9 days. Mice received either normal drinking water and peanut butter (control), 2% DSS in drinking water and peanut butter or 2% DSS in drinking water and AZD3241 (30 mg/kg) dispersed in peanut butter daily for 9 days. Administered AZD3241 attenuated body weight loss (10% p< 0.05) and improved clinical score (9 fold p< 0.05; a score comprising the time-dependent assessment of stool consistency and extent of rectal bleeding), loss of colonic crypts ( p< 0.001), preserved surface epithelium ( p< 0.001) and enhanced expression of the transcription factor Nrf-2 (regulator of antioxidants) and enhanced expression of the downstream antioxidant response element haeoxygenase-1 (HO-1) in the colon tissue. Also, the concentration of fecal hemoglobin and the myeloperoxidase specific oxidative damage biomarker 3-chlorotyrosine in the colon were significantly decreased in the presence of AZD3241. This latter result was consistent with AZD3241 inhibiting MPO activity in vitro . Overall, AZD3241 ameliorated the course and severity of experimental colitis through ameliorating MPO derived tissue damage and could be considered a potential therapeutic option, subject to further validation in chronic IBD models. (Copyright © 2020 Ahmad, Chami, Liu, Schroder, San Gabriel, Gao, Fong, Wang and Witting.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu