Olmesartan ameliorates chemically-induced ulcerative colitis in rats via modulating NFκB and Nrf-2/HO-1 signaling crosstalk

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Saber S.; Khalil R.M.; Abdo W.S.; Nassif D.; El-Ahwany E.

Journal: Toxicology and Applied Pharmacology

Publisher: Academic Press Inc.

Publication Date: February 2019

Volume / Issue: Volume 364

Pages: 120–132

ISSN: 0041008X

DOI: 10.1016/j.taap.2018.12.020

Scopus: View on Scopus

PubMed: 30594690

Document Type: Article

Authors and Affiliations

Saber S., Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa City, Mansoura, Dakahlia, Egypt; Khalil R.M., Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa City, Mansoura, Dakahlia, Egypt; Abdo W.S., Department of Pathology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt; Nassif D., Department of Pharmacy Practice, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa City, Mansoura, Dakahlia, Egypt; El-Ahwany E., Department of Immunology, Theodor Bilharz Research Institute, Giza, Egypt

Abstract

Alteration in the expression pattern of Nrf-2 and NFκB has been reported in ulcerative colitis (UC) in which functional crosstalk between these two critical pathways has been suggested. The ameliorative potential of the AT1R blocker olmesartan (OLM) on oxidative stress and inflammatory cytokines has received considerable attention in recent years. Acetic acid (AA)-induced UC demonstrates close resemblance to human UC regarding histopathological features and cytokine profile and is associated with local intense immune response, oxidative stress and release of inflammatory cytokines. Therefore, The effect of OLM (1, 5 and 10 mg/kg) administered orally to rats subjected to intra-rectal instillation of 2 ml of 3% AA in saline solution is investigated. The study revealed that OLM ameliorated colon injury and inflammatory signs as visualized by histopathological examination. Levels of colon IL-6, TNF-α IL-1β TGF-β and serum CRP were down-regulated, while the level of colon IL-10 was up-regulated. In a dose-dependent manner, OLM suppressed AA-induced neutrophils accumulation and improved colon anti-oxidant defense machinery. Also, OLM repressed the Bax:BCL-2 ratio and caspase3 expression. The mechanism of these protective effects was found to lay behind its ability to down-regulate gene expression and inhibit phosphorylation and nuclear translocation of p65 subunits. On the other hand, OLM up-regulated gene expression of Nrf-2 and HO-1. In conclusion, our data show that OLM is an Nrf2 activator, NFkB inhibitor and apoptosis inhibitor in an experimental model of ulcerative colitis. Overall, the study indicates that OLM shows promise as a potential therapy for the treatment of human inflammatory bowel diseases. © 2018 Elsevier Inc.

Keywords

Bax:BCL-2; NFκB; Nrf2, HO-1; Olmesartan; Ulcerative Colitis; Acetic Acid; Animals; Anti-Inflammatory Agents; Apoptosis; Apoptosis Regulatory Proteins; Colitis, Ulcerative; Colon; Cytokines; Disease Models, Animal; Heme Oxygenase (Decyclizing); Imidazoles; Inflammation Mediators; Male; NF-E2-Related Factor 2; NF-kappa B; NF-KappaB Inhibitor alpha; Oxidative Stress; Rats, Wistar; Signal Transduction; Tetrazoles; Transcription Factor RelA; C reactive protein; caspase 3; catalase; glutathione; heme oxygenase 1; interleukin 1beta; interleukin 6; malonaldehyde; myeloperoxidase; protein Bax; protein bcl 2; superoxide dismutase; transcription factor Nrf2; transforming growth factor beta; tumor necrosis factor; antiinflammatory agent; apoptosis regulatory protein; autacoid; cytokine; heme oxygenase; Hmox1 protein, rat; I kappa B kinase alpha; imidazole derivative; immunoglobulin enhancer binding protein; Nfe2l2 protein, rat; Nfkbia protein, rat; Rela protein, rat; tetrazole derivative; animal experiment; animal model; animal tissue; antibody labeling; antiinflammatory activity; antioxidant activity; Article; colon injury; controlled study; cytokine production; disease activity; disease severity; dose response; down regulation; drug dose comparison; drug effect; drug mechanism; enzyme activity; experimental model; gene expression; histopathology; lipid peroxidation; neutrophil chemotaxis; nonhuman; organ weight; protection; protein blood level; protein expression; rat; upregulation; Wistar rat; animal; chemically induced; disease model; enzymology; metabolism; pathology

Citation Information

Scopus Citations: 171

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