Thesis (M.Sc.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Scarce studies evaluated the impact of adrenoceptor (AR) modulators against ulcerative colitis (UC); nonetheless, the therapeutic potential of mirabegron (MA), a Ý3-AR agonist, and carvedilol (CR), a nonselective Ý-AR antagonist, and their mechanism(s) are not unveiled.Thus, iodoacetamide-induced ulcerated rats were either untreated or treated with MA and/or CR for 8 days after ulcer induction, beside the normal control group.The anti-colitic efficacy of MA and/or CR was evidenced by hindering colon edema and weight loss with reduced colon injury scores assessed microscopically. On the molecular level, treatments reduced colonic amyloidopathy by abating BACE-1 and presenilin (PS1) to minimize the deposition of AÝ. Additionally, they deterred the NOTCH/NICD/HES1 hub and the inflammatory trajectory GSK-3Ý/NF-mv/TNF-Ü, as well as the lipid peroxidation marker MDA. Besides, their anti-fibrotic effect was verified by boosting SMAD-7 and lessening TGF-Ý1 and Ü-SMA immunoexpression, besides MTC staining. Moreover, the ability of MA and/or CR to amend the gut barrier structure attested by the increased goblet cells along with the inhibition of pY654-Ý-catenin to preserve the E-cadherin/Ý-catenin adherens junction.These signaling pathways are suggested to be orchestrated by the replenished transcription factor PPAR-Þ known for its anti-colitic effect. Notably, the combination regimen proved a synergistic effect with GSK-3Ý and additive effects with NF-mv, TNF-Ü, MDA, goblet cells, and MTC. Therefore, the therapeutic hinges upon which MA and/or CR against UC depend on are partly related to enhancing PPAR-Þ, SMAD-7 and gut barrier integrity, while suppressing BACE-1/PS1/AÝ, NOTCH/NICD/HES1, GSK-3Ý/NF-mv/TNF-Ü and TGF-1Ý/Ü-SMA signaling pathways

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