The novel anti-colitic effect of β-adrenergic receptors via modulation of PS1/BACE-1/Aβ axis and NOTCH signaling in an ulcerative colitis model

• DOI: 10.3389/fphar.2022.1008085
• Publication Date: 2022-10-25T06:41:46Z
• Authors: Salma Nasser; Dalaal M. Abdallah; Kawkab A. Ahmed; Yousra Abdel-Mott...; Hanan S. El-Abhar
• Keywords: 0301 basic medicine; PPAR-γ; Alternative medicine; Physiology; Agonist; RM1-950; carvedilol; Wnt Signaling in Development and Disease; 03 medical and health sciences; Mechanisms of Alzheimer's Disease; Endocrinology; Neuroinflammation; Biochemistry, Genetics and Molecular Biology; Health Sciences; Pathology; presenilin; Disease; Molecular Biology; Internal medicine; Pharmacology; Mirabegron; Overactive bladder; Gastroenterology; Life Sciences; Functional Bowel Disorders and Gastrointestinal Health; mirabegron; 3. Good health; Ulcerative colitis; FOS: Biological sciences; Medicine; Therapeutics. Pharmacology; β-Amyloid; notch; Receptor

Although dysautonomia was documented in inflammatory bowel disease, with activation of the stress-related sympathetic system, the role of agonists/antagonists of the adrenergic receptors is not conclusive. Moreover, ulcerative colitis was recently linked to dementia, but the potential role of the presenilin 1(PS1)/BACE-1/beta-amyloid (Aβ) axis has not been evaluated. Hence, we investigated the impact of mirabegron (β3-agonist) and/or carvedilol (β1/β2 antagonist) on iodoacetamide-induced ulcerative colitis with emphasis on the novel pathomechanism of the PS1/BACE-1/Aβ axis in ulcerative colitis, and its relation to the inflammatory cascade, fibrotic processes, and the gut barrier dysfunction. Ulcerated rats were either left untreated or treated for 8 days with mirabegron and/or carvedilol. Besides minimizing colon edema and weight loss, and improving colon structure, mirabegron and/or carvedilol abated colonic PS1/BACE-1/Aβ axis and the NOTCH1/NICD/HES1 hub besides the inflammatory cascade GSK3-β/NF-κΒ/TNF-α, and the oxidative stress marker malondialdehyde. The anti-fibrotic effect was verified by boosting SMAD-7 and inhibiting TGF-β1, α-SMA immunoexpression, and MTC staining. Moreover, the drugs improved the gut barrier function, attested by the increased goblet cells and expression of E-cadherin, and the inhibited expression of p(Y654)-β-catenin to preserve the E-cadherin/β-catenin adherens junction (AJ). These signaling pathways may be orchestrated by the replenished PPAR-γ, a transcription factor known for its anti-colitic effect.Conclusion: Besides maintaining the gut barrier, mirabegron and/or carvedilol mediated their anti-colitic effect by their anti-oxidant, anti-inflammatory, and anti-fibrotic capacities. The therapeutic effect of these drugs depends partly on suppressing the harmful signaling pathways PS1/BACE-1/Aβ, NOTCH1/NICD/HES1, GSK3-β/NF-κΒ/TNF-α, and TGF-1β/α-SMA while enhancing PPAR-γ, SMAD-7, mucus, and AJ.