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

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 (A beta) axis has not been evaluated. Hence, we investigated the impact of mirabegron (beta 3-agonist) and/or carvedilol (beta 1/beta 2 antagonist) on iodoacetamide-induced ulcerative colitis with emphasis on the novel pathomechanism of the PS1/BACE-1/A beta 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/A beta axis and the NOTCH1/NICD/HES1 hub besides the inflammatory cascade GSK3-beta/NF-kappa B/TNF-alpha, and the oxidative stress marker malondialdehyde. The anti-fibrotic effect was verified by boosting SMAD-7 and inhibiting TGF-beta 1, alpha-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))-beta-catenin to preserve the E-cadherin/beta-catenin adherens junction (AJ). These signaling pathways may be orchestrated by the replenished PPAR-gamma, 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 antifibrotic capacities. The therapeutic effect of these drugs depends party on suppressing the harmful signaling pathways PS1/BACE-1/A beta, NOTCH1/NICD/HES1, GSK3-beta/NF-kappa B/TNF-alpha, and TGF-1 beta/alpha-SMA while enhancing PPAR-gamma, SMAD-7, mucus, and AJ.

Automated summary

The study investigated the impact of mirabegron and/or carvedilol on ulcerative colitis, finding that these drugs can improve inflammation cascade, fibrotic processes, and gut barrier function by modulating various signaling pathways and molecular mechanisms to exert anti-colitic effects.