A Novel Mast Cell Stabilizer JM25-1 Rehabilitates Impaired Gut Barrier by Targeting the Corticotropin-Releasing Hormone Receptors

Abstract

Mast cell (MC) plays a central role in intestinal permeability; however, few MC-targeting drugs are currently available for protection of the intestinal barrier in clinical practice. A nonfluorinated Lidocaine analog 2-diethylamino-N-2,5-dimethylphenyl acetamide (JM25-1) displays anti-allergic effect, but its impact on MC remains elusive. In this study, we explored whether JM25-1 has therapeutic potential on intestinal barrier defect through stabilizing MC. JM25-1 alleviated release of β-hexosaminidase and cytokine production of MC. The paracellular permeability was redressed by JM25-1 in intestinal epithelial cell monolayers co-cultured with activated MC. In vivo, JM25-1 diminished intestinal mucosal MC amount and cytokine production, especially downregulating the expression of CRHR1, accompanied by an increase of CRHR2. Protective effects appeared in JM25-1-treated stress rats with a recovery of weight and intestinal barrier integrity. Through network pharmacology analysis, JM25-1 showed a therapeutic possibility for irritable bowel syndrome (IBS) with predictive targeting on PI3K/AKT/mTOR signaling. As expected, JM25-1 reinforced p-PI3K, p-AKT, p-mTOR signaling in MC, while the mTOR inhibitor Rapamycin reversed the action of JM25-1 on the expression of CRHR1 and CRHR2. Moreover, JM25-1 successfully remedied intestinal defect and declined MC and CRHR1 expression in rat colon caused by colonic mucus of IBS patients. Our data implied that JM25-1 possessed therapeutic capacity against intestinal barrier defects by targeting the CRH receptors of MC through PI3K/AKT/mTOR signaling.

Visceral hypersensitivity induced by mild traumatic brain injury via the corticotropin‐releasing hormone receptor: An animal model

“…Although we did not examine the intestinal permeability after CRFR antagonist, a recent study showed that impaired gut barrier was recovered by targeting the CRFRs on mast cells. 52 Although we did not determine whether the relationship between increased ileal permeability and changes in CRFR in the rectum are independent or interacting, further exploration of these relationships may lead to a better understanding of the pathophysiology of this model.…”

“…Those mediators impair the tight junction between the intestinal epithelial cells, whose release from mast cells might be suppressed by CRFR antagonism, leading to rapid suppression of visceral hypersensitivity as shown in our study. Although we did not examine the intestinal permeability after CRFR antagonist, a recent study showed that impaired gut barrier was recovered by targeting the CRFRs on mast cells 52 . Although we did not determine whether the relationship between increased ileal permeability and changes in CRFR in the rectum are independent or interacting, further exploration of these relationships may lead to a better understanding of the pathophysiology of this model.…”

The Role of Mast Cells in Maintaining Homeostasis of the Colon Mucosa

“…The relationship between manifestations of stress and reactions from the gastrointestinal tract is mediated by the interaction of the brain and mast cells with the participation of the vagus nerve [56,57]. The further process of mast cell degranulation increases the permeability of the intestinal barrier, and pharmacological inhibition of their activation eliminates this effect in animal stress models [58][59][60]. Intestinal microorganisms (bacteria, fungi, etc.)…”

“…Взаємозв'язок між проявами стресу та реакціями з боку шлунково-кишкового тракту опосередковується взаємодією мозку і мастоцитів за участі блукаючого нерва [56,57]. Подальший процес дегрануляції мастоцитів посилює проникність кишкового бар'єру, а фармакологічне інгібування їх активації нівелює цей ефект на моделях стресу у тварин [58][59][60]. Кишкові мікроорганізми (бактерії, грибки тощо) можуть індукувати активацію тучних клітин [5,61], причому деякі мікроорганізми можуть викликати прозапальну реакцію, в той час як інші можуть її зменшити, що дозволяє модулювати інтенсивність та перебіг запалення і таким чином сприяти підтримці гомеостатичних умов у слизовій оболонці кишок [4,62].…”