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

Abstract

Although mast cell (MC) plays a central role in the occurrence of intestinal permeability, few drugs are currently available for clinical practice. A nonfluorinated lidocaine analog 2-diethylamino-N-2,5-dimethylphenyl acetamide (JM25-1) displays an anti-allergic effect, in this study we elucidate its impact on MC and evaluate its therapeutic potential on intestinal barrier defect. JM25-1 alleviated the release of β-hexosaminidase, regulated cytokine production of MC. The paracellular permeability was also redressed by JM25-1 in intestinal epithelial cell monolayers co-cultured with the secretion from activated MC. In vivo treatment, JM25-1 diminished mucosal MC amount and cytokine production in the small intestine, especially the expression of CRHR1 on MC accompanied by an increase of CRHR2. Protective effects appeared in JM25-1-treated rats with a recovery of weight and intestinal barrier integrity. Then, in the therapy for IBS, PI3K/AKT/mTOR exhibited a strong affinity with JM25-1 among the 71 potential therapeutic targets by network pharmacology analysis. Consequently, JM25-1 reinforced p-PI3K, p-AKT, p-mTOR signaling in MC. However, a mTOR inhibitor Rapamycin reversed the effects of JM25-1 on the expression of CRHR1 and CRHR2. Moreover, JM25-1 successfully remedied intestinal defect and declined MC amount and CRHR1 expression in rat colon caused by colonic mucus of IBS patients. Our research implied that JM25-1 possessed therapeutic capacity for intestinal barrier defect by targeting the CRH receptors of MC through the PI3K/AKT/mTOR signaling.

Note:
Funding Information: This study is supported by the Foundation of Science and Technology Department of Sichuan province [grant number 2022YFS0172], the Medical Research Project of Chengdu Municipal Health Commission [grant number 2021055], the Fifth Batch of Technological Innovation Research and Development Project of Chengdu [grant number 2021-YF05-00585-SN], and the Key Research and Development Project of Sichuan Province [grant number 2022YFS0340].

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: All animal and clinical experiments were approved by The Ethics Committee of Southwest Jiaotong University Approval, People’s Republic of China (Agreement No. SWJTU-2013-026). And all patients were asked to sign a written informed consent and IBS-symptomatic assessment.

Keywords: JM25-1, Mast cell, Intestinal barrier, CRHR, PI3K/AKT/mTOR