Evaluation of the Antifibrotic Effect of Serotonin Receptor Antagonists on Bleomycin Induced Pulmonary Fibrosis in Rats

Abstract

Idiopathic pulmonary fibrosis (IPF) is believed to be an epithelial-fibroblast disease. Activated epithelial cells are thought to release potent fibrogenic molecules and cytokines, such as tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta1 (TGF-β1), which in turn foster the transformation of fibroblasts into myofibroblasts and promote production of extracellular matrix molecules and so collagen deposition. Serotonin (5-hydroxy tryptamine, 5-HT) is an important mediator for lung fibrogenesis, with implication of 5-HT2A/B/C receptors. However, the antifibrotic effects of all 5-HT2 receptor subtypes versus 5-HT2A/C blockade is needing to be explored. So, the present study was conducted to evaluate the antifibrotic effects of mirtazapine (5-HT2A/C receptor blocker) and cyproheptadine (5-HT2A/B/C receptor blocker) on body weight changes, survival rates, the lung hydroxyproline and TGF-β1 levels as well as the histopathological changes of lung fibrosis, in bleomycin-induced rat pulmonary fibrosis. Eighty-eight adult rats were used and subdivided randomly into 11 groups. One normal control, five vehicle control groups and five groups with IPF that induced by intra-tracheal instillation of bleomycin alone (5mg/kg), or bleomycin and treated with either mirtazapine (15 mg/kg/day) or cyproheptadine (5 mg/kg/day) for 7 and 14 days. Oral treatment with either mirtazapine or cyproheptadine, significantly ameliorated losses in body weights, reduction in survival rates, lung hydroxyproline and TGF-β1 levels and the inflammatory effects in lungs induced by bleomycin. The mechanisms underlying these therapeutic effects could be dependent on the reduction of TGF-β1 actions as decreasing lung inflammation and production and deposition of collagen in fibrotic lung tissues.

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

“…Further studies suggested that the antiproliferative effects of EXT5 and EXT9 were related to the pAkt/p21 signaling pathway [38]. It is worth mentioning that in vivo studies in the BLM-induced pulmonary fibrosis rat model showed that 5-HT 2C R and 5-HT 7 R were also implicated in pulmonary fibrosis [37,47,48].…”

“…The 5-HT 2B R has been implicated in fibrotic disorders such as liver fibrosis [31][32][33], pulmonary fibrosis [34][35][36][37][38], systemic sclerosis (SSc) [39][40][41][42][43], and pancreatic fibrosis [44].…”

The Anticancer Effect of Rhubarb Officinale Fraction and Sorafenib Against Chemically Induced Hepatocellular Carcinoma in Rats

“…Rats of HCC were administered intraperitoneal (IP) a single dose of DEN (200 mg/kg dissolved in normal saline 0.9% at a final volume of 1ml/kg. Two weeks after DEN challenging, CCl4 solution (CCl4/olive oil; 1:1; 1 ml/kg) was administered IP three times weekly for 6 consecutive weeks (Elaidy et al, 2017). After detection of HCC development, the treatment by sorafenib and anthraquinones were done.…”

Development of Pharmacophore Models for the Important Off-Target 5-HT2B Receptor

“…In the cardiovascular system, 5-HT 2B is expressed in myocardial, endothelial, and vascular smooth muscle cells, and agonism is involved in cardiovascular diseases including cardiomyopathy, valvular heart disease (VHD), − and pulmonary arterial hypertension. ,− Drug-induced VHD was the cause of the withdrawal of fenfluramine and dexfenfluramine used for the indication of obesity from the U.S. market in 1997 and pergolide used for the indication of Parkinson’s disease in 2007. These compounds are partial or full agonists of 5-HT 2B with high affinity, and the pathogenesis of drug-induced VHD could be correlated with off-target activation of 5-HT 2B . ,, Furthermore, 5-HT 2B could be linked to the vascular heart diseases such as mitral valve prolapse and its involvement in calcific aortic valve disease; , fibrosis disorders such as liver fibrosis, − pulmonary fibrosis, − systemic sclerosis, − and pancreatic fibrosis; different types of cancer including hepatocellular carcinoma, − neuroendocrine tumor, , and pancreatic ductal adenocarcinomas; and irritable bowel syndrome of the gastrointestinal tract. − …”