Pharmacological antagonism of EP2 receptor does not modify basal cardiovascular and respiratory function, blood cell counts, and bone morphology in animal models.

Authors

Varun Rawat
Avijit Banik
Radhika Amaradhi
Asheebo Rojas
Shashidharamurthy Taval, Philadelphia College of Osteopathic MedicineFollow
Tamas Nagy
Raymond Dingledine
Thota Ganesh

Document Type

Article

Publication Date

3-1-2022

Abstract

The EP2 receptor has emerged as a therapeutic target with exacerbating role in disease pathology for a variety of peripheral and central nervous system disorders. We and others have recently demonstrated beneficial effects of EP2 antagonists in preclinical models of neuroinflammation and peripheral inflammation. However, it was earlier reported that mice with global EP2 knockout (KO) display adverse phenotypes on fertility and blood pressure. Other studies indicated that EP2 activation with an agonist has a beneficial effect of healing fractured bone in animal models. These results impeded the development of EP2 antagonists, and EP2 antagonism as therapeutic strategy. To determine whether treatment with EP2 antagonist mimics the adverse phenotypes of the EP2 global KO mouse, we tested two EP2 antagonists TG11-77. HCl and TG6-10-1 in mice and rats while they are on normal or high-salt diet, and by two different administration protocols (acute and chronic). There were no adverse effects of the antagonists on systolic and diastolic blood pressure, heart rate, respiratory function in mice and rats regardless of rodents being on a regular or high salt diet. Furthermore, chronic exposure to TG11-77. HCl produced no adverse effects on blood cell counts, bone-volume and bone-mineral density in mice. Our findings argue against adverse effects on cardiovascular and respiratory systems, blood counts and bone structure in healthy rodents from the use of small molecule reversible antagonists for EP2, in contrast to the genetic ablation model. This study paves the way for advancing therapeutic applications of EP2 antagonists against diseases involving EP2 dysfunction.

Publication Title

Biomedicine & Pharmacotherapy

Volume

147

Last Page

112646

PubMed ID

35091236

Comments

This article was published in Biomedicine & Pharmacotherapy, Volume 147.

The published version is available at https://doi.org/10.1016/j.biopha.2022.112646.

Copyright © 2021 The Authors. Published by Elsevier Masson SAS. CC BY-NC-ND 4.0.

Recommended Citation

Rawat, Varun; Banik, Avijit; Amaradhi, Radhika; Rojas, Asheebo; Taval, Shashidharamurthy; Nagy, Tamas; Dingledine, Raymond; and Ganesh, Thota, "Pharmacological antagonism of EP2 receptor does not modify basal cardiovascular and respiratory function, blood cell counts, and bone morphology in animal models." (2022). PCOM Scholarly Works. 2138.
https://digitalcommons.pcom.edu/scholarly_papers/2138