Targeting the mPGES-PGE₂-EP4 pathway with MF63, MK886, and Grapiprant as a potential therapeutic strategy for Escherichia coli-induced endometritis in dairy cows

Xiaolin Yang ¹, Lili Guo ¹, Pengfei Gong ²

⁰Key Laboratory of Clinical Diagnosis and Treatment Techniques for Animal Disease, Ministry of Agriculture, Inner Mongolia Agricultural University, No. 29, Erdosdong Road, Saihan District, 010011, Hohhot, China; Laboratory of Veterinary Clinical Pharmacology, College of Veterinary Medicine, Inner Mongolia Agricultural University, No. 29, Erdosdong Road, Saihan District, 010011, Hohhot, China.

Theriogenology +

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August 30, 2025

View abstract on PubMed

Summary

New therapies targeting the prostaglandin E2 pathway show promise for treating E. coli endometritis in dairy cows. These treatments reduced inflammation and tissue damage, offering a safer alternative to antibiotics and NSAIDs.

Area Of Science

Veterinary Medicine
Immunology
Reproductive Biology

Background

Escherichia coli (E. coli) causes endometritis in dairy cows, leading to reduced fertility.
Current treatments like antibiotics and NSAIDs have drawbacks, including bacterial resistance and impaired reproduction.
The prostaglandin E2 (PGE2) pathway, involving mPGES-1 and EP4 receptor, is crucial in the bovine uterine environment.

Purpose Of The Study

To investigate the therapeutic potential of mPGES-1 inhibitors (MF63, MK886) and an EP4 receptor antagonist (Grapiprant) for E. coli-induced endometritis in dairy cows.

Main Methods

Molecular docking to assess drug-target interactions.
In vitro assessment of PGE2 secretion in infected bovine endometrial tissues.
Histopathological analysis (H&E staining) and immunofluorescence for tissue damage and DAMPs (HMGB-1, HABP-2).
Measurement of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-8) and anti-inflammatory cytokine (IL-10).

Main Results

MF63 and MK886 effectively bound mPGES-1; Grapiprant bound EP4 receptor.
Inhibitors significantly suppressed PGE2 secretion in E. coli-infected tissues.
Treatments reduced E. coli-induced tissue damage and expression of HMGB-1 and HABP-2.
Pro-inflammatory cytokines decreased, while IL-10 expression increased.

Conclusions

Targeting the mPGES-PGE2-EP4 pathway presents a promising therapeutic strategy.
MF63, MK886, and Grapiprant demonstrate potential as safer, effective treatments for bovine endometritis.
This approach could mitigate infection while minimizing adverse reproductive effects.

Keywords:

Endometritis Escherichia coli Grapiprant MF63 MK886 Prostaglandin E(2)