PhD Scientific Days 2022

Pharmaceutical Sciences II. (Poster discussion will take place in the Aula during the Coffee Break)

The role of the lysophosphatidic acid 2 (LPA2) receptor in gastropathy caused by non-steroidal anti-inflammatory drugs

Text of the abstract

Introduction
The role of the lysophosphatidic acid 2 (LPA2) receptor in the gastrointestinal tract has not been sufficiently elucidated, and both protective and detrimental effects have been described in various animal models. Our previous results suggest that low receptor activation attenuates intestinal damage caused by indomethacin, a non-steroidal anti-inflammatory drug (NSAID), whereas overstimulation is already associated with increased intestinal inflammation. The effect of the LPA2 receptor on NSAID-induced gastric ulceration has hardly been investigated.

Aims
Investigation of the effect of the LPA2 receptor agonist DBIBB and the antagonist H2L5186303 on indomethacin-induced gastric damage and inflammation.

Methods
In our experiments, Wistar rats were treated intragastrically with different doses of the LPA2 receptor agonist DBIBB and the receptor antagonist H2L5186303 (0.01 - 10 mg/kg) or with their solvent twice, 23 and a half hours apart. Thirty minutes after the last treatment, the animals received indomethacin (30 mg/kg), and 6 hours later, the extent of ulcers was examined. In our next experiment, we examined the effect of DBIBB on C57BL/6 mice according to the protocol describe previously. The animals received 40 mg/kg indomethacin and after 24 hours the tissue inflammation was determined by Western blot.

Results
In Wistar rats, DBIBB at a dose of 1 mg/kg reduced the extent of indomethacin-induced ulcer area, but at a dose of 10 mg/kg it increased it. The 0.1 mg/kg dose of H2L5186303 increased the extent of the ulcer area caused by indomethacin, whereas at the other two doses had no significant effect on it. In mice, the 1 mg/kg dose of DBIBB did not yet affect gastric tissue inflammation, but the 10 mg/kg dose reduced the tissue levels of both myeloperoxidase and cyclooxygenase-2.

Conclusion
Based on our results, low stimulation of the LPA2 receptor can reduce indomethacin-induced epithelial damage and tissue inflammation in the stomach. However, higher doses of DBIBB may already exacerbate gastric damage. On the other hand, receptor inhibition exacerbates epithelial damage. Further experiments are planned to clarify the mechanisms underlying the observed effects.

Funding
NKFI FK 138842, ÚNKP-21-3-II-SE-33, EFOP-3.6.3-VEKOP-16-2017-00009