PhD Scientific Days 2025

Pharmaceutical Sciences and Health Technologies II.

Investigation of the Role of Anandamide in NSAID Enteropathy in Mice

Name of the presenter

Demeter Zsuzsanna Orsolya

Institute/workplace of the presenter

Department of Pharmacology and Pharmacotherapy, Semmelweis University

Authors

Zsuzsanna Demeter^1,2, Gerda Wachtl^1,2, Arezoo Haghighi^1,2, Lili Lengyel^1,2, Anna Zsidai^1,2, Klára Gyires^1,2, Zoltán S. Zádori^1,2

1: Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
2: Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary

Text of the abstract

Introduction: Chronic use of non - steroidal anti - inflammatory drugs (NSAIDs) can cause damage to the small intestine (enteropathy), the prevention and treatment of which is not yet understood. Although literature data suggest that activators of the endocannabinoid (EC) system, such as fatty acid amide hydrolase (FAAH) inhibitors, which increase anandamide (AEA) levels, may reduce gastrointestinal damage and inflammation in various animal models, in our previous experiments the FAAH inhibitor URB597 exacerbated indomethacin (IND) - induced enteropathy in mice, the mechanism of which remains unclear.
Aims: In the present experiments, we were interested in whether the exacerbating effect of URB597 on enteropathy was mediated by or independent of the increase in AEA levels. Our aim was 1) to determine the level of AEA in the small intestine of URB597 - treated animals and 2) to investigate the effect of AEA treatment on enteropathy in a separate experiment. 3) As cannabinoids can reduce gastric acid secretion, which can cause intestinal dysbiosis, we also aimed to measure the levels of Bifidobacteria in the small intestine of URB597 - treated animals.
Method: 1) AEA levels were determined by HPLC - MS. 2) C57BL/6 mice were treated with a single high dose of IND (30 mg/kg) and the severity of enteropathy was assessed after 24 h by macroscopy and by measuring the expression levels of various inflammatory mediators. AEA (1 and 10 mg/kg) or vehiculum was administered 3 times per os to the animals 2h before IND, 6 h after IND and 2 h before termination of the animals). 3) Bifidobacteria levels were determined by qPCR.
Results: 1) Although URB597 alone slightly increased AEA levels in the small intestine, enteropathy caused a more significant increase in AEA and there was no difference in AEA levels between the IND and IND+URB597 groups. 2) The AEA was able to reduce the effect of IND. 3) URB597 treatment had no effect on the levels of Bifidobacteria in the small intestine.
Conclusion: Our results indicate that AEA mitigated NSAID enteropathy in mice, but does URB597 treatment exacerbate it by increasing AEA levels. Although URB597 did not affect Bifidobacteria levels, the role of dysbiosis in exacerbating enteropathy cannot be excluded at this stage and further studies are planned to clarify this.
Funding: NKFI FK 138842