PhD Scientific Days 2026

Pharmaceutical Sciences and Health Technologies 2.

Investigation of the Role of Endocannabinoids in Indomethacin-Induced Enteropathy in Mice

Name of the presenter

Demeter, Zsuzsanna Orsolya

Institute/workplace of the presenter

Department of Pharmacology and Pharmacotherapy, Semmelweis University

Authors

Zsuzsanna O. Demeter^1,2, Gerda Wachtl^1,2, Arezoo Haghighi^1,2, Anna Zsidai^1,2, Lili Lengyel^1,2, Julian Steinhardt^1,2, Maximilian Manger^1,2, Klára Gyires^1,2, Zoltán S. Zádori^1,2
1: Department of Pharmacology and Pharmacotherapy, Semmelweis University Hungary
2: Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary

Text of the abstract

Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) frequently leads to damage of the distal small intestine, for which no effective therapy is currently available. The endocannabinoid system (ECS) plays a crucial role in maintaining gastrointestinal homeostasis. In our previous studies, increasing the levels of the two main endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), attenuated NSAID-induced gastric injury. However, inhibition of AEA metabolism with URB597 did not reduce the severity of NSAID-induced enteropathy.
The aim of this study was to determine whether inhibition of monoacylglycerol lipase (MAGL)—a key enzyme involved in 2-AG metabolism—or direct administration of AEA could alleviate indomethacin (IND)-induced enteropathy in mice.
C57BL/6 mice were treated with a single high dose of IND (30 mg/kg p.o.) or its vehicle (1% hydroxyethylcellulose). In the first experiment, animals received JZL184 (4 or 16 mg/kg p.o.) or its vehicle, while in the second experiment mice were treated with AEA (1 or 10 mg/kg p.o.), administered three times. Twenty-four hours after IND treatment, animals were sacrificed, and small intestinal length was measured. Tissue levels of inflammatory mediators and tight junction (TJ) proteins were determined, and AEA and 2-AG concentrations were quantified by LC–MS.
JZL184 treatment significantly increased 2-AG levels in the small intestine, as expected, but did not affect the severity of enteropathy. In contrast, AEA treatment significantly reduced the tissue levels of inflammatory mediators (COX-2, MPO, IL-1β) in enteropathic animals.
Our findings suggest that inhibition of endocannabinoid metabolism alone is not sufficient to alleviate NSAID-induced enteropathy. However, direct administration of AEA significantly reduces intestinal inflammation and may represent a promising therapeutic approach for the treatment of enteropathy. Further studies are needed to clarify the mechanisms underlying the lack of efficacy of metabolism inhibitors.
Grant: NKFI FK 138842