Nanì, Maria Francesca (2024) Palmitoylethanolamide (PEA) in Preclinical Experimental Models of Intestinal Disorders. [Tesi di dottorato]

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Abstract

Intestinal diseases considered in this PhD project (i.e., gut fibrosis associated with Crohn’s disease- and colorectal cancer) are a heterogeneous worldwide group of disorders that impact the global healthcare system and reduce the quality of life due to various characteristic symptoms. Despite considerable advancements in managing pathological conditions, colorectal cancer (CRC) remains a challenge. On the other hand, for CD patients with intestinal fibrosis, surgical resection remains the only therapeutic option for alleviating intestinal strictures, and a little headway has been made in the development of efficient pharmacological treatments. Palmitoylethanolamide (PEA) is a fatty acid belonging to the family of Acylethanolamides (AEs) produced both endogenously that present in nature in many food sources (i.e., egg yolk, soy lecithin, milk, and peanuts). Moreover, PEA is already commercially available and sold as food supplements and/or foods for medical purposes. PEA actions are preferentially terminated by its hydrolytic enzyme N-acylethanolamine acid amidase (NAAA), a lysosomal enzyme whose inhibition determines an increase of endogenous PEA levels. NAAA inhibitors have opened new promise for developing new and effective therapies for various diseases, including those affecting the gut. Evidence suggests that by interacting with multiple targets, PEA reduces inflammation in murine and human colon tissues, suggesting a possible involvement in CRC and intestinal fibrosis. Concurrently, NAAA pharmacological inhibition by using a selective pharmacological inhibitor (i.e., AM9053) is reported to exert beneficial effects in inflammatory conditions, with no shreds of evidence in CRC and intestinal fibrosis. Here, we investigate the functional role of PEA and its primary degradative enzyme inhibitor, NAAA, in preclinical experimental CRC and intestinal fibrosis models.

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