2-Pentadecyl-2-oxazoline alleviates anxiety-like behaviour and modulates the microbiota-gut-brain axis in obese mice.

Authors

Nicola Opallo, Adriano Lama, Stefania Melini, Lorena Coretti, Federica Comella, Filomena Del Piano, Nicole Pia Navatti, Alessia D'Andrea, Carmen De Caro, Francesca Lembo, Maria Carmela Ferrante, Rosaria Meli, Giuseppina Mattace Raso, Claudio Pirozzi

Published in

Frontiers in pharmacology. Volume 17. Pages 1878488. Epub Jun 17, 2026.

Abstract

A bidirectional relationship between obesity and anxiety disorders has been increasingly associated with neuroinflammation and dysregulation of the gut-brain axis. Here, we investigated the pharmacological effects of the N-palmitoylethanolamine oxazoline derivative 2-pentadecyl-2-oxazoline (C15OXA) in a mouse model of high-fat diet (HFD)-induced obesity, with particular attention to its central and peripheral mechanisms of action. Male C57Bl/6J mice were fed an HFD for 12 weeks and subsequently treated with C15OXA (30 mg·kg^-1, p. o.) for 7 weeks. Behavioural, molecular, and microbiota analyses were performed to evaluate the effects of the compound. C15OXA significantly reduced anxiety-like behaviour in obese mice without affecting body weight, fat mass, or glucose tolerance. At the central level, C15OXA attenuated hippocampal neuroinflammation, as shown by reduced expression of COX-2, TLR4, NLRP3 and IL-1β. In parallel, C15OXA restored tight junction gene expression associated with blood-brain barrier integrity, and modulated unfolded protein response signalling. In addition, C15OXA enhanced markers of neurogenesis and synaptic plasticity. At the peripheral level, C15OXA treatment reduced colonic inflammation and improved gut barrier integrity. These effects were associated with a targeted reshaping of gut microbiota composition. In particular, C15OXA promoted the enrichment of butyrate- and menaquinone-producing bacteria, as taxa linked to beneficial metabolic functions. Overall, these findings suggest that C15OXA exerts anxiolytic-like effects associated with coordinated central and peripheral pathways involving the modulation of neuroinflammatory pathways, barrier integrity, and gut-brain axis signalling. This study provides novel pharmacological insight into the therapeutic potential of C15OXA for the treatment of obesity-associated neuropsychiatric disorders.

PMID:
42389262
Bibliographic data and abstract were imported from PubMed on 16 Sep 2026.

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