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Open AccessArticle

Different Routes to Inhibit Fatty Acid Amide Hydrolase: Do All Roads Lead to the Same Place?

1
Fondazione Santa Lucia IRCCS, Preclinical Neuroscience, Via del Fosso di Fiorano 64, 00143 Rome, Italy
2
Endocannabinoid Research Group, Institute of Translational Pharmacology, CNR, Via Fosso del Cavaliere 100, 00133 Rome, Italy
3
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Via C. Flegrei 34, 80078 Pozzuoli, Italy
4
Faculty of Veterinary Medicine, University of Teramo, via R. Balzarini 1, 64100 Teramo, Italy
5
Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy
6
Institute for Complex Systems (ISC), C.N.R., Via dei Taurini 19, 00185 Rome, Italy
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(18), 4503; https://doi.org/10.3390/ijms20184503
Received: 25 July 2019 / Revised: 6 September 2019 / Accepted: 9 September 2019 / Published: 11 September 2019
There is robust evidence indicating that enhancing the endocannabinoid (eCB) tone has therapeutic potential in several brain disorders. The inhibition of eCBs degradation by fatty acid amide hydrolase (FAAH) blockade, is the best-known option to increase N-acyl-ethanolamines-(NAEs)-mediated signaling. Here, we investigated the hypothesis that intranasal delivery is an effective route for different FAAH inhibitors, such as URB597 and PF-04457845. URB597 and PF-04457845 were subchronically administered in C57BL/6 male mice every other day for 20 days for overall 10 drug treatment, and compared for their ability to inhibit FAAH activity by the way of three different routes of administration: intranasal (i.n.), intraperitoneal (i.p.) and oral (p.o.). Lastly, we compared the efficacy of the three routes in terms of URB597-induced increase of NAEs levels in liver and in different brain areas. Results: We show that PF-04457845 potently inhibits FAAH regardless the route selected, and that URB597 was less effective in the brain after p.o. administration while reached similar effects by i.n. and i.p. routes. Intranasal URB597 delivery always increased NAEs levels in brain areas, whereas a parallel increase was not observed in the liver. By showing the efficacy of intranasal FAAH inhibition, we provide evidence that nose-to-brain delivery is a suitable alternative to enhance brain eCB tone for the treatment of neurodegenerative disorders and improve patients’ compliance.
Keywords: fatty acid amide hydrolase; intranasal drug delivery; URB597; PF-04457845; endocannabinoid tone; patients’ compliance fatty acid amide hydrolase; intranasal drug delivery; URB597; PF-04457845; endocannabinoid tone; patients’ compliance
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Giacovazzo, G.; Bisogno, T.; Piscitelli, F.; Verde, R.; Oddi, S.; Maccarrone, M.; Coccurello, R. Different Routes to Inhibit Fatty Acid Amide Hydrolase: Do All Roads Lead to the Same Place? Int. J. Mol. Sci. 2019, 20, 4503.

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