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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00180

The endocannabinoid reuptake inhibitor WOBE437 is orally bioavailable and exerts indirect polypharmacological effects via different endocannabinoid receptors

 Inés Reynoso-Moreno1,  Andrea Chicca1, Mario E. Flores-Soto2, Juan M. Viveros-Paredes2* and  Jürg Gertsch1*
  • 1Institute of Biochemistry and Molecular Medicine, Universität Bern, Switzerland
  • 2Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, Mexico

Different anandamide (AEA) transport inhibitors show antinociceptive and antiinflammatory effects in vivo, but due to their concomitant inhibition of fatty acid amide hydrolase (FAAH) and overall poor bioavailability, they cannot be used unequivocally to study the particular role of endocannabinoid (EC) transport in pathophysiological conditions in vivo. Here, the potent and selective endocannabinoid reuptake inhibitor WOBE437, which inhibits AEA and 2-arachidonoylglycerol (2-AG) transport, was tested for its oral bioavailability to the brain. WOBE437 is assumed to locally increase EC levels in tissues in which facilitated EC reuptake intermediates subsequent hydrolysis. Given the marked polypharmacology of ECs, we hypothesized to see differential effects on distinct EC receptors in animal models of acute and chronic pain/inflammation. In C57BL6 male mice, WOBE437 is orally bioavailable with an estimated tmax value of ≤ 20 min in plasma (Cmax ~ 2000 pmol/mL after 50 mg/kg, p.o.) and brain (Cmax ~ 500 pmol/g after 50 mg/kg, p.o.). WOBE437 was cleared from the brain after approximately 180 min. In addition, in BALB/c male mice, acute oral administration of WOBE437 (50 mg/kg) exhibits similar brain concentrations after 60 min and inhibits analgesia in the hot plate test in a cannabinoid CB1 receptor-dependent manner, without inducing catalepsy or affecting locomotion. WOBE437 significantly elevated AEA in the somatosensory cortex, while showing dose-dependent biphasic effects on 2-AG levels in plasma but no significant changes in N-acylethanolamines other than AEA in any of the tissues. In order to explore the presumed polypharmacology mediated via elevated EC levels, we tested this EC reuptake inhibitor in complete Freud’s adjuvant induced monoarthritis in BALB/c mice as a model of chronic inflammation. Repetitive doses of WOBE437 (10 mg/kg, i.p.) attenuated allodynia and edema via cannabinoid CB2, CB1 and PPARγ receptors. The allodynia inhibition of WOBE437 treatment for three days was fully reversed by antagonists of any of the receptors. In the single dose treatment the CB2 and TRPV1 antagonists significantly blocked the effect of WOBE437. Overall, our results show the broad utility of WOBE437 for animal experimentation for both p.o. and i.p. administrations. Furthermore, the data indicate the possible involvement of EC reuptake/transport in pathophysiological processes

Keywords: allodynia, Endocannabinoids, Inflammation, monoarthritis, polypharmacology, bioavailability, endocannabinoid transport

Received: 26 Feb 2018; Accepted: 09 May 2018.

Edited by:

Ildikó Rácz, Universitätsklinikum Bonn, Germany

Reviewed by:

James H. Peters, Washington State University, United States
Meliha Karsak, Universitätsklinikum Hamburg-Eppendorf, Germany  

Copyright: © 2018 Reynoso-Moreno, Chicca, Flores-Soto, Viveros-Paredes and Gertsch. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Juan M. Viveros-Paredes, Universidad de Guadalajara, Centro Universitario de Ciencias Exactas e Ingenierías, Laboratorio de Investigación y Desarrollo Farmacéutico, Guadalajara, Mexico,
Prof. Jürg Gertsch, Universität Bern, Institute of Biochemistry and Molecular Medicine, Bühlstrasse 28, Bern, 3012, Switzerland,