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Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation

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Abstract

Augmentation of endogenous cannabinoid (eCB) signaling represents an emerging approach to the treatment of affective disorders. Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid to form prostaglandins, but also inactivates eCBs in vitro. However, the viability of COX-2 as a therapeutic target for in vivo eCB augmentation has not been explored. Using medicinal chemistry and in vivo analytical and behavioral pharmacological approaches, we found that COX-2 is important for the regulation of eCB levels in vivo. We used a pharmacological strategy involving substrate-selective inhibition of COX-2 to augment eCB signaling without affecting related non-eCB lipids or prostaglandin synthesis. Behaviorally, substrate-selective inhibition of COX-2 reduced anxiety-like behaviors in mice via increased eCB signaling. Our data suggest a key role for COX-2 in the regulation of eCB signaling and indicate that substrate-selective pharmacology represents a viable approach for eCB augmentation with broad therapeutic potential.

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Figure 1: Molecular determinants of substrate-selective pharmacology.
Figure 2: LM-4131 is an in vivo bioactive SSCI.
Figure 3: LM-4131 selectively increases brain eCBs without affecting related lipids.
Figure 4: LM-4131 selectively increases AEA in peripheral tissues.
Figure 5: LM-4131 reduces anxiety-like behaviors in the novel open field.
Figure 6: LM-4131 reduces anxiety behaviors in the light-dark box.
Figure 7: LM-4131 does not exert overt cannabimimetic effects in vivo.

Change history

  • 11 August 2013

    In the version of this article initially published online, red and blue were switched in the Figure 1h key. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank K. Masuda, M. Brown, R. Stevens and B. Cravatt (Scripps Research Institute) for FAAH knockout mice. This work was supported by US National Institutes of Health grants MH090412 and MH100096 (S.P.), CA89450, GM15431, NS064278 (L.J.M.), DA031572 (D.J.H.), HL96967, HL109199 (J.R.), NS078291 (R.J.C.) and T32-MH065215 (B.C.S.), and the A.B. Hancock Jr. Memorial Laboratory for Cancer Research. Analytical studies were conducted in the Vanderbilt University Mass Spectrometry Core facility and all behavioral experiments were conducted in the Vanderbilt University Medical Center Mouse Neurobehavioral Core facility. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.

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LM-4131 was synthesized and characterized in vitro by D.J.H. in the laboratory of L.J.M. In vivo biochemical and behavioral experiments were designed, executed and analyzed by D.J.H., N.D.H. and S.P. in the laboratory of S.P. Analysis of LM-4131 hydrolysis was performed by D.J.H. and P.J.K. in the laboratory of L.J.M. Analysis of LM-4131 inhibition of MAGL and DAGL was performed by D.J.H. and B.C.S. in the laboratory of R.J.C. J.G.-G. completed cannabinoid tetrad behavioral studies in the laboratory of S.P. Ptgs2−/− mice were bred and genotyped by N.B. in the laboratory of J.R. The manuscript was written by D.J.H., L.J.M. and S.P. and edited by all authors.

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Correspondence to Lawrence J Marnett or Sachin Patel.

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D.J.H., L.J.M. and S.P. have submitted a patent application entitled “Compositions and Methods for Substrate-Selective Inhibition of Endocannabinoid Oxygenation”, which includes the compound LM-4131.

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Hermanson, D., Hartley, N., Gamble-George, J. et al. Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation. Nat Neurosci 16, 1291–1298 (2013). https://doi.org/10.1038/nn.3480

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