Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation

doi:10.1016/j.tips.2014.04.006

Trends in Pharmacological Sciences

Volume 35, Issue 7, July 2014, Pages 358-367

https://doi.org/10.1016/j.tips.2014.04.006 Get rights and content

Highlights

•
Endocannabinoid augmentation may have broad therapeutic implications.
•
COX-2 is a third endocannabinoid metabolic mechanism.
•
Substrate-selective COX-2 inhibition increases central endocannabinoid signaling.
•
Substrate-selective COX-2 inhibition decreases anxiety.

Pharmacologic augmentation of endogenous cannabinoid (eCB) signaling is an emerging therapeutic approach for the treatment of a broad range of pathophysiological conditions. Thus far, pharmacological approaches have focused on inhibition of the canonical eCB inactivation pathways – fatty acid amide hydrolase (FAAH) for anandamide and monoacylglycerol lipase (MAGL) for 2-arachidonoylglycerol. We review here the experimental evidence that cyclooxygenase-2 (COX-2)-mediated eCB oxygenation represents a third mechanism for terminating eCB action at cannabinoid receptors. We describe the development, molecular mechanisms, and in vivo validation of ‘substrate-selective’ COX-2 inhibitors (SSCIs) that prevent eCB inactivation by COX-2 without affecting prostaglandin (PG) generation from arachidonic acid (AA). Lastly, we review recent data on the potential therapeutic applications of SSCIs with a focus on neuropsychiatric disorders.

Section snippets

The endocannabinoid system

Two decades of intense scientific inquiry have defined a prominent role for central eCB signaling in a variety of physiological and pathophysiological processes 1, 2. eCBs are AA-containing lipid signaling molecules that exert biological actions via activation of cannabinoid type 1 and 2 receptors (CB₁ and CB₂) in addition to other targets including vanilloid receptor 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR), and some ion channels [1]. The two best-studied eCBs, N

Molecular biology of COX-2

COX-2 is a homodimer encoded by Ptgs2, an immediate-early gene that produces a 4 kb mRNA in response to a wide range of stimuli [19]. Upon synthesis, COX-2 localizes to the nuclear envelope and lumen of the endoplasmic reticulum 20, 21. COX-2 contains two separate active sites: a cyclooxygenase active site, which catalyzes the oxygenation of polyunsaturated fatty acids to hydroperoxy endoperoxides, and a peroxidase active site, which reduces the hydroperoxide to an alcohol [22]. The

Oxygenation of endocannabinoids by COX-2

In addition to the oxygenation of AA, COX-2 also catalyzes the oxygenation of AEA and 2-AG to form prostaglandin ethanolamides (PG-EAs) [39] and prostaglandin glycerol esters (PG-Gs), respectively (Box 1) [40]. Although PGH₂ is converted to PGE₂, PGD₂, PGF_2α, PGI₂, and TxA₂ by downstream synthases, PGH₂-EA and PGH₂-G are not good substrates for thromboxane synthase; thus, they each only form four of the five downstream products [41]. The production of PG-EAs has been demonstrated in several

Substrate-selective inhibition of COX-2

SSCIs represent a novel pharmacological approach to COX-2 inhibition by inhibiting the oxygenation of 2-AG and AEA but not AA by COX-2 (Box 3) 43, 56, 57. The discovery of ‘substrate-selective’ inhibition prompted several studies assessing the generalizability of this phenomenon among NSAIDs. The initial report identified ibuprofen, mefenamic acid, and 2′-des-methyl indomethacin (but not indomethacin) as SSCIs [56]. A more comprehensive investigation found that all rapidly reversible inhibitors

In vivo effects of substrate-selective COX-2 inhibition

Although in vitro and cellular studies clearly validate the pharmacology of SSCIs, whether this selectivity is retained in vivo is a crucial question. Although (R)-flurbiprofen is an excellent probe in vitro, in mice (but to a lesser extent in rats, humans, and monkeys) it undergoes unidirectional isomerization to the non-SSCI (S)-flurbiprofen, rendering it suboptimal for in vivo studies [60]. Therefore, we focused our initial in vivo SSCI validation studies on the morpholino amide of

Therapeutic implications of SSCIs

Augmenting eCB signaling has shown preclinical efficacy in reducing behavioral signs of anxiety in laboratory animals 10, 65, 66, 67, 68, 69. Seminal studies by Piomelli and coworkers demonstrate that inhibiting FAAH reduces anxiety in multiple preclinical models via a CB₁ receptor-dependent mechanism [10]. Importantly, some studies suggest that COX-2 inhibition may have anxiolytic effects in preclinical models 70, 71, and some clinical studies have identified therapeutic effects of adjunctive

Predicting the adverse effect profile of SSCIs in the CNS and beyond

The mechanism of action of SSCIs predicts two potential sets of adverse effects. First, adverse effects such as gastrointestinal and cardiovascular or cerebrovascular toxicity are associated with most NSAIDs and are mediated by the inhibition of PG synthesis by COX-1, COX-2, or both enzymes 88, 89, 90, 91. Second, adverse cognitive, metabolic, and motor side effects are associated with direct CB₁ receptor activation. The selective inhibition of eCB-derived PGs, but not of AA-derived PGs,

Concluding remarks

Despite the recent elucidation of COX-2 as a key regulator of eCB signaling, several fundamental questions remain unanswered. For example, why is there significant redundancy in eCB metabolic pathways? It is now clear that both FAAH and COX-2 can metabolize AEA; blockade of either enzyme can elevate AEA levels, and the effects of FAAH and COX-2 inhibition are additive. In many cases this occurs in tissues and/or cells where both enzymes are coexpressed, as they are in neurons [103]. These data

Acknowledgments

These studies were supported by National Institutes of Health Grants K08MH090412, R01MH100096 (S.P.), P30GM15431, R01CA89450 (L.J.M.), and F31DA031572 (D.J.H).

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Trends in Pharmacological Sciences

ReviewSubstrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation

Highlights

Section snippets

The endocannabinoid system

Molecular biology of COX-2

Oxygenation of endocannabinoids by COX-2

Substrate-selective inhibition of COX-2

In vivo effects of substrate-selective COX-2 inhibition

Therapeutic implications of SSCIs

Predicting the adverse effect profile of SSCIs in the CNS and beyond

Concluding remarks

Acknowledgments

Immunobiology

Trends Pharmacol. Sci.

Life Sci.

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Biol. Chem.

J. Biol. Chem.

Brain Res.

Pharmacol. Ther.

J. Biol. Chem.

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Lipid Res.

J. Biol. Chem.

Anal. Biochem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell. Neurosci.

Biol. Psychiatry

Pharmacol. Res.

Neuropharmacology

Eur. J. Pharmacol.

Gen. Pharmacol.

Blood

Lancet

Alzheimers Dement.

Lancet Neurol.

Am. J. Gastroenterol.

Endocannabinoid-mediated control of synaptic transmission

Physiol. Rev.

The endocannabinoid system and the brain

Annu. Rev. Psychol.

Enzymatic pathways that regulate endocannabinoid signaling in the nervous system

Chem. Rev.

The molecular logic of endocannabinoid signalling

Nat. Rev. Neurosci.

Endocannabinoids: synthesis and degradation

Rev. Physiol. Biochem. Pharmacol.

FAAH and MAGL inhibitors: therapeutic opportunities from regulating endocannabinoid levels

Curr. Opin. Investig. Drugs

The endocannabinoid system: a drug discovery perspective

Curr. Opin. Investig. Drugs

Chemical probes of endocannabinoid metabolism

Pharmacol. Rev.

Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase

Proc. Natl. Acad. Sci. U.S.A.

Modulation of anxiety through blockade of anandamide hydrolysis

Nat. Med.

Peroxisome proliferator-activated receptor alpha mediates acute effects of palmitoylethanolamide on sensory neurons

J. Neurosci.

Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha

Nature

Brain monoglyceride lipase participating in endocannabinoid inactivation

Proc. Natl. Acad. Sci. U.S.A.

Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain

Nat. Rev. Drug Discov.

New insights into endocannabinoid degradation and its therapeutic potential

Mini Rev. Med. Chem.

Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2

Eur. J. Biochem.

The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1

Nature

Higher oxidation states of prostaglandin H synthase. Rapid electronic spectroscopy detected two spectral intermediates during the peroxidase reaction with prostaglandin G2

Review
Substrate-selective COX-2 inhibition as a novel strategy for therapeutic endocannabinoid augmentation