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Life Sci Author manuscript available in PMC 2011 Apr 10Published in final edited form as

Life Sci 2010 Apr 10 86(15-16) 615ndash623Published online 2009 Jun 13 doi 101016jlfs200906003

PMCID PMC2848893NIHMSID NIHMS124364

Enhancement of endocannabinoid signaling by fatty acid amidehydrolase inhibition A neuroprotective therapeutic modalityJeannie Hwang Crista Adamson David Butler David R Janero Alexandros Makriyannisand Ben A Bahr

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The publishers final edited version of this article is available at Life SciSee other articles in PMC that cite the published article

Abstract

Aim

This review posits that fatty acid amide hydrolase (FAAH) inhibition has therapeuticpotential against neuropathological states including traumatic brain injury AlzheimersHuntingtons and Parkinsons diseases and stroke

Main Methods

This proposition is supported by data from numerous in vitro and in vivo experimentsestablishing metabolic and pharmacological contexts for the neuroprotective role of theendogenous cannabinoid (ldquoendocannbinoidrdquo) system and selective FAAH inhibitors

Key Findings

The systems biology of endocannabinoid signaling involves two main cannabinoid receptorsthe principal endocannabinoid lipid mediators N-arachidonoylethanolamine (ldquoanandamiderdquo)(AEA) and 2-arachidonoyl glycerol (2-AG) related metabolites and the proteins involvedin endocannabinoid biosynthesis biotransformation and transit The endocannabinoidsystem is capable of activating distinct signaling pathways on-demand in response topathogenic events or stimuli thereby enhancing cell survival and promoting tissue repairAccumulating data suggest that endocannabinoid system modulation at discrete targets is apromising pharmacotherapeutic strategy for treating various medical conditions In particularneuronal injury activates cannabinoid signaling in the central nervous system as an intrinsicneuroprotective response Indirect potentiation of this salutary response throughpharmacological inhibition of FAAH an endocannabinoid-deactivating enzyme andconsequent activation of signaling pathways downstream from cannabinoid receptors havebeen shown to promote neuronal maintenance and function

Significance

This therapeutic modality has the potential to offer site- and event-specific therapeutic reliefin those tissues where endocannabinoids are being produced as part of a physiologicalprotective mechanism In contrast direct application of cannabinoid receptor agonists to thecentral nervous system may activate CB receptors indiscriminately and invite unwantedpsychotrophic effects

Keywords Alzheimers disease anandamide brain trauma cannabinoid CB1 receptorendocannabinoid FAAH Huntingtons disease neurodegeneration neuroinflammationParkinsons disease stroke

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Introduction

Demonstration that cannabinoid (CB) constituents of the Cannabis plant including Δ -tetrahydrocannabinol (THC) exert their effects by engaging and activating discrete cellularCB receptors prompted the search in animals for naturally produced CB-receptor agonistligands This quest led to the discovery of a ubiquitous mammalian signaling system in whichendogenous cannabinoids (endocannabinoids) synthesized by the body act as signaling lipidsplay varied homeostatic and regulatory roles (Mackie 2006 Pacher et al 2006 Pertwee2008) Experimental and clinical data have unequivocally demonstrated that one of the mostimportant functions of the endocannabinoid signaling system is tissue protection againstpathological insult or injury-- a function that has opened several attractive therapeuticmodalities for pharmacological endocannabinoid-system modulation (Chang et al 2006Mackie 2008 Pacher and Haskoacute 2008 Vemuri et al 2008 Janero and Makriyannis2009ab) In particular great advances have been made toward targetedpharmacotherapeutic manipulation of endocannabinoid signaling for neuroprotection Onewell-studied endocannabinoid in particular N-arachidonoylethanolamine (or ldquoanandamiderdquo)(AEA) has been linked to the neuroprotective property of CB-receptor transmission (Table 1) (see reviews Bahr et al 2006 Pavlopoulos et al 2006 Janero and Makriyannis2007 Micale et al 2007) Distributed throughout the brain as an integral membrane proteinthe enzyme fatty acid amide hydrolase (FAAH) is primarily responsible for inactivating AEAand quenching AEA-induced biological responses (Basavarajappa 2007 Vandevoorde andLambert 2007 Di Marzo 2008 Ahn et al 2008 Fezza et al 2008) Whereas THC andother direct CB-receptor agonists can negatively influence psychomotor cognitive andappetitive behaviors (Freund 2003 Iversen 2003 Di Marzo and Matias 2005) selectiveFAAH inhibitors appear to offer site- and event-specific therapeutic relief in those tissueswhere endocannabinoids are being produced as part of a physiological protectivemechanism (Vemuri et al 2008 Janero and Makriyannis 2009a) By virtue of thispharmacological mode of action FAAH inhibitors are advantageously poised to exploit theneuroprotective nature of endocannabinoid signaling without risk of eliciting adversepsychotropic (or other) effects associated with chronic application of cannabinoid receptoragonists

Table 1Pathogenic events that increase anandamide levels

The foregoing implies that endocannabinoid signaling may be enhanced indirectly totherapeutic levels through FAAH inhibition making FAAH an attractivepharmacotherapeutic target and selective FAAH inhibitors attractive drug candidates forvarious neurological and neurodegenerativeneuroinflammatory disorders (Table 2) Thisproposition will be examined herein from the perspectives of endocannabinoid metabolismand endocannabinoid-system neuropharmacology

Table 2Medicinal applications for controlled FAAH inhibitors

I Endocannabinoid Metabolic Pathways

A growing number of endocannabinoid amide and ester long-chain fatty-acid derivatives areeither known agonists or candidate ligands for one or both principal CB receptor subtypesCB1 and CB2 (Mackie 2008 Pei et al 2008 Pertwee 2008 Wood et al 2008) It shouldalso be noted that there have been other studies identifying potential cannabinoid receptorsincluding a species named GPR55 (Begg et al 2005 Pertwee 2007 Lauckner et al 2008)The two signaling lipids first identified as endocannabinoids AEA and 2-AG remainnonetheless the most intensively studied and best characterized CB-receptor agonists(Bisogno 2008) AEA is a partial CB1-receptor activator with modest affinity [K = 61 nM(rat) and 240 nM (human)] and a relatively weak CB2-receptor ligand (K = 440-1930 nMfor rodent and human CB2 receptors) with low overall efficacy 2-AG is a full agonist at theCB1 and CB2 receptors albeit with lower affinity (K = 472 and 1400 nM respectively)and greater efficacy relative to AEA (Vemuri et al 2008 Janero and Makriyannis 2009a)Their distinctive biochemical and pharmacological properties notwithstanding homeostaticregulation of AEA and 2-AG signaling depends critically upon controlled endocannabinoidgeneration and biotransformationinactivation The balanced actions of endocannabinoid

9

ii

i

See more

Review Cannabinoid receptors astherapeutic targets[Annu Rev Pharmacol Toxicol 2006]Review The endocannabinoid system asan emerging target of pharmacotherapy[Pharmacol Rev 2006]Review Ligands that target cannabinoidreceptors in the brain from THC toanandamide and beyond

[Addict Biol 2008]Review Cannabinoid receptors wherethey are and what they do[J Neuroendocrinol 2008]Review Endocannabinoids andcannabinoid receptors in ischaemia-reperfusion injury and preconditioning

[Br J Pharmacol 2008]Review Pharmacotherapeutic targeting ofthe endocannabinoid signaling systemdrugs for obesity and the metabolic

[Physiol Behav 2008]Review Pharmacotherapeutic modulationof the endocannabinoid signalling systemin psychiatric disorders drug-discovery

[Int Rev Psychiatry 2009]Review Cannabinoid receptorantagonists pharmacologicalopportunities clinical experience and

[Expert Opin Emerg Drugs 2009]Review Targeting the endocannabinoidsystem in treating brain disorders[Expert Opin Investig Drugs 2006]Review Cannabinoid receptors astherapeutic targets[Curr Pharm Des 2006]Review Targeted modulators of theendogenous cannabinoid system futuremedications to treat addiction disorders

[Curr Psychiatry Rep 2007]Review Endocannabinoids andneurodegenerative diseases[Pharmacol Res 2007]Review Critical enzymes involved inendocannabinoid metabolism[Protein Pept Lett 2007]The multiple pathways ofendocannabinoid metabolism a zoomout

[Chem Biodivers 2007]Review Endocannabinoids synthesisand degradation[Rev Physiol Biochem Pharmacol 2008]Review Enzymatic pathways thatregulate endocannabinoid signaling in thenervous system

[Chem Rev 2008]Review Fatty acid amide hydrolase agate-keeper of the endocannabinoidsystem

[Subcell Biochem 2008]Review Interneuron Diversity seriesRhythm and mood in perisomaticinhibition

[Trends Neurosci 2003]Review Cannabis and the brain

[Brain 2003]


synthesizing and metabolizing enzymes help localize and direct the intrinsically broadinfluence these lipid mediators may exert (Alexander and Kendall 2007) It is not surprisingtherefore that spatiotemporal changes in the expressionactivity of endocannabinoidbiosynthetic and inactivating enzymes are associated with both normal physiologicalprocesses as well as pathological states in humans (Wang et al 2007 Ludaacutenyi et al 2008)As distinct from most water-soluble neurotransmitters that are mobilized from membrane-delimited storage vesicles in bioactive form AEA and 2-AG are synthesized on-demand inresponse to (patho)physiological stimuli (Figure 1) and their signaling functions are efficientlyterminated by cellular uptake through a presently ill-defined transporter system and therapid enzyme-catalyzed hydrolytic inactivation (Figure 2) (Di Marzo 2008 Ahn et al2008) Reflecting the importance of AEA and 2-AG to intercellular communication withinthe central nervous system (CNS) investigations into the metabolism of theseendocannabinoids have made extensive use of brain tissue and neuronal cells (Ahn et al2008 Lovinger 2008) For this reason a synopsis of key metabolic pathways implicated inthe regulation of endocannabinoid biosignaling primarily in the CNS is presented hereRecent reviews may be consulted for additional primary literature as well as details on themolecular and structural properties of various endocannabinoid-metabolizing enzymes theirphysiological chemistry and their potential as therapeutic targets (Bahr et al 2006Basavarajappa 2007 Vandevoorde and Lambert 2007 Saario and Laitinen 2007Schneider et al 2007 Ahn et al 2008 Fezza et al 2008 Vemuri et al 2008 Janero andMakriyannis 2009ab Kano et al 2009)

Figure 1Diagrammatic representation of the major metabolicpathways implicated in the biosynthesis of the principalendocannabinoids anandamide and 2-arachidonoylglycerol

Figure 2Diagrammatic representation of the major hydrolyticinactivation and oxidative biotransformation pathwaysimplicated in anandamide and 2-arachidonoyl glycerolcatabolism

A Endocannabinoid Biosynthesis

Enzymatic synthesis of both AEA and 2-AG draws upon pools of membrane phospholipidssuch as phosphatidylethanolamine (PE) phosphatidylcholine (PC) and phosphatidylinositol45-bisphosphate (PtdIns(45)P ) (Figure 1) (Ahn et al 2008 Lovinger 2008) (Figure 1)The pathways by which N-acyl ethanolamines (NAEs) such as AEA are synthesized hadbeen studied well before AEA was identified as an endocannabinoid Early data suggested atwo-step pathway involving the sequential action of a calcium-dependent transacylase (Ca-TA) that transfers a fatty-acyl chain from a membrane phospholipid molecule onto theprimary amine of membrane PE to generate N-acyl phosphatidylethanolamine (NAPE) anda NAPE-selective phospholipase D (NAPE-PLD) that hydrolyzes NAPE to NAEs such asAEA (Natarajan et al 1983 1984 Cadas et al 1997) Two NAPE-PLD-independentpathways have also been implicated in NAEAEA formation One involves the hydrolysis ofNAPE (and perhaps lyso-NAPE) to a glycerophospho(GP)-NAE intermediate byphospholipase A1A2 (PLA12) or-- perhaps more importantly in the CNS-- by the serinehydrolase αβ-hydrolase-4 (ABHD4) GP-NAE ester cleavage byglycerophosphodiesterase-1 (GDE1) then generates NAEAEA (Simon and Cravatt 20062008) Another candidate NAPE-PLD-independent pathway for AEA biosynthesis involvesthe conversion of NAPE to phospho-AEA (pAEA) by phospholipase C (PLC) followed bythe phosphatase-mediated hydrolysis of pAEA (Liu et al 2006 2008) Formation ofpolyunsaturated NAEs such as AEA appears to rely more upon NAPE-PLD-independentroutes whereas synthesis of long-chain saturated or monounsaturated NAEs proceedsmainly through NAPE-PLD (Ahn et al 2008) All of these candidate pathways forNAEAEA formation however likely have NAPEs as key lipid precursors

As is the case for AEA multiple incompletely characterized pathways for 2-AGbiosynthesis by neurons have been proposed each of which involves sequential enzyme-catalyzed transformations (Figure 1) The first and best-studied pathway is implicated in 2-AG formation elicited by intracellular calcium elevation or by G -coupled receptor

2

αq11

Review Cannabinoid receptors wherethey are and what they do[J Neuroendocrinol 2008]Ligand-binding architecture of human CB2cannabinoid receptor evidence forreceptor subtype-specific binding motif

[Chem Biol 2008]Review Ligands that target cannabinoidreceptors in the brain from THC toanandamide and beyond

[Addict Biol 2008]Comprehensive profiling of the humancirculating endocannabinoid metabolomeclinical sampling and sample storage

[Clin Chem Lab Med 2008]Review Evidence for novel cannabinoidreceptors [Pharmacol Ther 2005]Review GPR55 a new member of thecannabinoid receptor clan[Br J Pharmacol 2007]GPR55 is a cannabinoid receptor thatincreases intracellular calcium andinhibits M current

[Proc Natl Acad Sci U S A 2008]Review Endogenous cannabinoidsstructure and metabolism[J Neuroendocrinol 2008]Review Pharmacotherapeutic targeting ofthe endocannabinoid signaling systemdrugs for obesity and the metabolic


[Int Rev Psychiatry 2009]Review The complications ofpromiscuity endocannabinoid action andmetabolism

[Br J Pharmacol 2007]Differential regulation of endocannabinoidsynthesis and degradation in the uterusduring embryo implantation[Prostaglandins Other Lipid Mediat 2007]Downregulation of the CB1 cannabinoidreceptor and related molecular elementsof the endocannabinoid system in

[J Neurosci 2008]Review Endocannabinoids synthesisand degradation[Rev Physiol Biochem Pharmacol 2008]Review Enzymatic pathways thatregulate endocannabinoid signaling in thenervous system

[Chem Rev 2008]Review Presynaptic modulation byendocannabinoids[Handb Exp Pharmacol 2008]Review Targeting the endocannabinoidsystem in treating brain disorders[Expert Opin Investig Drugs 2006]Review Critical enzymes involved inendocannabinoid metabolism[Protein Pept Lett 2007]The multiple pathways ofendocannabinoid metabolism a zoomout

[Chem Biodivers 2007]Review Monoglyceride lipase as anenzyme hydrolyzing 2-arachidonoylglycerol

[Chem Biodivers 2007]Review Control of oxygenation inlipoxygenase and cyclooxygenasecatalysis

[Chem Biol 2007]Review Fatty acid amide hydrolase agate-keeper of the endocannabinoidsystem

[Subcell Biochem 2008]Review Cannabinoid receptorantagonists pharmacologicalopportunities clinical experience and

[Expert Opin Emerg Drugs 2009]Review Endocannabinoid-mediatedcontrol of synaptic transmission[Physiol Rev 2009]


activation Both of these signals stimulate membrane-bound phospholipase C β (PLC-β) tohydrolyze the minor membrane phospholipid PtdIns(45)P generating inositol 145-triphosphate (InsP ) and diacylglycerol (DAG) Two developmentally-regulated serinehydrolases the sn-1-selective DAG lipases (DAGLs) DAGL-α and -β then catalyze thefinal step of 2-AG formation from DAG (Figure 1) (Jung et al 2005 2007 Vandevoordeand Lambert 2007 Ahn et al 2008) Although both DAGL-α and -β are highly enriched inbrain the latter is expressed primarily in early development whereas DAGL-α expression issustained throughout adulthood and shifts from a predominantly pre- to post-synaptic locusduring neuronal maturation (Bisogno et al 2003) Another presumptive pathway for 2-AGformation involves the synergistic actions of calcium elevation and receptor activation leadingto DAG hydrolysis by DAGL-αβ as its final step (Hashimotodani et al 2007 2008)

Most enzymes implicated in AEA or 2-AG biosynthesis presently lack sufficiently selectivegenetic or pharmacological tools (eg potent small-molecule inhibitors) for experimentalprovocation to quantify the relative contribution of each endocannabinoid biosyntheticpathway discussed Among the recognized endocannabinoid biosynthesizing enzymesDAGL is the focus of much current research The strategic positioning of DAGL in multiple2-AG biosynthetic pathways suggests that selective DAGL inhibition might offer an attractivetherapeutic modality for medical conditions to which heightened 2-AG signaling through thecannabinoid 1 (CB1) receptor may contribute such as obesity metabolic syndrome andsubstance abuse disorders (Vemuri et al 2008 Ortar et al 2008 Hoover et al 2008Janero and Makriyannis 2009ab)

B Endocannabinoid Inactivation and Biotransformation

In marked contrast to the multiplicity and partial redundancy of putative pathways for AEAand 2-AG biosynthesis each of these two principal endocannabinoids is inactivated in thenervous system primarily by a specific relatively well-characterized hydrolase that generatesthe biologically important polyunsaturated fatty acid arachidonic acid (AA) (Figure 2) Fattyacid amide hydrolase (FAAH) is the principal enzyme responsible for terminating AEAsignaling and is widely expressed throughout the CNS as an integral membrane protein(Basavarajappa 2007 Vandevoorde and Lambert 2007 Di Marzo 2008 Ahn et al 2008Fezza et al 2008) Another amidase-signature serine hydrolase with FAAH activity shareslimited sequence identity with the original so-called FAAH-1 enzyme and has beendesignated as FAAH-2 (Wei et al 2006) FAAH-1 and -2 display several distinctbiochemical phylogenic and tissue-distribution characteristics In the CNS FAAH-1 is themore abundant FAAH and it hydrolyzes NAEs (including AEA) at greater rates thanFAAH-2 which is enriched in select peripheral tissues but is absent in lower mammalsincluding rodents (Wei et al 2006) FAAH-1 and -2 also display quantitatively distinctinhibitor sensitivities (Wei et al 2006) An NAE-hydrolyzing acid amidase (NAAA)identified in immune system cells and select peripheral tissues has been cloned (Tsuboi et al2007ab) NAAA is not a serine hydrolase and is also quite different from FAAH in itsintracellular (lysosomal) localization acidic pH optimum and lack of preference for AEA assubstrate The contribution of NAAA to AEA inactivation in vivo is unknown

Genetic polymorphisms in FAAH that disturb endocannabinoid biosignaling are associatedwith increased risk for substance abuse (Flanagan et al 2006) gastrointestinal dysfunction(Storr et al 2008a) and overweightobesity issues (Aberle et al 2008) in certain humansubpopulations Because of the important roles of AEA in neuronal plasticity memory andprotection against neurological insult selective FAAH inhibitors are a prime translationalfocus as potential drugs for important medical problems including pain managementpsychobehavioral states (anxiety depression) inflammation excitotoxic events (ie strokeseizures) and age-related neurodegenerative disorders including Huntingtons Parkinsonsand Alzheimers diseases (Bahr et al 2006 Karanian et al 2005b 2007 Centonze et al2007 Scherma et al 2008 Storr et al 2008b Naidu et al 2009) (vide infra) TargetedFAAH inhibition (ie blocking AEA inactivation) is considered an attractive therapeuticapproach to enhance indirectly cannabinergic signaling for it would take place preferentiallyin regions where endocannabinoid synthesis and release are ongoing as a salutary tissue-protective response The site- and event-specific character of the pharmacological inhibitionof endocannabinoid deactivating enzymes such as FAAH may offer increased selectivity withless risk of the undesirable side effects that have been observed with CB-receptor agonistscapable of activating all accessible receptors indiscriminately (Vemuri et al 2008 Janeroand Makriyannis 2009)

23

Review Enzymatic pathways thatregulate endocannabinoid signaling in thenervous system

[Chem Rev 2008]Review Presynaptic modulation byendocannabinoids[Handb Exp Pharmacol 2008]Biosynthesis of N-acylethanolaminephospholipids by dog brain preparations[J Neurochem 1983]Biosynthesis of N-acylethanolaminephospholipids by dog brain preparations[J Neurochem 1983]Occurrence and biosynthesis ofendogenous cannabinoid precursor N-arachidonoyl phosphatidylethanolamine

[J Neurosci 1997]Endocannabinoid biosynthesisproceeding through glycerophospho-N-acyl ethanolamine and a role for

[J Biol Chem 2006]Anandamide biosynthesis catalyzed bythe phosphodiesterase GDE1 anddetection of glycerophospho-N-acyl

[J Biol Chem 2008]A biosynthetic pathway for anandamide

[Proc Natl Acad Sci U S A 2006]Multiple pathways involved in thebiosynthesis of anandamide[Neuropharmacology 2008]

Stimulation of endocannabinoid formationin brain slice cultures through activationof group I metabotropic glutamate

[Mol Pharmacol 2005]A key role for diacylglycerol lipase-alphain metabotropic glutamate receptor-dependent endocannabinoid mobilization

[Mol Pharmacol 2007]The multiple pathways ofendocannabinoid metabolism a zoomout

[Chem Biodivers 2007]Review Enzymatic pathways thatregulate endocannabinoid signaling in thenervous system

[Chem Rev 2008]Cloning of the first sn1-DAG lipasespoints to the spatial and temporalregulation of endocannabinoid signaling in

[J Cell Biol 2003]Roles of phospholipase Cbeta and NMDAreceptor in activity-dependentendocannabinoid release

[J Physiol 2007]Pharmacological evidence for theinvolvement of diacylglycerol lipase indepolarization-induced endocanabinoid

[Neuropharmacology 2008]

Review Pharmacotherapeutic targeting ofthe endocannabinoid signaling systemdrugs for obesity and the metabolic

[Physiol Behav 2008]Tetrahydrolipstatin analogues asmodulators of endocannabinoid 2-arachidonoylglycerol metabolism

[J Med Chem 2008]Selectivity of inhibitors ofendocannabinoid biosynthesis evaluated[Bioorg Med Chem Lett 2008]


Go to

Although FAAH hydrolyzes both AEA and 2-AG at similar rates in vitro (Goparaju et al1998) multiple lines of genetic biochemical and pharmacological evidence suggest thatenzyme(s) other than FAAH regulate 2-AG inactivation in vivo In particular a solubleserine hydrolase monoacylglycerol lipase (MGL) is considered the principal enzymeresponsible for terminating 2-AG signaling in the CNS by catalyzing 2-AGs conversion toAA (Figure 2) (Vandevoorde and Lambert 2007 Saario and Laitinen 2007 Ahn et al2008 Zvonok et al 2008a and 2008b) Four other hydrolases are capable of generatingAA from 2-AG αβ-hydrolase-6 (ABHD6) αβ-hydrolase-12 (ABHD4) neuropathy-target esterase (NTE) and hormone-sensitive lipase (H-S lipase) (Figure 2) (Belfrage et al1977 van Tienhoven et al 2002 Blankman et al 2007) Some 85 of total brain 2-AGhydrolysis has been assigned to MGL the remaining sim 15 catalyzed mostly by ABHD6and ABHD12 (Blankman et al 2007) The distinct subcellular distributions of MGLABHD6 and ABHD12 suggest that they may modulate specific CNS 2-AG pools (Ahn etal 2008)

Enzymatic conversion of AEA and 2-AG to AA constitutes the hydrolytic deactivation modeof endocannabinoid metabolism AEA and 2-AG can also serve as indirect and directsources of substrates for oxidative transformation to various lipid derivatives (Figure 2) TheAA product of both FAAH and MGL catalysis is a second-messenger molecule whosepositional oxygenation epoxidation or hydroxylation by cyclooxygenase (COX)lipoxygenase (LOX) epoxygenase or hydroxylase enzymes can generate an array of fattyacid derivatives including prostaglandin prostacyclin thromboxane and leukotrieneeicosanoids and hydroxyeicosatetraenoic and epoxyeicosatrienoic acids (Khanapure et al2007) Many of these AA derivatives have important physiological functions egprostaglandin E (PGE ) is a potent modulator of vascular tone and mediates diverseimmune and inflammatory responses (Khanapure et al 2007) Both AEA and 2-AG can beoxygenated directly by COX to generate prostaglandin ethanolamides (ldquoprostamidesrdquo) [egprostaglandin E ethanolamine (PGE -EA)] and glyceryl prostaglandins [eg prostaglandinE glycerol ester (PGE -G)] respectively (Figure 2) COX-1 is much less effective thanCOX-2 in catalyzing oxidative endocannabinoid metabolism (Woodward et al 2008)Likewise AEA and 2-AG can serve as LOX and cytochrome P450 substrates leading toan array of oxygenated compounds including hydroxyeicosatetraenoic acid ethanolamides[eg 12-S-OH arachidonoyl ethanolamine (12-S-HEA)] hydroxyeicosatetraenoic acidglycerol esters [eg 12-S-OH arachidonoylglycerol (12-S-HG)] (Figure 2)epoxyeicosatetraenoic acid ethanolamides and epoxyeicosatetraenoic acid glycerol esters(Prusakiewicz et al 2007 Chen et al 2008) The production and physiological activity ofmost products of direct AEA and 2-AG oxidative metabolism in vivo largely remain to beestablished (Guindon and Hohmann 2008) In this regard it has recently been observed thatCOX-2 converts 2-AG into PGE -G which induces hyperalgesia in the rat (Shu-Jung et al2008) and that fat ingestion elicits NAPE biosynthesis to suppress food intake (Gillum et al2008) The finding that AEA and 2-AG induce COX-2 expression and stimulateprostaglandin production in human gestational tissue (Mitchell et al 2008) is suggestive ofphysiologically significant cross-talk between endocannabinoids and enzymes regulating theirmetabolism This suggestion is reinforced by the ability of AEA to inhibit 2-AG biosynthesisand activity in mouse-brain striatum by interfering with DAGL-α catalysis through activationof a nonselective cation channel transient receptor potential vanilloid 1 (TRPV1)(Maccarrone et al 2008)

II Neuroprotection Through Endocannabinoid Modulation

Responses to CB receptor activation include opening of potassium channels inhibition ofcalcium currents and stimulation of various protein kinases (Deadwyler et al 1995 GomezDel Pulgar et al 2000 Galve-Roperh et al 2002 Molina-Holgado et al 2005 Karanian etal 2005b 2007) Some of the many such signaling elements activated by endocannabinoidsplay important roles in neuronal maintenance (Bahr et al 2006 Galve-Roperh et al 2008)CB receptor transmission elicits modulatory effects on calcium channels resulting in reducedneurotransmitter (eg GABA glutamate) release (Hajos et al 2000 Kreitzer and Regehr2001 Ohno-Shosaku et al 2001 Wilson et al 2001) One particular mitogen-activatedprotein kinase extracellular signal-regulated kinase (ERK) is involved in cannabinergicsignaling as are focal adhesion kinase (FAK) and phosphatidylinositol 3prime-kinase (PI3K)These signaling elements appear to play key roles in the neuroprotective nature of theendocannabinoid system and the associated signaling pathways are disrupted by blockingCB receptor activation (Wallace et al 2003 Khaspekov et al 2004 Karanian et al

2 2

2 22 2

2

Review Pharmacotherapeutic modulationof the endocannabinoid signalling systemin psychiatric disorders drug-discovery


[Expert Opin Emerg Drugs 2009]

Review Critical enzymes involved inendocannabinoid metabolism[Protein Pept Lett 2007]The multiple pathways ofendocannabinoid metabolism a zoomout



[Subcell Biochem 2008]A second fatty acid amide hydrolase withvariable distribution among placentalmammals

[J Biol Chem 2006]Predominant expression of lysosomal N-acylethanolamine-hydrolyzing acidamidase in macrophages revealed by

[Biochim Biophys Acta 2007]Review The N-acylethanolamine-hydrolyzing acid amidase (NAAA)[Chem Biodivers 2007]

The fatty acid amide hydrolase 385 AA(P129T) variant haplotype analysis of anancient missense mutation and validation

[Hum Genet 2006]The role of fatty acid hydrolase genevariants in inflammatory bowel disease[Aliment Pharmacol Ther 2009]Genetic variation may influence obesityonly under conditions of diet analysis ofthree candidate genes

[Mol Genet Metab 2008]Review Targeting the endocannabinoidsystem in treating brain disorders[Expert Opin Investig Drugs 2006]Dual modulation of endocannabinoidtransport and fatty acid amide hydrolaseprotects against excitotoxicity

[J Neurosci 2005]Endocannabinoid enhancement protectsagainst kainic acid-induced seizures andassociated brain damage

[J Pharmacol Exp Ther 2007]Review The endocannabinoid system intargeting inflammatory neurodegenerativediseases

[Trends Pharmacol Sci 2007]The endogenous cannabinoidanandamide has effects on motivationand anxiety that are revealed by fatty acid

[Neuropharmacology 2008]Targeting endocannabinoid degradationprotects against experimental colitis inmice involvement of CB1 and CB2

[J Mol Med (Berl) 2008]Synergy between enzyme inhibitors offatty acid amide hydrolase andcyclooxygenase in visceral nociception

[J Pharmacol Exp Ther 2009]Review Pharmacotherapeutic targeting ofthe endocannabinoid signaling systemdrugs for obesity and the metabolic


[Int Rev Psychiatry 2009]

Anandamide amidohydrolase reactingwith 2-arachidonoylglycerol anothercannabinoid receptor ligand

[FEBS Lett 1998]The multiple pathways of

[Chem Biodivers 2007]

Cannabinoids modulate voltage sensitive potassiumA-current in hippocampal neurons via a cAMP-dependent process

[J Pharmacol Exp Ther 1995]The CB1 cannabinoid receptor is coupled to theactivation of protein kinase BAkt [Biochem J 2000]Mechanism of extracellular signal-regulated kinaseactivation by the CB(1) cannabinoid receptor[Mol Pharmacol 2002]Neuroprotective effects of the synthetic cannabinoidHU-210 in primary cortical neurons are mediated byphosphatidylinositol 3-kinaseAKT signaling

[Mol Cell Neurosci 2005]Dual modulation of endocannabinoid transport andfatty acid amide hydrolase protects againstexcitotoxicity

[J Neurosci 2005]Endocannabinoid enhancement protects againstkainic acid-induced seizures and associated braindamage

[J Pharmacol Exp Ther 2007]Review Targeting the endocannabinoid system intreating brain disorders[Expert Opin Investig Drugs 2006]Review Mechanisms of control of neuron survival by

[Curr Pharm Des 2008]


2005ab) Compromise of basal cross-talk among pathways involving ERK FAK andgrowth-factor receptors during endocannabinergic blockade elicits a corresponding increasein neuronal pathogenic susceptibility and a decrease in synaptic maintenance Several reportsfurther indicate that genetic ablation of CB receptors and their associated downstreamsignaling increases susceptibility to seizure induction traumatic and ischemic brain injury andneuronal inflammatory damage (Parmentier-Batteur et al 2002 Marsicano et al 2003Jackson et al 2005 Panikashvili et al 2005) Conversely promoting CB receptorresponses through the action of exogenous or endogenous ligands can generate enhancedlevels of signaling via ERK FAK and other pathways This makes FAAH and otherendocannabinoid deactivation mechanisms ideal targets for neuroprotective modulation ofthe cannabinergic system Selective FAAH inhibitors and FAAH knockout studies havedescribed the outcome of elevated endogenous signaling through CB1 receptors (Cravatt etal 2001 Kathuria et al 2003 Karanian et al 2005b 2007) Dual modulation ofendocannabinoid action was achieved by combining a FAAH inhibitor with another blockerof endocannabinoid deactivation (anandamide transport inhibitor) resulting in pronouncedincreases in FAK and ERK responses to levels similar to those triggered by CB1-receptoragonists The effects of exogenously applied AEA are also potentiated by FAAH inhibition(Gifford et al 1999 Arizzi et al 2004) Together these studies indicate that positivemodulation of endocannabinoid responses can harness endogenous signaling networks thatsupport neuroprotection

A Neuroprotective Effects of FAAH Inhibitors

In the CNS endocannabinoids are produced by neurons on demand (Figure 1) and theirefficient catalytic inactivation (Figure 2) helps ensure that they act locally near their site ofsynthesis Endocannabinoids are synthesized and released in response to neuronal injuryand the cannabinergic action of the released CB-receptor ligands can be enhanced byattenuating FAAH activity Since AEA is effectively inactivated by the endocannabinoid-hydrolyzing enzyme FAAH (vide supra) inhibiting FAAH would increase the availability ofreleased AEA to activate local CB receptors to elevate the initial neuroprotective responseto a therapeutic level The significance of FAAH inhibition as a means of enhancingcannabinergic signaling has been demonstrated through both knockout strategies as well aspharmacological FAAH blockade by synthetic inhibitors (Cravatt et al 2001 Karanian etal 2005a Moreira et al 2008) Not surprisingly potential therapeutic indications to whichthis strategy could be applied for therapeutic purposes are expanding and includemanagement of multiple sclerosis (Benito et al 2007) spinal cord injury (Garcia-Ovejero etal 2009) ischemic events (Nucci et al 2007) and other disorders particularly thoseinvolving the CNS (Table 2)

Endocannabinoid production and signaling through CB receptors elicit neuronal-cell survivalresponses that could play a salutary role against diverse neuropathologies Table 3 lists thegrowing number of neuroprotective effects associated with FAAH inhibition For examplethe FAAH inhibitor URB597 attenuated hippocampal neuronal hyperactivity (Coomber etal 2008) and systemic administration of URB597 minimized the retinal damage observed inischemic-reperfusion studies (Nucci et al 2007) Another FAAH inhibitor palmitylsulfonylfluoride (AM374) enhanced the effects of AEA (Gifford et al 1999 Arizzi et al 2004) andpromoted endogenous CB-related signaling in brain tissue (Karanian et al 2005b)Pharmacological modulation of endocannabinoid deactivation to promote signaling resultedin excitotoxic protection in both hippocampal slice and animal models The neuroprotectionwas demonstrated cellularly and functionally ie by a reduction in neuronal loss in thehippocampus enhanced synaptic integrity reduced behavioral abnormalities and improvedmemory performance (Karanian et al 2005b) These neuroprotective effects werecompletely abrogated by a selective CB1-receptor antagonist thus indicating that CB1-receptor transmission was responsible for the neuroprotection

Table 3Effects of FAAH inhibitors

Another example of neuroprotective FAAH modulation is provided by data from the kainaterat model As an excitotoxin kainic acid (KA) induces seizures and damage to thehippocampus a brain region involved in higher-order brain functions Uncontrolled seizuresproduce excitotoxic brain damage reminiscent of that in many disease states Recurring

endocannabinoid metabolism a zoom[Chem Biodivers 2007]

Review Monoglyceride lipase as anenzyme hydrolyzing 2-arachidonoylglycerol


[Chem Rev 2008]Full mass spectrometric characterizationof human monoacylglycerol lipasegenerated by large-scale expression and

[J Proteome Res 2008]Hormone-sensitive lipase of rat adiposetissue identification and some propertiesof the enzyme protein

[FEBS Lett 1977]Human neuropathy target esterasecatalyzes hydrolysis of membrane lipids[J Biol Chem 2002]A comprehensive profile of brain enzymesthat hydrolyze the endocannabinoid 2-arachidonoylglycerol

[Chem Biol 2007]

Review Eicosanoids in inflammationbiosynthesis pharmacology andtherapeutic frontiers

[Curr Top Med Chem 2007]Review Prostamides (prostaglandin-ethanolamides) and their pharmacology[Br J Pharmacol 2008]Oxidative metabolism of lipoamino acidsand vanilloids by lipoxygenases andcyclooxygenases

[Arch Biochem Biophys 2007]Identification of novel endogenouscytochrome p450 arachidonatemetabolites with high affinity for

[J Biol Chem 2008]A physiological role for endocannabinoid-derived products of cyclooxygenase-2-mediated oxidative metabolism

[Br J Pharmacol 2008]Prostaglandin E2 glycerol ester anendogenous COX-2 metabolite of 2-arachidonoylglycerol induces

[Br J Pharmacol 2008]N-acylphosphatidylethanolamine a gut-derived circulating factor induced by fatingestion inhibits food intake

[Cell 2008]Cannabinoids stimulate prostaglandinproduction by human gestational tissuesthrough a tissue- and CB1-receptor-

[Am J Physiol Endocrinol Metab 2008]Anandamide inhibits metabolism andphysiological actions of 2-arachidonoylglycerol in the striatum

[Nat Neurosci 2008]

See more

the endocannabinoid system[Curr Pharm Des 2008]Cannabinoids inhibit hippocampal GABAergictransmission and network oscillations[Eur J Neurosci 2000]Retrograde inhibition of presynaptic calcium influxby endogenous cannabinoids at excitatorysynapses onto Purkinje cells

[Neuron 2001]Endogenous cannabinoids mediate retrogradesignals from depolarized postsynaptic neurons topresynaptic terminals

[Neuron 2001]Presynaptic specificity of endocannabinoid signalingin the hippocampus [Neuron 2001]The endogenous cannabinoid system regulatesseizure frequency and duration in a model oftemporal lobe epilepsy

[J Pharmacol Exp Ther 2003]Involvement of brain-derived neurotrophic factor incannabinoid receptor-dependent protection againstexcitotoxicity

[Eur J Neurosci 2004]Blocking cannabinoid activation of FAK and ERK12compromises synaptic integrity in hippocampus[Eur J Pharmacol 2005]Increased severity of stroke in CB1 cannabinoidreceptor knock-out mice [J Neurosci 2002]CB1 cannabinoid receptors and on-demand defenseagainst excitotoxicity [Science 2003]

Supersensitivity to anandamide and enhancedendogenous cannabinoid signaling in mice lackingfatty acid amide hydrolase

[Proc Natl Acad Sci U S A 2001]Blocking cannabinoid activation of FAK and ERK12compromises synaptic integrity in hippocampus[Eur J Pharmacol 2005]Reduced anxiety-like behaviour induced by geneticand pharmacological inhibition of theendocannabinoid-degrading enzyme fatty acid

[Neuropharmacology 2008]Cannabinoid CB1 and CB2 receptors and fatty acidamide hydrolase are specific markers of plaque cellsubtypes in human multiple sclerosis

[J Neurosci 2007]The endocannabinoid system is modulated inresponse to spinal cord injury in rats[Neurobiol Dis 2009]Involvement of the endocannabinoid system inretinal damage after high intraocular pressure-induced ischemia in rats

[Invest Ophthalmol Vis Sci 2007]

Inhibition of endocannabinoid metabolism attenuatesenhanced hippocampal neuronal activity induced bykainic acid

[Synapse 2008]Involvement of the endocannabinoid system inretinal damage after high intraocular pressure-induced ischemia in rats

[Invest Ophthalmol Vis Sci 2007]Potentiation of the action of anandamide onhippocampal slices by the fatty acid amidehydrolase inhibitor palmitylsulphonyl fluoride (AM

[Eur J Pharmacol 1999]Behavioral effects of inhibition of cannabinoidmetabolism The amidase inhibitor AM374enhances the suppression of lever pressing

[Life Sci 2004]Dual modulation of endocannabinoid transport andfatty acid amide hydrolase protects againstexcitotoxicity

[J Neurosci 2005]

Potential value of changes in cell markers inorganotypic hippocampal cultures associated withchronic EtOH exposure and withdrawal comparison

[Alcohol Clin Exp Res 2006]Review Role of nitrergic system in behavioral andneurotoxic effects of amphetamine analogs[Pharmacol Ther 2006]Fischer and Lewis rat strains show differentialcocaine effects in conditioned place preference and[J Pharmacol Exp Ther 1994]


seizures can result from epilepsy brain injury and genetic conditions Among the medicalcomplications associated with substance abusedrug addiction excitotoxic brain injury canbe caused by alcohol (Wilkins et al 2006) diverse amphetamine derivatives (Itzhak andAli 2006) and cocaine (Kosten et al 1994 Mets et al 1998 Arai et al 2003Matsumoto et al 2004 Witkins et al 2008) The selective FAAH inhibitor AM374 wasshown to enhance AEA levels and decrease seizure severity in KA-treated rats (Karanian etal 2007) This study also documented a dose-dependent and accelerated rate of seizurerecovery with AM374 treatment which protected against excitotoxic cytoskeletal damageand synaptic decay The controlled modulation of cannabinergic signals also protectedagainst the cellular and functional deficits in the kainate rats These salutary responses wereprevented by the CB1-receptor antagonist AM251 indicating that the neuroprotectiveaction of FAAH inhibition was mediated through endocannabinoid transmission ThisFAAH-inhibitor study further implicated the activated MAPKERK pathway in thereduction of neuronal damage Another selective FAAH inhibitor URB597 has been foundto attenuate the damaging effects of KA-induced neuronal activity (Coomber et al 2008)Together these studies show dose-dependent congruence in vivo among 1) reducedseizure severity 2) enhanced synaptic integrity and 3) improved behavioral performanceThe endocannabinoid enhancement attenuated seizure severity perhaps by reducingintracellular calcium via cannabinergic actions on voltage-gated calcium channels throughinhibition of adenylyl cyclase (Deadwyler et al 1993 Shen and Thayer 1996 1998 Mu etal 1999) or by eliciting nonspecific and synapse-specific depression of excitatory circuits(Shen et al 1996 Kim and Thayer 2000 Gerdeman and Lovinger 2001 Singla et al2007) Clinical studies indicate that epileptic seizures in humans can result from perturbationof the endocannabinoid system including the down-regulation of CB receptors located inhippocampal glutamatergic terminals (Ludanyi et al 2008) In sum manipulation of theendocannabinoid system a key regulator of synaptic transmission in the brain throughFAAH inhibition is a potentially attractive approach for treating seizures of diverse etiology

The neuroprotective action of FAAH inhibitors is reminiscent of the compensatoryprotective response in which AEA levels are elevated 2- to 13-fold after KA-inducedseizures (Marsicano et al 2003) ischemia (Amantea et al 2007) concussive head trauma(Hansen et al 2001) and neurotoxin exposure (Hansen et al 2001 Maccarrone et al2003) In humans experiencing stroke-related excitotoxic insult AEA release during theinjury process has been observed as a compensatory protective response to potentiateintrinsic survival signaling (Schaumlbitz et al 2002) Cannabinergic modulation of networkexcitability may also have the potential to offset the neuronal over-activation produced bydrugs of abuse that can involve various transmitters including dopamine serotoninnorepinephrine GABA and glutamate Note that inhibitors of The strategy of developingFAAH inhibitors as neuroprotective drugs gains attractiveness from findings that FAAHinhibitors are devoid of cataleptic effects (Beltramo et al 2000 Arizzi et al 2004Karanian et al 2007) and do not carry an abuse potential themselves (Justinova et al2008) These properties suggest that FAAH inhibitors could represent novel safe drugs fortreating brain damage from epileptic seizures traumatic injury and drugs of abuse

Other medical indications where FAAH inhibition may be an effective pharmacotherapeuticstrategy include multiple sclerosis and neurodegenerativeneuroinflammatory diseases such asAlzheimers Huntingtons and Parkinsons diseases (Benito et al 2003 Maccarrone et al2003 Ramirez et al 2005 Micale et al 2007 Bisogno and Di Marzo 2008) Recent datapresented in abstract indicate that the content of AEA and a prime AEA precursor N-arachidonoyl phosphatidylethanolamine (Figure 1) were markedly reduced in the temporaland frontal cortices of Alzheimers patients whereas 2-AG and 2-AG-related related lipidswere largely unchanged (Jung et al 2008) Interestingly AEA levels in different brain regionsof the Alzheimers patients correlated with region-specific cognitive test scores implicatingthe importance of endocannabinoid signaling for cognition In another clinical Alzheimersstudy AEA was shown to prevent toxicity of the human amyloid-β peptide (Milton 2002)which is believed responsible for the neurodegenerative changes in the Alzheimers brain Inan animal model of multiple sclerosis AM374 significantly reduced a hallmark symptomspasticity a therapeutic response similar to that elicited by treatment with potentcannabinergic agonists (Baker et al 2001)

Further support for beneficial effects of FAAH inhibition in multiple sclerosis was recentlydemonstrated in a chronic encephalitis model with the observation that that FAAH knockoutmice exhibited a more substantial remission compared to wild-type mice (Webb et al

A catalytic antibody against cocaine preventscocaines reinforcing and toxic effects in rats[Proc Natl Acad Sci U S A 1998]Chronic inhibition of the norepinephrine transporterin the brain participates in seizure sensitization tococaine and local anesthetics

[Brain Res 2003]Novel analogs of the sigma receptor ligand BD1008attenuate cocaine-induced toxicity in mice[Eur J Pharmacol 2004]Endocannabinoid enhancement protects againstkainic acid-induced seizures and associated braindamage

[J Pharmacol Exp Ther 2007]Inhibition of endocannabinoid metabolism attenuatesenhanced hippocampal neuronal activity induced bykainic acid

[Synapse 2008]Cannabinoids modulate potassium current incultured hippocampal neurons[Receptors Channels 1993]Cannabinoid receptor agonists inhibit glutamatergicsynaptic transmission in rat hippocampal cultures[J Neurosci 1996]The cannabinoid agonist Win55212-2 inhibitscalcium channels by receptor-mediated and directpathways in cultured rat hippocampal neurons

[Brain Res 1998]Cannabinoid receptors differentially modulatepotassium A and D currents in hippocampalneurons in culture

[J Pharmacol Exp Ther 1999]Activation of CB1 cannabinoid receptors inhibitsneurotransmitter release from identified synapticsites in rat hippocampal cultures

[Brain Res 2000]CB1 cannabinoid receptor inhibits synaptic releaseof glutamate in rat dorsolateral striatum[J Neurophysiol 2001]Mechanisms for synapse specificity during striatallong-term depression [J Neurosci 2007]Downregulation of the CB1 cannabinoid receptor andrelated molecular elements of the endocannabinoidsystem in epileptic human hippocampus

[J Neurosci 2008]

See more

CB1 cannabinoid receptors and on-demand defenseagainst excitotoxicity [Science 2003]Modulation of the endocannabinoid system by focalbrain ischemia in the rat is involved inneuroprotection afforded by 17beta-estradiol

[FEBS J 2007]Anandamide but not 2-arachidonoylglycerolaccumulates during in vivo neurodegeneration[J Neurochem 2001]Levodopa treatment reverses endocannabinoidsystem abnormalities in experimental parkinsonism[J Neurochem 2003]Release of fatty acid amides in a patient withhemispheric stroke a microdialysis study[Stroke 2002]Reversal of dopamine D(2) receptor responses by ananandamide transport inhibitor [J Neurosci 2000]Behavioral effects of inhibition of cannabinoidmetabolism The amidase inhibitor AM374enhances the suppression of lever pressing

[Life Sci 2004]

Cannabinoid CB2 receptors and fatty acid amidehydrolase are selectively overexpressed in neuriticplaque-associated glia in Alzheimers disease

[J Neurosci 2003]Levodopa treatment reverses endocannabinoidsystem abnormalities in experimental parkinsonism[J Neurochem 2003]Prevention of Alzheimers disease pathology bycannabinoids neuroprotection mediated byblockade of microglial activation

[J Neurosci 2005]Review Endocannabinoids and neurodegenerativediseases [Pharmacol Res 2007]Review The role of the endocannabinoid system inAlzheimers disease facts and hypotheses[Curr Pharm Des 2008]Anandamide and noladin ether prevent neurotoxicityof the human amyloid-beta peptide[Neurosci Lett 2002]Endocannabinoids control spasticity in a multiplesclerosis model [FASEB J 2001]


Go to

Go to

Go to

2008) The reduced endocannabinoid signaling associated with Huntingtons disease couldbe reversed through the blockade of FAAH activity (see review Micale et al 2007) FAAHinhibition by methylarachidonoyl fluorophosphonate (MAFP) also restored normalglutamatergic activity in an animal model of Parkinsons disease (Maccarrone et al 2003)These experimental and clinical data suggest that FAAH inhibition will gain importance as apotential therapeutic modality for age-related neurodegenerative diseases

III Conclusion

The growing understanding of the biosynthetic and inactivation pathways that help regulateendocannabinoid signaling and the successful biochemical description and functionalannotation of several molecular constituents of the endocannabinoid metabolome havesuggested new treatment approaches for several important disease states ill-satisfied bycurrently available drugs Therapeutic exploitation of ldquoon-demandrdquo tissue-protectiveendocannabinoid responses is particularly attractive with respect to many neuropathologicalconditions Blocking the inactivation of the endogenous tissue-protective CB-receptorligands promotes beneficial neuromodulatory and neuroprotective events (eg reducedtransmitter release) as well as various downstream signaling pathways Enhancing AEAlevels by inhibiting a critical deactivation step-- ie the hydrolytic enzyme FAAH-- is aparticularly noteworthy example of exploiting the protective nature of the endocannabinoidsystem Selective inhibitors of FAAH boost the endogenous tissue-protective responses in asite- and event-specific manner thereby avoiding the risk of unwanted psychotropic effectsthat may result from the prolonged systemic application of CB-receptor agonists FAAHinhibition is especially effective at attenuating excitotoxic progression in the brain andprotecting against synaptic compromise neuronal death and the behavioral symptoms ofexcitotoxic brain damage Future advances in identifying critical targets of endocannabinoidmetabolism and metabolic intermediates whose pharmacological modulation can enhanceendocannabinoid signaling to therapeutic levels will undoubtedly open new drug-discoveryavenues Accumulated data already encourage continued preclinical profiling of newer-generation FAAH inhibitors with the aim of promoting lead development candidates into theclinic for first-in-man proof-of-principal studies (Janero and Makriyannis 2009a)

FootnotesPublishers Disclaimer This is a PDF file of an unedited manuscript that has been acceptedfor publication As a service to our customers we are providing this early version of themanuscript The manuscript will undergo copyediting typesetting and review of the resultingproof before it is published in its final citable form Please note that during the productionprocess errors may be discovered which could affect the content and all legal disclaimers thatapply to the journal pertain

References

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3 Alexander SPH Kendall DA The complications of promiscuity Endocannabinoidaction and metabolism British Journal of Pharmacology 2007152602ndash623[PMC free article] [PubMed]

4 Amantea D Spagnuolo P Bari M Fezza F Mazzei C Tassorelli C Morrone LACorasaniti MT Maccarrone M Bagetta G Modulation of the endocannabinoidsystem by focal brain ischemia in the rat is involved in neuroprotection afforded by17beta-estradiol The FEBS Journal 20072744464ndash4775 [PubMed]

5 Arai S Morita K Kitayama S Kumagai K Kumagai M Kihira K Dohi TChronic inhibition of the norepinephrine transporter in the brain participates inseizure sensitization to cocaine and local anesthetics Brain Research 2003183ndash90 [PubMed]

6 Arizzi MN Cervone KM Aberman JE Betz A Liu Q Lin S Makriyannis ASalamone JD Behavioral effects of inhibition of cannabinoid metabolism Theamidase inhibitor AM374 enhances the suppression of lever pressing produced byexogenously administered anandamide Life Sciences 2004741001ndash1011


[PubMed]7 Bahr BA Karanian DA Makanji SS Makriyannis A Targeting the

endocannabinoid system in treating brain disorders Expert Opinion onInvestigational Drugs 200615351ndash365 [PubMed]

8 Baker D Pryce G Croxford JL Brown P Pertwee RG Makriyannis AKhanolkar A Layward L Fezza F Bisogno T Di Marzo V Endocannabinoidscontrol spasticity in a multiple sclerosis model FASEB Journal 200115300ndash302[PubMed]

9 Basavarajappa BS Critical enzymes involved in endocannabinoid metabolismProtein and Peptide Letters 200714237ndash246 [PMC free article] [PubMed]

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12 Beltramo M Stella N Calignano A Lin SY Makriyannis A Piomelli DFunctional role of high-affinity anandamide transport as revealed by selectiveinhibition Science 19972771094ndash1097 [PubMed]

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14 Benito C Nuacutentildeez E Toloacuten RM Carrier EJ Raacutebano A Hillard CJ Romero JCannabinoid CB2 receptors and fatty acid amide hydrolase are selectivelyoverexpressed in neuritic plaque-associated glia in Alzheimers disease brainsJournal of Neuroscience 20032311136ndash11141 [PubMed]

15 Benito C Kim WK Chavarriacutea I Hillard CJ Mackie K Toloacuten RM Williams KRomero J A glial endogenous cannabinoid system is upregulated in the brains ofmacaques with simian immunodeficiency virus-induced encephalitis Journal ofNeuroscience 2005252530ndash2536 [PubMed]

16 Benito C Romero JP Toloacuten RM Clemente D Docagne F Hillard CJ Guaza CRomero J Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolaseare specific markers of plaque cell subtypes in human multiple sclerosis Journal ofNeuroscience 2007272396ndash2402 [PubMed]

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21 Blankman JL Simon GM Cravatt BF A comprehensive profile of brain enzymesthat hydrolyze the endocannabinoid 2-arachidonoylglycerol Chemistry andBiology 2007141347ndash1356 [PMC free article] [PubMed]

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25 Chen JK Chen J Imig JD Wei S Hachey DL Guthi JS Falck JR Capdevila JHHarrris RC Identification of novel endogenous cytochrome p450 arachidonatemetabolites with high affinity for cannaibnoid receptors The Journal of BiologicalChemistry 200828324514ndash24524 [PMC free article] [PubMed]

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29 Deadwyler SA Hampson RE Mu J Whyte A Childers S Cannabinoidsmodulate voltage sensitive potassium A-current in hippocampal neurons via acAMP-dependent process The Journal of Pharmacology and ExperimentalTherapeutics 1995273734ndash743 [PubMed]

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31 Di Marzo V Fontana A Cadas H Schinelli S Cimino G Schwartz JC PiomelliD Formation and inactivation of endogenous cannabinoid anandamide in centralneurons Nature 1994372686ndash691 [PubMed]

32 Di Marzo V Matias I Endocannabinoid control of food intake and energybalance Nature Neuroscience 20058585ndash589 [PubMed]

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48 Guindon J Hohmann AG A physiological role for endocannabinoid-derivedproducts of cyclooxygenase-2-mediated oxidative metabolism British Journal ofPharmacology 20081531341ndash1343 [PMC free article] [PubMed]

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51 Hashimotodani Y Ohno-Shosaku T Watanabe M Kano M Roles ofphospholipase Cβ and NMDA receptor in activity-dependent endocannabinoidrelease The Journal of Physiology 2007584373ndash380 [PMC free article][PubMed]

52 Hashimotodani Y Ohno-Shosaku T Maejima T Fukami K Kano MPharmacological evidence for the involvement of diacylglycerol lipase indepolarization-induced endocannabinoid release Neuropharmacology20085458ndash67 [PubMed]

53 Hillard CJ Biochemistry and pharmacology of the endocannabinoidsarachidonylethanolamide and 2-arachidonylglycerol Prostaglandins and OtherLipid Mediators 2000613ndash18 [PubMed]

54 Hoover HS Blankman JL Niessen S Cravatt BF Selectivity of inhibitors ofendocannabinoid biosynthesis evaluated by activity-based protein profilingBioorganic and Medicinal Chemistry Letters 2008185838ndash5841[PMC free article] [PubMed]

55 Itzhak Y Ali SF Role of nitrergic system in behavioral and neurotoxic effects ofamphetamine analogs Pharmacology and Therapeutics 2006109246ndash262[PubMed]

56 Iversen L Cannabis and the brain Brain 20031261252ndash1270 [PubMed]57 Jackson SJ Pryce G Diemel LT Cuzner ML Baker D Cannabinoid-receptor 1

null mice are susceptible to neurofilament damage and caspase 3 activationNeuroscience 2005134261ndash268 [PubMed]

58 Janero DR Makriyannis A Targeted modulators of the endogenous cannabinoidsystem Future medications to treat addiction disorders and obesity CurrentPsychiatry Reports 20079365ndash373 [PubMed]

59 Janero DR Makriyannis A International Review of Psychiatry AbingdonEngland 2009a Pharmacotherapeutic modulation of the endocannabinoid signalingsystem in psychiatric disorders Drug-discovery strategies in press [PubMed]

60 Janero DR Makriyannis A Cannabinoid receptor antagonists Pharmacologicalopportunities clinical experience and translational prognosis Expert Opinion onEmerging Drugs 2009b1443ndash65 [PubMed]


61 Jung KM Mangieri R Stapleton C Fegley D Wallace M Mackie K Piomelli DStimulation of endocannabinoid formation in brain slice cultures through activationof group 1 metabotropic glutamate receptors Molecular Pharmacology2005681196ndash1202 [PubMed]

62 Jung KM Astarita G Zhu C Wallace M Mackie K Piomelli D A key role fordiacylglycerol lipase-α in metabotropic glutamate receptor-dependentendocannabinoid mobilization Molecular Pharmacology 200772612ndash621[PubMed]

63 Jung KM Astarita G Yasar S Head E Cotman CW Piomelli D Deficits inanandamide signaling underlie cognitive dysfunction in Alzheimers Disease Societyfor Neuroscience Abstracts 2008626(1)

64 Justinova Z Mangieri RA Bortolato M Chefer SI Mukhin AG Clapper JR KingAR Redhi GH Yasar S Piomelli D Goldberg SR Fatty acid amide hydrolaseinhibition heightens anandamide signaling without producing reinforcing effects inprimates Biological Psychiatry 200864930ndash937 [PMC free article] [PubMed]

65 Kano M Ohno-Shoakau T Hashimotodani Y Uchigashima M Watanabe MEndocannabinoid-mediated control of synaptic transmission PhysiologicalReviews 200989309ndash380 [PubMed]

66 Karanian DA Brown QB Makriyannis A Bahr BA Blocking cannabinoidactivation of FAK and ERK12 compromises synaptic integrity in hippocampusEuropean Journal of Pharmacology 2005a50847ndash56 [PubMed]

67 Karanian DA Brown QB Makriyannis A Kosten TA Bahr BA Dual modulationof endocannabinoid transport and fatty acid amide hydrolase protects againstexcitotoxicity Journal of Neuroscience 2005b257813ndash7820 [PubMed]

68 Karanian DA Karim SL Wood JT Williams JS Lin S Makriyannis A Bahr BAEndocannabinoid enhancement protects against kainic acid-induced seizures andassociated brain damage Journal of Pharmacology and Experimental Therapeutics20073221059ndash1066 [PubMed]

69 Kathuria S Gaetani S Fegley D Valintildeo F Duranti A Tontini A Mor M TarziaG La Rana G Calignano A Giustino A Tattoli M Palmery M Cuomo VPiomelli D Modulation of anxiety through blockade of anandamide hydrolysisNature Medicine 2003976ndash81 [PubMed]

70 Khanapure SP Garvey DS Janero DR Letts LG Eicosanoids in inflammationBiosynthesis pharmacology and therapeutic frontiers Current Topics in MedicinalChemistry 20077311ndash340 [PubMed]

71 Khaspekov LG Brenz Verca MS Frumkina LE Hermann H Marsicano G LutzB Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity The European Journal ofNeuroscience 2004191691ndash1698 [PubMed]

72 Kim DJ Thayer SA Activation of CB1 cannabinoid receptors inhibitsneurotransmitter release from identified synaptic sites in rat hippocampal culturesBrain Research 2000852398ndash405 [PubMed]

73 Kosten TA Miserendino MJ Chi S Nestler EJ Fischer and Lewis rat strainsshow differential cocaine effects in conditioned place preference and behavioralsensitization but not in locomotor activity or conditioned taste aversion The Journalof Pharmacology and Experimental Therapeutics 1994269137ndash144 [PubMed]

74 Kreitzer AC Regehr WG Retrograde inhibition of presynaptic calcium influx byendogenous cannabinoids at excitatory synapses onto Purkinje cells Neuron200129717ndash727 [PubMed]

75 Kreutz S Koch M Boumlttger C Ghadban C Korf HW Dehghani F 2-Arachidonoylglycerol elicits neuroprotective effects on excitotoxically lesioneddentate gyrus granule cells via abnormal-cannabidiol-sensitive receptors onmicroglial cells Glia 200957286ndash294 [PubMed]

76 Lauckner JE Jensen JB Chen HY Lu HC Hille B Mackie K GPR55 is acannabinoid receptor that increases intracellular calcium and inhibits M currentProceedings of the National Academy of Sciences of the United States ofAmerica 20081052699ndash2704 [PMC free article] [PubMed]

77 Liu J Wang L Harvey-White J Osei-Hyiaman D Razdan RK Gong Q ChanAC Zhou Z Huang BX Kim HY Kunos G A biosynthetic pathway foranandamide Proceedings of the National Academy of Sciences of the UnitedStates of America 200610313345ndash13350 [PMC free article] [PubMed]


78 Liu J Wang L Harvey-White J Huang BX Kim HY Luquet S Palmiter RDKrystal G Rai R Mahadevan A Razdan RK Kunos G Multiple pathwaysinvolved in the biosynthesis of anandamide Neuropharmacology 2008541ndash7[PMC free article] [PubMed]

79 Lovinger DM Presynaptic modulation by endocannabinoids Handbook ofExperimental Pharmacology 2008184435ndash477 [PubMed]

80 Ludaacutenyi A Eross L Czirjaacutek S Vajda J Halaacutesz P Watanabe M Palkovits MMagloacuteczky Z Freund TF Katona I Downregulation of the CB1 cannabinoidreceptor and related molecular elements of the endocannabinoid system in epileptichuman hippocampus Journal of Neuroscience 2008282976ndash2990 [PubMed]

81 Maccarrone M Gubellini P Bari M Picconi B Battista N Centonze D BernardiG Finazzi-Agrograve A Calabresi P Levodopa treatment reverses endocannabinoidsystem abnormalities in experimental parkinsonism Journal of Neurochemistry2003851018ndash1025 [PubMed]

82 Maccarrone M Rossi S Bari M De Chiara V Fezza F Musella A Gasperi VProsperetti C Bernardi G Finazzi-Agrograve A Cravatt BF Centonze D Anandamideinhibits metabolism and physiological actions of 2-arachidonoylglycerol in thestriatum Nature Neuroscience 200811152ndash159 [PubMed]

83 Mackie K Cannabinoid receptors as therapeutic targets Annual Review ofPharmacology and Toxicology 200646101ndash122 [PubMed]

84 Mackie K Cannabinoid receptors What they are and what they do Journal ofNeuroendocrinology 20082010ndash14 [PubMed]

85 Marsicano G Goodenough S Monory K Hermann H Eder M Cannich A AzadSC Cascio MG Gutieacuterrez SO van der Stelt M Loacutepez-Rodriguez ML CasanovaE Schuumltz G Zieglgaumlnsberger W Di Marzo V Behl C Lutz B CB1 cannabinoidreceptors and on-demand defense against excitotoxicity Science 200330284ndash88 [PubMed]

86 Matsuda LA Lolait SJ Brownstein MJ Young AC Bonner TI Structure of acannabinoid receptor and functional expression of cloned cDNA Nature1990346561ndash564 [PubMed]

87 Matsumoto RR Gilmore DL Pouw B Bowen WD Williams W Kausar A CoopA Novel analogs of the sigma receptor ligand BD1008 attenuate cocaine-inducedtoxicity in mice European Journal of Pharmacology 200449221ndash26 [PubMed]

88 Mechoulam R Ben-Shabat S Hanus L Ligumsky M Kaminski NE Schatz ARGopher A Almog S Martin BR Compton DR et al Identification of anendogenous 2-monoglyceride present in canine gut that binds to cannabinoidreceptors Biochemical Pharmacology 19955083ndash90 [PubMed]

89 Mechoulam R Fride E Di Marzo V Endocannabinoids European Journal ofPharmacology 19983591ndash18 [PubMed]

90 Mets B Winger G Cabrera C Seo S Jamdar S Yang G Zhao K Briscoe RJAlmonte R Woods JH Landry DW A catalytic antibody against cocaine preventscocaines reinforcing and toxic effects in rats Proceedings of the NationalAcademy of Sciences of the United States of America 19989510176ndash10181[PMC free article] [PubMed]

91 Micale V Mazzola C Drago F Endocannabinoids and neurodegenerativediseases Pharmacological Research 200756382ndash392 [PubMed]

92 Milton NG Anandamide and noladin ether prevent neurotoxicity of the humanamyloid- beta peptide Neuroscience Letters 2002332127ndash130 [PubMed]

93 Mitchell MD Sato TA Wang A Keelan JA Ponnampalam AP Glass MCannabinoids stimulate prostaglandin production by human gestational tissuesthrough a tissue- and CB1-receptor-specific mechanism American Journal ofPhysiology Endocrinology and Metabolism 2008294352ndash356 [PubMed]

94 Molina-Holgado F Pinteaux E Heenan L Moore JD Rothwell NJ Gibson RMNeuroprotective effects of the synthetic cannabinoid HU-210 in primary corticalneurons are mediated by phosphatidylinositol 3-kinaseAKT signaling Molecularand Cellular Neuroscience 200528189ndash194 [PubMed]

95 Moreira FA Kaiser N Monory K Lutz B Reduced anxiety-like behaviourinduced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1receptors Neuropharmacology 200854141ndash150 [PubMed]

96 Mu J Zhuang SY Kirby MT Hampson RE Deadwyler SA Cannabinoidreceptors differentially modulate potassium A and D currents in hippocampal


neurons in culture The Journal of Pharmacology and Experimental Therapeutics1999291893ndash902 [PubMed]

97 Munro S Thomas KL Abu-Shaar M Molecular characterization of a peripheralreceptor for cannabinoids Nature 199336561ndash65 [PubMed]

98 Naidu PS Booker L Cravatt BF Lichtman AH Synergy between enzymeinhibitors of fatty acid amide hydrolase and cyclooxygenase in visceral nociceptionThe Journal of Pharmacology and Experimental Therapeutics 2009[PMC free article] [PubMed]

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100 Natarajan V Schmid PC Reddy PV Schmid HH Catabolism of N-acylethanolamine phospholipids by dog brain preparations Journal ofNeurochemistry 1984411303ndash1312 [PubMed]

101 Nucci C Gasperi V Tartaglione R Cerulli A Terrinoni A Bari M De Simone CAgrograve AF Morrone LA Corasaniti MT Bagetta G Maccarrone M Involvementof the endocannabinoid system in retinal damage after high intraocular pressure-induced ischemia in rats Investigative Ophthalmology and Visual Science2007482997ndash3004 [PubMed]

102 Ohno-Shosaku T Maejima T Kano M Endogenous cannabinoids mediateretrograde signals from depolarized postsynaptic neurons to presynaptic terminalsNeuron 200129729ndash738 [PubMed]

103 Ortar G Bisogno T Ligresti A Morera E Nalli M Di Marzo VTetrahydrolipstatin analogues as modulators of endocannabinoid 2-arachidonoylglycerol metabolism Journal of Medicinal Chemistry 2008516970ndash6979 [PubMed]

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106 Panikashvili D Mechoulam R Beni SM Alexandrovich A Shohami E CB1cannabinoid receptors are involved in neuroprotection via NF-kappa B inhibitionJournal of Cerebral Blood Flow and Metabolism 200525477ndash484 [PubMed]

107 Parmentier-Batteur S Jin K Mao XO Xie L Greenberg DA Increased severityof stroke in CB1 cannabinoid receptor knock-out mice Journal of Neuroscience2002229771ndash9775 [PubMed]

108 Pavlopoulos S Thakur GA Nikas SP Makriyannis A Cannabinoid receptors astherapeutic targets Current Pharmaceutical Design 2006121751ndash1769[PubMed]

109 Pei Y Mercier RW Anday JK Thakur GA Zvonok AM Hurst D Reggio PHJanero DR Makriyannis AM Ligand-binding architecture of human CB2cannabinoid receptor Evidence for receptor subtype-specific binding motif andmodeling GPCR activation Chemistry amp Biology 2008151207ndash1219[PMC free article] [PubMed]

110 Pertwee RG GPR55 A new member of the cannabinoid receptor clan BritishJournal of Pharmacology 2007152984ndash986 [PMC free article] [PubMed]

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112 Piomelli D Beltramo M Glasnapp S Lin SY Goutopoulos A Xie XQMakriyannis A Structural determinants for recognition and translocation by theanandamide transporter Proceedings of the National Academy of Sciences of theUnited States of America 1999965802ndash5807 [PMC free article] [PubMed]

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114 Ramiacuterez BG Blaacutezquez C Goacutemez del Pulgar T Guzmaacuten M de Ceballos MLPrevention of Alzheimers disease pathology by cannabinoids Neuroprotectionmediated by blockade of microglial activation Journal of Neuroscience


2005251904ndash1913 [PubMed]115 Saario SM Laitinen JT Monoglyceride lipase as an enzyme hydrolyzing 2-

arachidonoylglycerol Chemistry and Biodiversity 200741903ndash1913 [PubMed]116 Schaumlbitz WR Giuffrida A Berger C Aschoff A Schwaninger M Schwab S

Piomelli D Release of fatty acid amides in a patient with hemispheric stroke Amicrodialysis study Stroke 2002332112ndash2114 [PubMed]

117 Scherma M Medalie J Fratta W Vadivel SK Makriyannis A Piomelli D MikicsE Haller J Yasar S Tanda G Goldberg SR The endogenous cannabinoidanandamide has effects on motivation and anxiety that are revealed by fatty acidamide hydrolase (FAAH) inhibition Neuropharmacology 200854129ndash140[PMC free article] [PubMed]

118 Schneider C Pratt DA Porter NA Brash AR Control of oxygenation inlipoxygenase and cyclooxygenase catalysis Chemistry and Biology 200714473ndash488 [PMC free article] [PubMed]

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120 Shen M Piser TM Seybold VS Thayer SA Cannabinoid receptor agonists inhibitglutamatergic synaptic transmission in rat hippocampal cultures Journal ofNeuroscience 1996164322ndash4334 [PubMed]

121 Shen M Thayer SA The cannabinoid agonist Win55212-2 inhibits calciumchannels by receptor-mediated and direct pathways in cultured rat hippocampalneurons Brain Research 199878377ndash84 [PubMed]

122 Shu-Jung S Bradshaw HB Chen JS Tan B Walker JM Prostaglandin Eglycerol ester an endogenous COX-2 metabolite of 2-arachidonoylglycerolinduces hyperalgesia and modulates NFκB activity British Journal ofPharmacology 20081531538ndash1549 [PMC free article] [PubMed]

123 Simon GM Cravatt BF Endocannabinoid biosynthesis proceeding throughglycerophospho-N-acyl ethanolamine and a role for αβ-hydrolase in this pathwayThe Journal of Biological Chemistry 200628126465ndash26472 [PubMed]

124 Simon GM Cravatt BF Anandamide biosynthesis catalyzed by thephosphodiesterase GDE1 and detection of glycerophospho-N-acyl ethanolamineprecursors in mouse brain The Journal of Biological Chemistry 20082839341ndash9349 [PMC free article] [PubMed]

125 Singla S Kreitzer AC Malenka RC Mechanisms for synapse specificity duringstriatal long-term depression Journal of Neuroscience 2007275260ndash5264[PubMed]

126 Storr M Emmerdinger D Diegelmann J Yuumlce B Pfenning S Ochsenkuumln T GoumlkeB Brand S The role of fatty acid hydrolase (FAAH) gene variants in inflammatorybowel disease Alimentary Pharmacology and Therapeutics 2008a29542ndash551[PubMed]

127 Storr MA Keenan CM Emmerdinger D Zhang H Yuumlce B Sibaev A Massa FBuckley NE Lutz B Goumlke B Brand S Patel KD Sharkey KA Targetingendocannabinoid degradation products against experimental colitis in miceInvolvement of CB1 and CB2 receptors Journal of Molecular Medicine2008b86925ndash936 [PubMed]

128 Sugiura T Kondo S Sukagawa A Tonegawa T Nakane S Yamashita A IshimaY Waku K Transacylase-mediated and phosphodiesterase-mediated synthesis ofN-arachidonoylethanolamine an endogenous cannabinoid-receptor ligand in ratbrain microsomes Comparison with synthesis from free arachidonic acid andethanolamine European Journal of Biochemistry 199624053ndash62 [PubMed]

129 Tsuboi K Zhao LY Okamoto Y Araki N Ueno M Sakamoto H Udea NPredominanat expression of lysosomal N-acylethanolamine-hydrolyzing acidamidase in macrophages revealed by immunochemical studies Biochimica etBiophysica Acta 2007a1771623ndash632 [PubMed]

130 Tsuboi K Takezaki N Udea N The N-acylethanolamine-hydrolyzing acidamidase (NAAA) Chemistry and Biodiversity 2007b41914ndash1925 [PubMed]

131 Vandevoorde S Lambert DM The multiple pathways of endocannabinoidmetabolism A zoom out Chemistry and Biodiversity 200741858ndash1881[PubMed]

132 Van Sickle MD Duncan M Kingsley PJ Mouihate A Urbani P Mackie K StellaN Makriyannis A Piomelli D Davison JS Marnett LJ Di Marzo V Pittman QJ

2


NLM NIH DHHS

Patel KD Sharkey KA Identification and functional characterization of brainstemcannabinoid CB2 receptors Science 2005310329ndash332 [PubMed]

133 van Tienhoven M Atkins J Li Y Glynn P Human neuropathy target esterasecatalyzes hydrolysis of membrane lipids The Journal of Biological Chemistry200227720942ndash20948 [PubMed]

134 Vemuri VK Janero DR Makriyannis A Pharmacotherapeutic targeting of theendocannabinoid signaling system Drugs for obesity and the metabolic syndromePhysiology and Behavior 200893671ndash686 [PMC free article] [PubMed]

135 Wallace MJ Blair RE Falenski KW Martin BR DeLorenzo RJ The endogenouscannabinoid system regulates seizure frequency and duration in a model oftemporal lobe epilepsy The Journal of Pharmacology and ExperimentalTherapeutics 2003307129ndash137 [PubMed]

136 Wang H Xie H Sun X Kingsley PJ Marnett LJ Cravatt BF Dey SKDifferential regulation of endocannabinoid synthesis and degradation in the uterusduring embryo implantation Prostaglandins and Other Lipid Mediators20078362ndash74 [PMC free article] [PubMed]

137 Webb M Luo L Ma JY Tham CS Genetic deletion of fatty acid amide hydrolaseresults in improved long-term outcome in chronic autoimmune encephalitisNeuroscience Letters 2008439106ndash110 [PubMed]

138 Wei BO Mikkelsen TS McKinney MK Lander ES Cravatt BF A second fattyacid amide hydrolase with variable distribution among placental mammals TheJournal of Biological Chemistry 200628136569ndash36578 [PubMed]

139 Wilkins LH Jr Prendergast MA Blanchard J Holley RC Chambers ER LittletonJM Potential value of changes in cell markers in organotypic hippocampal culturesassociated with chronic EtOH exposure and withdrawal Comparison withNMDA-induced changes Alcoholism Clinical and Experimental Research2006301768ndash1780 [PubMed]

140 Wilson RI Kunos G Nicoll RA Presynaptic specificity of endocannabinoidsignaling in the hippocampus Neuron 200131453ndash462 [PubMed]

141 Wood JT Williams JS Pandarinathan L Courville A Keplinger MR Janero DRVouros P Makriyannis A Lammi-Keefe CJ Comprehensive profiling of thehuman circulating endocannabinoid metabolome Clinical sampling and samplestorage parameters Clinical Chemistry and Laboratory Medicine 2008461289ndash1295 [PMC free article] [PubMed]

142 Woodward DF Liang Y Krauss AH Prostamides (prostaglandin-ethanolamides)and their pharmacology British Journal of Pharmacology 2008153410ndash419[PMC free article] [PubMed]

143 Zvonok N Pandarinathan L Williams J Johnston M Karageorgos I Janero DRKrishnan SC Makriyannis A Covalent inhibitors of human monoacylglycerollipase Ligand-assisted characterization of the catalytic site by mass spectrometryand mutational analysis Chemistry amp Biology 2008a15854ndash862[PMC free article] [PubMed]

144 Zvonok N Williams J Johnston M Pandarinathan L Janero DR Li L KrishnanSC Makriyannis A Full mass spectrometric characterization of humanmonoacylglycerol lipase generated by large-scale expression and single-steppurification Journal of Proteome Research 200872158ndash2164[PMC free article] [PubMed]

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Introduction

Demonstration that cannabinoid (CB) constituents of the Cannabis plant including Δ -tetrahydrocannabinol (THC) exert their effects by engaging and activating discrete cellularCB receptors prompted the search in animals for naturally produced CB-receptor agonistligands This quest led to the discovery of a ubiquitous mammalian signaling system in whichendogenous cannabinoids (endocannabinoids) synthesized by the body act as signaling lipidsplay varied homeostatic and regulatory roles (Mackie 2006 Pacher et al 2006 Pertwee2008) Experimental and clinical data have unequivocally demonstrated that one of the mostimportant functions of the endocannabinoid signaling system is tissue protection againstpathological insult or injury-- a function that has opened several attractive therapeuticmodalities for pharmacological endocannabinoid-system modulation (Chang et al 2006Mackie 2008 Pacher and Haskoacute 2008 Vemuri et al 2008 Janero and Makriyannis2009ab) In particular great advances have been made toward targetedpharmacotherapeutic manipulation of endocannabinoid signaling for neuroprotection Onewell-studied endocannabinoid in particular N-arachidonoylethanolamine (or ldquoanandamiderdquo)(AEA) has been linked to the neuroprotective property of CB-receptor transmission (Table 1) (see reviews Bahr et al 2006 Pavlopoulos et al 2006 Janero and Makriyannis2007 Micale et al 2007) Distributed throughout the brain as an integral membrane proteinthe enzyme fatty acid amide hydrolase (FAAH) is primarily responsible for inactivating AEAand quenching AEA-induced biological responses (Basavarajappa 2007 Vandevoorde andLambert 2007 Di Marzo 2008 Ahn et al 2008 Fezza et al 2008) Whereas THC andother direct CB-receptor agonists can negatively influence psychomotor cognitive andappetitive behaviors (Freund 2003 Iversen 2003 Di Marzo and Matias 2005) selectiveFAAH inhibitors appear to offer site- and event-specific therapeutic relief in those tissueswhere endocannabinoids are being produced as part of a physiological protectivemechanism (Vemuri et al 2008 Janero and Makriyannis 2009a) By virtue of thispharmacological mode of action FAAH inhibitors are advantageously poised to exploit theneuroprotective nature of endocannabinoid signaling without risk of eliciting adversepsychotropic (or other) effects associated with chronic application of cannabinoid receptoragonists

Table 1Pathogenic events that increase anandamide levels

The foregoing implies that endocannabinoid signaling may be enhanced indirectly totherapeutic levels through FAAH inhibition making FAAH an attractivepharmacotherapeutic target and selective FAAH inhibitors attractive drug candidates forvarious neurological and neurodegenerativeneuroinflammatory disorders (Table 2) Thisproposition will be examined herein from the perspectives of endocannabinoid metabolismand endocannabinoid-system neuropharmacology

Table 2Medicinal applications for controlled FAAH inhibitors

I Endocannabinoid Metabolic Pathways

A growing number of endocannabinoid amide and ester long-chain fatty-acid derivatives areeither known agonists or candidate ligands for one or both principal CB receptor subtypesCB1 and CB2 (Mackie 2008 Pei et al 2008 Pertwee 2008 Wood et al 2008) It shouldalso be noted that there have been other studies identifying potential cannabinoid receptorsincluding a species named GPR55 (Begg et al 2005 Pertwee 2007 Lauckner et al 2008)The two signaling lipids first identified as endocannabinoids AEA and 2-AG remainnonetheless the most intensively studied and best characterized CB-receptor agonists(Bisogno 2008) AEA is a partial CB1-receptor activator with modest affinity [K = 61 nM(rat) and 240 nM (human)] and a relatively weak CB2-receptor ligand (K = 440-1930 nMfor rodent and human CB2 receptors) with low overall efficacy 2-AG is a full agonist at theCB1 and CB2 receptors albeit with lower affinity (K = 472 and 1400 nM respectively)and greater efficacy relative to AEA (Vemuri et al 2008 Janero and Makriyannis 2009a)Their distinctive biochemical and pharmacological properties notwithstanding homeostaticregulation of AEA and 2-AG signaling depends critically upon controlled endocannabinoidgeneration and biotransformationinactivation The balanced actions of endocannabinoid

9

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See more

Review Cannabinoid receptors astherapeutic targets[Annu Rev Pharmacol Toxicol 2006]Review The endocannabinoid system asan emerging target of pharmacotherapy[Pharmacol Rev 2006]Review Ligands that target cannabinoidreceptors in the brain from THC toanandamide and beyond

[Addict Biol 2008]Review Cannabinoid receptors wherethey are and what they do[J Neuroendocrinol 2008]Review Endocannabinoids andcannabinoid receptors in ischaemia-reperfusion injury and preconditioning

[Br J Pharmacol 2008]Review Pharmacotherapeutic targeting ofthe endocannabinoid signaling systemdrugs for obesity and the metabolic



[Expert Opin Emerg Drugs 2009]Review Targeting the endocannabinoidsystem in treating brain disorders[Expert Opin Investig Drugs 2006]Review Cannabinoid receptors astherapeutic targets[Curr Pharm Des 2006]Review Targeted modulators of theendogenous cannabinoid system futuremedications to treat addiction disorders

[Curr Psychiatry Rep 2007]Review Endocannabinoids andneurodegenerative diseases[Pharmacol Res 2007]Review Critical enzymes involved inendocannabinoid metabolism[Protein Pept Lett 2007]The multiple pathways ofendocannabinoid metabolism a zoomout



[Subcell Biochem 2008]Review Interneuron Diversity seriesRhythm and mood in perisomaticinhibition

[Trends Neurosci 2003]Review Cannabis and the brain

[Brain 2003]








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III Conclusion



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III Conclusion



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III Conclusion



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2


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2 2

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[Nat Neurosci 2008]

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[Life Sci 2004]





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III Conclusion



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III Conclusion



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III Conclusion



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Enhancement of endocannabinoid signaling by fatty acid...

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