Pharmacology & Therapeutics 244 (2023) 108394

Contents lists available at ScienceDirect

Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/pharmthera

Inhibiting degradation of 2-arachidonoylglycerol as a therapeutic

strategy for neurodegenerative diseases
Chu Chen ⁎
Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX
78229, USA

a r t i c l e i n f o a b s t r a c t

Article history: Endocannabinoids are endogenous lipid signaling mediators that participate in a variety of physiological and
Received 9 February 2023 pathological processes. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid and is a full ago-
Received in revised form 17 March 2023 nist of G-protein-coupled cannabinoid receptors (CB1R and CB2R), which are targets of Δ9-tetrahydrocannabinol
Accepted 21 March 2023
(Δ9-THC), the main psychoactive ingredient in cannabis. While 2-AG has been well recognized as a retrograde
Available online 24 March 2023
messenger modulating synaptic transmission and plasticity at both inhibitory GABAergic and excitatory gluta-
Associate editor: S.J. Enna matergic synapses in the brain, growing evidence suggests that 2-AG also functions as an endogenous terminator
of neuroinflammation in response to harmful insults, thus maintaining brain homeostasis. Monoacylglycerol
lipase (MAGL) is the key enzyme that degrades 2-AG in the brain. The immediate metabolite of 2-AG is arachi-
Keywords:: donic acid (AA), a precursor of prostaglandins (PGs) and leukotrienes. Several lines of evidence indicate that
Endocannabinoid pharmacological or genetic inactivation of MAGL, which boosts 2-AG levels and reduces its hydrolytic metabo-
2-Arachidonoylglycerol lites, resolves neuroinflammation, mitigates neuropathology, and improves synaptic and cognitive functions in
Monoacylglycerol lipase animal models of neurodegenerative diseases, including Alzheimer’s disease (AD), multiple sclerosis (MS),
Neurodegenerative disease
Parkinson’s disease (PD), and traumatic brain injury (TBI)-induced neurodegenerative disease. Thus, it has
Alzheimer’s disease
been proposed that MAGL is a potential therapeutic target for treatment of neurodegenerative diseases. As the
Traumatic brain injury
main enzyme hydrolyzing 2-AG, several MAGL inhibitors have been identified and developed. However, our
understanding of the mechanisms by which inactivation of MAGL produces neuroprotective effects in neurode-
generative diseases remains limited. A recent finding that inhibition of 2-AG metabolism in astrocytes, but not in
neurons, protects the brain from TBI-induced neuropathology might shed some light on this unsolved issue. This
review provides an overview of MAGL as a potential therapeutic target for neurodegenerative diseases and
discusses possible mechanisms underlying the neuroprotective effects of restraining degradation of 2-AG in
the brain.
© 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Synthesis and metabolism of 2-AG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3. 2-AG signaling in resolving neuroinflammation and protecting neurons . . . . . . . . . . . . . . . . . . . . 6
4. MAGL in neurodegenerative diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
5. Signaling pathways mediating neuroprotection following inactivation of MAGL . . . . . . . . . . . . . . . . . 10

Abbreviations: ABHD6/12, α/β-hydrolase domain containing 6/12; AC, adenylyl cyclase; AD, Alzheimer’s disease; AEA, anandamide; AA, arachidonic acid; 2-AG, 2-
arachidonoylglycerol; BBB, blood-brain barrier; CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2; CBD, cannabidiol; CHI, closed head injury; COX-2, cyclooxygen-
ase-2; DAGLα/β, diacylglycerol lipase α/β; EET, epoxyeicosatrienoic acids; ERK1/2, extracellular signal-regulated kinases 1 and 2; FAAH, fatty acid amide hydrolase; FABPs, fatty-acid
binding proteins; GABA, gamma-aminobutyric acid; HETE, hydroxyeicosatetraene; HPETE, hydroperoxyeicosatetraenoic acid; IL-1β,6, interleukin-1β,6; LTP, long-term potentiation;
MAGL, monoacylglycerol lipase; MS, multiple sclerosis; NAPE, N-arachidonoyl phosphatidyl ethanolamine; NAPE-PLD, NAPE phospholipase D; NF-κB, nuclear factor kappa-light-
chain-enhancer of activated B cells; PD, Parkinson’s disease; PG, prostaglandin; PG-G, prostaglandin glycerol; PPARγ, peroxisome proliferator-activated receptor γ; TBI, traumatic brain
injury; Δ9-THC, Δ9-tetrahydrocannabinol; TNFα, tumor necrosis factor α.
⁎ Corresponding author at: Department of Cellular and Integrative Physiology, School of Medicine, University of Texas Health San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229,
USA.
E-mail address: chenc7@uthscsa.edu (C. Chen).

https://doi.org/10.1016/j.pharmthera.2023.108394
0163-7258/© 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
C. Chen Pharmacology & Therapeutics 244 (2023) 108394

6. MAGL inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
7. Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

1. Introduction & Newquist, 2013; Hoffman et al., 2007; Messinis, Kyprianidou,

Marijuana has been used by humans over a few thousand years for
both recreational and medical purposes. The active ingredients in
marijuana remained unknown until the mid-1960 when Dr. Raphael
Mechoulam, the “Father of Cannabinoid Research”, isolated Δ9-
tetrahydrocannabinol (Δ9-THC) and identified it to be the main psycho-
active constituent in cannabis (Mechoulam, 1970; Mechoulam & Parker,
2013). The Mechoulam team also identified another prevalent
phytocannabinoid in cannabis, cannabidiol (CBD) (Mechoulam &
Shvo, 1963). A most recent review article provides an overview on
similarities and differences between Δ9-THC and CBD in terms of their
molecular structures, mechanisms of biological effects on brain func-
tions, and side effects (Stella, 2023). CBD has been thought
non-psychotropic and fewer side effects. However, recent studies sug-
gested that CBD should be considered psychotropic as well (Stella,
2023). In rodent studies, it has been observed that CBD impairs memory
reconsolidation, affects motor behavior, and impairs attentional
set-shifting and spatial working memory (Bayer et al., 2022; Espejo-
Porras, Fernández-Ruiz, Pertwee, Mechoulam, & García, 2013; Stella,
2023; Szkudlarek et al., 2019). It has long been known that Δ9-THC
induces neuropsychological and cognitive side effects, including
anxiety-like and impaired locomotor behavior, synaptic and memory
impairments (Carlini, 2004; Chen et al., 2013; Hoffman, Oz, Yang,
Lichtman, & Lupica, 2007; Stella, 2023). Both Δ9-THC and CBD are FDA
approved cannabinoid medicines. However, due to the undesirable
side effects (Amin & Ali, 2019; Chen et al., 2013; Fitzgerald, Bronstein,
Malefaki, & Papathanasopoulos, 2006; Pope Jr. & Yurgelun-Todd, 1996;
Puighermanal et al., 2009; Solowij, et al., 2002; Taffe, 2012; Volkow,
Baler, Compton, & Weiss, 2014), medical use of Δ9-THC (Dronabinol or
Marinol) is limited to some conditions for treatment of nausea and
vomiting caused by cancer chemotherapy or weight loss and for poor
appetite in patients with acquired immunodeficiency syndrome
(AIDS). Since then, over 400 chemicals in marijuana have been identi-
fied, of which more than 100 are chemically and biosynthetically related
cannabinoids (Ligresti, De Petrocellis, & Di Marzo, 2016). Synthetic can-
nabinoids, including CP-55940, Hu-210, and Win55,212-2, emerged
from the identification of Δ9-THC (Fig. 1). In the mid-1980s, the ground-
breaking work by Dr. Allyn Howlett’s lab using radiolabeled [3H]-
CP55940 provided solid and conclusive evidence that cannabinoids
inhibit adenylyl cyclase (AC) through GTP-binding proteins (Devane,
Dysarz 3rd, Johnson, Melvin, & Howlett, 1988; Howlett, 1987; Howlett
et al., 2004; Howlett & Fleming, 1984; Howlett, Qualy, & Khachatrian,
1986). These findings led to identification and cloning of two types of
cannabinoid receptors, type 1 (CB1R) and type 2 (CB2R) in the early
1990s in both animals and humans (Herkenham et al., 1990;
Herkenham et al., 1991; Howlett et al., 1990; Matsuda, Lolait,
Brownstein, Young, & Bonner, 1990; Munro, Thomas, & Abu-Shaar,
1993; Van Sickle et al., 2005). Both CB1R and CB2R are seven-
transmembrane domain receptors, and they display similar pharmaco-
logical and biochemical properties, coupling to GTP binding proteins
to inhibit activity of AC (Fig. 2) (Felder et al., 1995; Howlett & Abood,
2017). While CB1R is primarily expressed in the brain, CB2R is

Fig. 1. Δ9-tetrahydrocannabinol (Δ9-THC) and synthetic cannabinoids.

2
C. Chen
predominantly expressed in the peripheral immune system and in
microglial cells, the primary innate immune cells of the brain (Howlett
et al., 2002; Howlett et al., 2004; Mackie, 2005, 2008; Pertwee, 2006).
Discovery and identification of CB1R and CB2R, and especially the
discovery of high levels of CB1R expression in the brain, provided
clues to the existence of endogenous lipid ligands that bind to and acti-
vate CB1R or CB2R, prompting the search for endogenous cannabinoid
ligands. The first endocannabinoid, N-arachidonylethanolamine (AEA),
also known as anandamide, was isolated and identified in 1992
(Devane et al., 1992; Felder et al., 1993). Soon thereafter, in 1995, a sec-
ond endocannabinoid, 2-arachidonoylglycerol (2-AG), was indepen-
dently identified by two groups of investigators, Drs. Mechoulam and
Sugiura (Mechoulam et al., 1995; Sugiura et al., 1995; Sugiura,
Kishimoto, Oka, & Gokoh, 2006). These discoveries were soon con-
firmed by other groups (Gonsiorek et al., 2000; Hillard, 2000; Stella,
Schweitzer, & Piomelli, 1997) and several putative endogenous canna-
binoids have been identified (Fig. 3). AEA and 2-AG have been investi-
gated most thoroughly and they differ in several aspects in terms of
binding activity for CB1R or CB2R. For instance, 2-AG is the most abun-
dant endocannabinoid and a full agonist for CB1R and CB2R, whereas
AEA is a partial agonist for CB1R and CB2R (Howlett & Abood, 2017;
Howlett et al., 2002; Howlett et al., 2004; Kano, Ohno-Shosaku,
Hashimotodani, Uchigashima, & Watanabe, 2009; Piomelli, 2003;
Sugiura et al., 2006). AEA is also involved in pain sensation and chronic
inflammation through activation of a transient receptor potential cation
channel subfamily V member 1 (TRPV1), also known as a vanilloid
receptor (Aghazadeh Tabrizi et al., 2017; Muller, Morales, & Reggio,
2018; Starowicz, Nigam, & Di Marzo, 2007).
Fig. 2. GTP-binding protein-coupled cannabinoid receptors (CB1R and CB2R). Cannabinoid
(Δ9-THC) or endocannabinoid (2-AG) binds to CB1R or CB2R to activate the receptor-
coupled G protein, resulting in dissociation of the Gαi subunit from Gβγ subunits. Disso-
ciated Gαi subunit inhibits activity of adenylyl cyclase (AC) that catalyzes ATP to cAMP,
leading to reduction of protein kinase A (PKA) activity. Dissociated Gβγ subunits interact
with other effectors to regulate biological function through different signaling pathways.
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Pharmacology & Therapeutics 244 (2023) 108394
It has been almost six decades since the Mechoulam’s group isolated
and identified Δ9-THC as the primary psychoactive constituent of can-
nabis (Howlett et al., 2004; Mechoulam, 1970; Mechoulam, Braun, &
Gaoni, 1967; Mechoulam & Gaoni, 1967; Mechoulam, Hanuš, Pertwee,
& Howlett, 2014). Their pioneering work opened a new era of cannabi-
noid research and greatly enhanced our understanding of the ingredi-
ents of marijuana and actions of cannabinoids. Their research
promoted and facilitated discovery of the endogenous cannabinoid sys-
tem. Through extensive and rigorous research by scientists over the past
30 years, we have now recognized and confirmed the existence of the
endogenous cannabinoid system, which elicits biological effects when
it is activated (Lu & Mackie, 2021). The endocannabinoid system con-
sists of cannabinoid receptors (CB1R and CB2R), endocannabinoids
(e.g., AEA and 2-AG), transporters, and the enzymes that synthesize
and degrade endocannabinoids (Fig. 4). In addition, there are a few ad-
ditional putative cannabinoid receptors, one of which is GPR55 (Kano
et al., 2009; Ligresti et al., 2016; Lu & Mackie, 2021). Recent evidence
shows that fatty acid-binding protein 5 (FABP5) is an important trans-
porter for endocannabinoids (Haj-Dahmane et al., 2018; Kaczocha,
Glaser, & Deutsch, 2009; Kaczocha & Haj-Dahmane, 2022). It is clear
now that the endocannabinoid system participates in a variety of phys-
iological and pathological processes, which have been discussed in
several previous reviews in details (Baggelaar, Maccarrone, & van der
Stelt, 2018; Castillo, Younts, Chávez, & Hashimotodani, 2012; Cristino,
Bisogno, & Di Marzo, 2020; Di Marzo, Stella, & Zimmer, 2015; Egmond,
Straub, & der Stelt, 2021; Freund, Katona, & Piomelli, 2003; Howlett
et al., 2004; Kaczocha & Haj-Dahmane, 2022; Kano et al., 2009; Katona
& Freund, 2012; Ligresti et al., 2016; Lu & Mackie, 2021; Mechoulam
et al., 2014; Mechoulam & Parker, 2013; Pertwee, 2006, 2015). This re-
view primarily focuses on the latest developments in 2-AG signaling
and its metabolism by inactivation of monoacylglycerol lipase
(MAGL), also known as monoglyceride lipase, the primary enzyme
that hydrolyzes 2-AG, in animal models of neurodegenerative diseases
(Blankman, Simon, & Cravatt, 2007; Dinh et al., 2002; Dinh, Freund, &
Piomelli, 2002; Long, Nomura, & Cravatt, 2009; Viader et al., 2015).
2. Synthesis and metabolism of 2-AG
Since 2-AG was identified as an endogenous cannabinoid, 2-AG
functioning as a retrograde messenger in modulation of synaptic trans-
mission and plasticity at both GABAergic and glutamatergic synapses
has been extensively studied. It has been recognized that 2-AG is re-
leased from postsynaptic neurons and activates presynaptically
expressed CB1R, resulting in a reduction of neurotransmitter release
through inhibition of voltage-gated Ca2+ channel activity and a con-
comitant increase in K+ channel conductance in presynaptic nerve ter-
minals (Alger, 2002; Castillo et al., 2012; Chevaleyre & Castillo, 2003,
2004; Freund & Hajos, 2003; Gao et al., 2010; Gerdeman, Ronesi, &
Lovinger, 2002; Hashimotodani, Ohno-Shosaku, & Kano, 2007; Heifets
& Castillo, 2009; Iversen, 2003; Kano et al., 2009; Katona & Freund,
2012; Kreitzer & Regehr, 2002; Lovinger, 2008; Pitler & Alger, 1994;
Stella et al., 1997; Tanimura et al., 2010; Vigh & von Gersdorff, 2007;
Wilson, Kunos, & Nicoll, 2001; Wilson & Nicoll, 2001, 2002). Accumulat-
ing evidence indicates that 2-AG possesses anti-inflammatory and
neuroprotective effects in response to proinflammatory, neurotoxic,
and mechanical insults and maintains brain homeostasis (Chen, 2015,
2023; Du, Chen, Zhang, & Chen, 2011; Panikashvili, Mechoulam, Beni,
Alexandrovich, & Shohami, 2005; Panikashvili et al., 2006; Panikashvili
et al., 2001; Song, Zhang, & Chen, 2015; Sugiura et al., 2006; Zhang &
Chen, 2008; Zhang, Hu, Teng, Tang, & Chen, 2014), suggesting that
2-AG is an important endogenous lipid mediator involved in multiple
functions in the brain.
2-AG is the most abundant endocannabinoid and has been recog-
nized as a true natural ligand for both CB1R and CB2R (Sugiura et al.,
2006). 2-AG is generated from membrane phospholipids (e.g., phos-
phatidylinositol, phosphatidylinositol 4,5-bisphosphate, triacylglycerol,
C. Chen
Fig. 3. Substances that have been identified as endogenous cannabinoids. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most studied endocannabinoids (Adapted from
Kano et al., 2009 with permission from American Physiological Society).
or lysophosphatidylinositol) through multiple pathways (Murataeva,
Straiker, & Mackie, 2014). However, the primary pathway of biosynthe-
sis 2-AG is via conversion of membrane phospholipids to diacylglycerols
(DAG) by phospholipase C-β (PLCβ) and then hydrolysis of DAG to 2-AG
by diacylglycerol lipase α and diacylglycerol lipase β (DAGLα/β)
(Fig. 5). Diacylglycerol lipases were cloned in 2003 (Bisogno et al.,
2003), advancing our understanding of the key pathway for biosynthe-
sis of 2-AG. There is evidence that DAGLα is the major biosynthetic en-
zyme for 2-AG in neurons and astrocytes in the brain, while DAGLβ is
responsible for synthesis of 2-AG in microglia (Gao et al., 2010;
Murataeva et al., 2014; Shin et al., 2018; Tanimura et al., 2010; Viader
et al., 2016; Xue et al., 2019; Yoshida et al., 2006). The presence of
DAGLα in the postsynaptic site and loss of retrograde endocannabinoid
signaling when DAGLα is pharmacologically or genetically inactivated
further support the notion that 2-AG functions as a retrograde signaling
messenger modulating synaptic transmission and plasticity (Castillo
et al., 2012; Diana & Marty, 2004; Gao et al., 2010; Hashimotodani
et al., 2007; Kano et al., 2009; Murataeva et al., 2014; Ogasawara et al.,
2016; Ohno-Shosaku & Kano, 2014; Tanimura et al., 2010; Yoshida
et al., 2006).
Like the synthesis of 2-AG, there are several pathways involving en-
zymes that degrade 2-AG (Fig. 5), including MAGL, α/β hydrolase
domain-containing protein 6 and 12 (ABHD6 and ABHD12), and
cyclooxygenase-2 (COX-2). MAGL was first identified as an enzyme hy-
drolyzing 2-AG by the Piomelli’s lab where they found that MAGL par-
ticipates in 2-AG inactivation (Dinh, Carpenter, et al., 2002; Dinh,
Freund, & Piomelli, 2002). While MAGL is expressed in most cells, its
4
Pharmacology & Therapeutics 244 (2023) 108394
hydrolysis of 2-AG displays tissue-specificity. For example, systemic ad-
ministration of a potent and irreversible MAGL inhibitor JZL184 results
in a dramatic elevation of 2-AG levels in the brain, but has less effect
in peripheral tissues (Long, Nomura, & Cravatt, 2009), suggesting that
2-AG in the brain is predominantly metabolized by MAGL. Indeed, it
has been estimated that 85% of 2-AG in the brain is hydrolyzed by
MAGL, whereas about 12% of 2-AG is hydrolyzed by ABHD6 and
ABHD12 (Alhouayek, Masquelier, & Muccioli, 2014; Blankman et al.,
2007; Dinh, Carpenter, et al., 2002; Dinh, Freund, & Piomelli, 2002;
Fiskerstrand et al., 2010; Labar, Wouters, & Lambert, 2010; Long,
Nomura, & Cravatt, 2009; Marrs et al., 2010; Muccioli et al., 2007;
Murataeva et al., 2014; Navia-Paldanius, Savinainen, & Laitinen, 2012;
Nomura et al., 2011; Savinainen, Saario, & Laitinen, 2012; Scalvini,
Piomelli, & Mor, 2016; Schlosburg et al., 2010). ABHD6 has been identi-
fied in postsynaptic dendrites (Marrs et al., 2010), suggesting that
ABHD6 may play an important role in maintaining the efficacy of
2-AG-mediated retrograde signaling in synaptic transmission
(Baggelaar et al., 2018; Marrs et al., 2010). The latest studies demon-
strated that MAGL is the primary enzyme hydrolyzing 2-AG in neurons
and astrocytes, whereas ABHD12 is the major enzyme degrading 2-AG
in microglial cells (X. Liu et al., 2016; Viader et al., 2015; Viader et al.,
2016). These studies provide important information suggesting involve-
ment of diverse pathways in biosynthesis and metabolism of 2-AG in
the brain. Moreover, 2-AG can be oxidatively catalyzed by COX-2 to
form new types of prostaglandins, specifically prostaglandin glycerols
(PG-Gs), when expression and activity of COX-2 are elevated during in-
flammation (Kingsley, Rouzer, Morgan, Patel, & Marnett, 2019; Morgan
C. Chen Pharmacology & Therapeutics 244 (2023) 108394

Fig. 4. The endocannabinoid system. There are five components of the endocannabinoid system consisting of endocannabinoids, cannabinoid receptors, enzymes synthesizing and
degrading endocannabinoids, and endocannabinoid transporters. AEA is a partial agonist for CB1R and CB2R but is a full agonist for TRPV1. 2-AG is a full agonist for CB1R and CB2R.
AA: arachidonic acid; ABHD6/12: α/β-hydrolase domain containing 6 and 12; AEA: Anandamide; 2-AG: 2-arachidonoylglycerol; COX-2: cyclooxygenase-2; DAG: diacylglycerol;
DAGLα/β: diacylglycerol lipase α/β; FAAH: fatty acid amide hydrolase; FABP5: fatty acid-binding protein 5; GPR55: G protein-coupled receptor 55; MAGL: monoacylglycerol lipase;
NAPE: N-arachidonyl-phosphatidyl ethanolamine; NAPE-PLD: N-acetylphosphatidylethanolamine-hydrolysing phospholipase D; PG-EA: prostaglandin ethanolamine; PG-G: prostaglan-
din ethanolamine glycerol; TRPV1: transient receptor potential vanilloid 1

et al., 2018; Rouzer & Marnett, 2008). There are two isoforms of
cyclooxygenases, COX-1 and COX-2, which convert arachidonic acid
(AA) to prostaglandins (PGs), including PGE2, PGD2, PGF2α, PGI2, TXA2
(Vane, Bakhle, & Botting, 1998; Yang & Chen, 2008). COX-1 is constitu-
tively expressed in all tissues and functions as a housekeeper. However,
COX-2 is inducible and its expression is immediately upregulated in re-
sponse to infection or insults (Chen & Bazan, 2005; Vane et al., 1998;
Yang & Chen, 2008). Basal expression of COX-2 is only detected in the
brain, kidney, and testis under resting conditions. In the early 2000s, it
was found that endocannabinoids AEA and 2-AG can be oxidatively me-
tabolized by COX-2, but not by COX-1. Pioneering work by the Marnett
group identified 2-AG as a substrate for COX-2 (Duggan et al., 2011;
Hermanson et al., 2013; Hermanson, Gamble-George, Marnett, & Patel,
2014; Kingsley et al., 2019; Kozak, Prusakiewicz, & Marnett, 2004;
Kozak, Prusakiewicz, Rowlinson, Schneider, & Marnett, 2001; Kozak,
Rowlinson, & Marnett, 2000; Morgan et al., 2018; Rouzer & Marnett,
2008). Oxygenation of 2-AG by COX-2 produces PG-Gs, which are
distinct from classical PGs derived from AA. The biological function of
PG-Gs remained unclear, and it is uncertain whether there are specific
receptors for these 2-AG metabolites catalyzed by COX-2 (Alhouayek
& Muccioli, 2014; Kingsley et al., 2019; Murataeva et al., 2014).
However, earlier studies showed that PGE2-G enhances both excitatory
and inhibitory synaptic transmission and induces neurotoxicity,
whereas 2-AG suppresses synaptic transmission, resolves neuroinflam-
mation, and protects neurons from harmful insults, suggesting that the
effects of COX-2 metabolites of 2-AG are opposite to that of 2-AG (Chen,
Zhang, & Chen, 2011; Lindgren et al., 2013; Sang & Chen, 2006; Sang,
Zhang, & Chen, 2006, 2007; Zhang & Chen, 2008). Currently available
information indicates that different COX-2 metabolites of 2-AG may
display distinct effects on inflammatory responses (Alhouayek,
Masquelier, Cani, Lambert, & Muccioli, 2013; Alhouayek & Muccioli,
2014; Hu, Bradshaw, Chen, Tan, & Walker, 2008; Kingsley et al., 2019).
Therefore, COX-2 plays unique roles not only in catalyzing AA to
form PGs, but also in oxidatively metabolizing 2-AG to PG-Gs
(Alhouayek & Muccioli, 2014; Baggelaar et al., 2018; Guindon &
Hohmann, 2008; Sang & Chen, 2006). In addition, carboxylesterases
have been reported to hydrolyze 2-AG in peripheral tissues, includ-
ing lung, spleen, and macrophages (Szafran, Borazjani, Lee, Ross, &
Kaplan, 2015; Szafran et al., 2022; Xie et al., 2010). However, there
are not reports about 2-AG hydrolysis by carboxylesterases in the
brain.
Arachidonic acid is the immediate metabolite of 2-AG hydrolyzed by
MAGL, ABHD6 or ABHD12 and is a precursor of prostaglandins (PGs)
and leukotrienes (Fig. 5). AA is an important lipid mediator that partic-
ipates in numerous biological events through conversion to PGs,
hydroperoxyeicosatetraenoic acids (HPETEs), hydroxyeicosatetraenes
(HETEs), leukotrienes, lipoxins, and epoxyeicosatrienoic acids (EETs)
catalyzed by COX-1/2, lipoxygenases (LOX), and cytochrome P450 oxi-
dases (CYP), respectively (Fig. 5). Certain metabolites of AA (e.g., PGE2
and LTB4) are proinflammatory mediators (Henderson Jr., 1994;
Ricciotti & FitzGerald, 2011; Salmon & Higgs, 1987; Xu & Chen, 2015;
Yao & Narumiya, 2019). It has been long thought that AA is primarily de-
rived from membrane phospholipids through phospholipase A2 (PLA2)/
PLC pathways. However, it has been shown that 2-AG hydrolysis-
delivered AA contributes a significant proportion to the AA pool
(Nomura et al., 2011), suggesting that control of 2-AG metabolism by
manipulation of the various enzymes that degrade 2-AG will have a sig-
nificant impact on AA-mediated signaling cascades in physiology and
diseases (Alhouayek et al., 2014; Baggelaar et al., 2018; Grabner,
Zimmermann, Schicho, & Taschler, 2017).

5
C. Chen Pharmacology & Therapeutics 244 (2023) 108394

Fig. 5. Biosynthesis and metabolism of 2-arachidonoylglycerol (2-AG). 2-AG is generated from membrane phospholipids (e.g., phosphatidylinositol and phosphatidylinositol 4,5-
bisphosphate) through phospholipase C-β (PLCβ) to diacylglycerols (DAG). DAG is then converted to 2-AG by two isoforms of diacylglycerol lipase α and diacylglycerol lipase β
(DAGLα/β). 2-AG is primarily degraded by monoacylglycerol lipase (MAGL) as well as by α/β-hydrolase domain containing 6 and 12 (ABHD6/12) to arachidonic acid (AA). 2-AG is
also oxidatively converted by cyclooxygenase-2 (COX-2) to prostaglandin glycerols (PG-Gs). AA is further metabolized by COX-1/2 to prostaglandins (PGs) and by lipoxygenase (LOX)
to hydroperoxyeicosatetraenoic acids (HPETEs), hydroxyeicosatetraenes (HETEs), and leukotrienes (LT4s). AA is also catalyzed by cytochrome P450 oxidases (CYP) to HETEs or
epoxyeicosatrienoic acids (EETs).

3. 2-AG signaling in resolving neuroinflammation and protecting
neurons
The earliest evidence that 2-AG acts to resolve neuroinflammation
and protect neurons comes from the studies of Mechoulam and
Shohami in which animals received a traumatic brain injury (TBI), spe-
cifically a closed head injury (Panikashvili et al., 2001). The authors ob-
served that TBI induces release of 2-AG in the brain and that direct
administration of synthetic 2-AG significantly reduces TBI-induced
edema and cell death. The protective effects appear to be mediated by
G protein-coupled CB1R as the beneficial effects of 2-AG are attenuated
by SR141716 (rimonabant), a potent and selective antagonist of CB1R,
or by genetic deletion of CB1R (Panikashvili et al., 2001; Panikashvili
et al., 2005). They provided further evidence that 2-AG-produced neu-
roprotection in TBI is a consequence of CB1R-mediated inhibition of nu-
clear factor kappa B (NF-κB), which results in inhibition of transcription
and expression of cytokines, including tumor necrosis factor α (TNFα),
interleukin-1β (IL-1β), and IL-6 (Mechoulam, Spatz, & Shohami, 2002;
Panikashvili et al., 2001; Panikashvili et al., 2005; Panikashvili et al.,
2006; Shohami, Cohen-Yeshurun, Magid, Algali, & Mechoulam, 2011).
Neuroinflammation is one of the early neurochemical responses after
TBI (Jassam, Izzy, Whalen, McGavern, & El Khoury, 2017). The neuropro-
tective effects of 2-AG are largely associated with suppression of neuro-
inflammatory responses following TBI, suggesting that 2-AG is an
endogenous terminator of inflammation in response to harmful insults
that elicit inflammatory responses (Chen, 2023). This assumption has
been supported by several studies. For example, 2-AG produces a
dose-dependent suppression of proinflammatory factor lipopolysaccha-
ride (LPS)- or excitotoxic kainic acid-induced COX-2 expression and
prevents IL-1β- or glutamate-induced neurodegeneration. These effects
are mediated through CB1R-dependnet inhibition of mitogen-activated
protein kinase (MAPK)/NF-κB signaling (Zhang & Chen, 2008). Appar-
ently, 2-AG inhibition of COX-2 is primarily restricted to glial cells. How-
ever, synthetic cannabinoids CP-55940 and Win55,212-2 failed to
prevent LPS-induced elevation of COX-2 in vitro (Zhang & Chen,
2008). In addition, LPS-induced COX-2 is reduced by enhancement of
endogenous 2-AG by URB602, a MAGL inhibitor but not by URB597,
an inhibitor of fatty acid amide hydrolase (FAAH), which hydrolyzes
AEA. These results suggest that 2-AG functions as an endogenous inhib-
itor of COX-2, which protects neurons from harmful insults, as elevated
COX-2 is a key player and also an important indicator in many
neuroinflammation-associated neurodegenerative diseases, including
Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease
(PD), and TBI-induced neurodegenerative disease (Ferrer et al., 2019;
Hoozemans & O'Banion, 2005; Hurley, Olschowka, & O'Banion, 2002;
Minghetti, 2004; Teismann et al., 2003; Turini & DuBois, 2002; Vane
et al., 1998). Consistent with the studies described above, other studies
also found that direct application of synthetic 2-AG or blockade of

6
C. Chen
endogenous 2-AG degradation by MAGL inhibitors URB602 or JZL184
attenuate β-amyloid (Aβ)-induced neuronal apoptosis and degenera-
tion via CB1R-mediated suppression of extracellular signal-regulated ki-
nases 1 and 2 (ERK1/2), NF-κB, and COX-2 in cultured hippocampal
neurons (X. Chen et al., 2011). Other studies also found similar neuro-
protective effects of 2-AG in caudate nucleus (CN) neurons against LPS
stimulus by CB1R-dependent suppression of MAPK-NF-κB and COX-2
(Y. Lu, Peng, Dong, & Yang, 2014). The Chen group provided further ev-
idence that peroxisome proliferator-activated receptor gamma γ
(PPARγ) is a downstream signaling molecule of CB1R in mediating 2-
AG-induced suppression of LPS- or cytokine-induced increases in syn-
aptic release of glutamate, expression of COX-2, and phosphorylation
of NF-κB (Du et al., 2011). They observed that exogenous or endogenous
2-AG-induced suppression of these changes in response to LPS or IL-1β
stimulus is blocked by GW9662, a PPARγ antagonist, whereas 15-
deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2), an endogenous PPARγ
agonist, or rosiglitazone, a synthetic PPARγ agonist mimics the effects
of 2-AG-induced suppression of synaptic release of glutamate, expres-
sion of COX-2, and phosphorylation of NF-κB (Du et al., 2011). Using a
PPARγ luciferase assay and immunoblot analysis, it was found that 2-
AG is capable of activating PPARγ and increasing expression of PPARγ,
suggesting that 2-AG is an endogenous PPARγ agonist (Du et al., 2011;
Hu et al., 2022; Zhang et al., 2014). It was also observed that direct ad-
ministration of 2-AG delays disease onset, reduces axonal pathology,
and reduces mortality in experimental autoimmune encephalomyelitis
(EAE), a widely used model of MS. This effect is likely associated with
activation of cannabinoid receptors (Lourbopoulos et al., 2011). How-
ever, other studies showed that inhibition of LPS-stimulated expression
and release of TNFα in microglial cells by 2-AG are independent of CB1R
or CB2R (Facchinetti, Del Giudice, Furegato, Passarotto, & Leon, 2003). In
addition, there are studies showing that 2-AG-induced suppression of
IL-2 in T-cells is independent of CB1R or CB2R but dependent on
PPARγ (Rockwell, Snider, Thompson, Vanden Heuvel, & Kaminski,
2006). These findings suggest that resolving inflammation by 2-AG
may involve CB1R/2R-dependent and independent mechanisms and
that PPARγ is a downstream signaling mediator of CB1R/2R in 2-AG-
produced anti-inflammatory and neuroprotective effects (Chen, 2023;
Chen et al., 2012; Du et al., 2011; Hu et al., 2022; Xu & Chen, 2015;
Zhang et al., 2014).
Several previous studies revealed that 2-AG, but not AEA, is re-
leased in the brain following TBI, infusion of Aβ, or by high frequency
stimulation that induces long-term potentiation (LTP) in brain slices
(Panikashvili et al., 2001; Stella et al., 1997; van der Stelt et al.,
2006). Correspondingly, exogenous administration of 2-AG or aug-
mentation of 2-AG levels by inactivation of MAGL to prevent 2-AG
breakdown attenuates TBI-induced neuroinflammation and neuropa-
thology (Hu et al., 2022; Katz et al., 2015; Panikashvili et al., 2001; Piro
et al., 2018; Zhang, Teng, Song, Hu, & Chen, 2015), suggesting that re-
lease of 2-AG is an endogenous defense mechanism to increase resil-
ience of the brain in response to injury, infection, or other stimuli,
thereby maintaining brain homeostasis. Thus, it is likely that 2-AG
maintains brain homeostatic conditions primarily through modulat-
ing synaptic transmission and plasticity, resolving neuroinflamma-
tion, and protecting neurons from harmful insults (Chen, 2015,
2023; Mulvihill & Nomura, 2013; Xu & Chen, 2015).
4. MAGL in neurodegenerative diseases
MAGL was originally purified from adipose tissues and recog-
nized as the rate-limiting enzyme involved in the last step of hydro-
lyzing triacylglycerol to fatty acid and glycerol in white adipose
tissue (Fredrikson, Tornqvist, & Belfrage, 1986; Tornqvist &
Belfrage, 1976; Zechner, Kienesberger, Haemmerle, Zimmermann,
& Lass, 2009). Triacylglycerol is first cleaved by adipose triglyceride
lipase (ATGL) to yield diacylglycerols (DAGs), which are then con-
verted by hormone-sensitive lipase (HSL) into monoacylglycerols.
7
Pharmacology & Therapeutics 244 (2023) 108394
Finally, monoacylglycerols are hydrolyzed by MAGL to fatty acid
and glycerol. MAGL was cloned in 1997 (Karlsson et al., 2001;
Karlsson, Contreras, Hellman, Tornqvist, & Holm, 1997). It has a mo-
lecular weight of 33 kDa and is expressed in cytoplasm and plasma
membrane of many tissues and cells and in lipid droplets (Gulyas
et al., 2004; Zechner et al., 2009). Importantly, MAGL is not only an
intracellular α/β serine hydrolase that hydrolyzes monoacylglycerol
but is also the main enzyme that degrades 2-AG in the brain
(Blankman et al., 2007; Dinh, Carpenter, et al., 2002; Dinh, Freund,
& Piomelli, 2002; Long & Cravatt, 2011; Long, Nomura, & Cravatt,
2009; Nomura et al., 2011; Scalvini et al., 2016; Schlosburg et al.,
2010). MAGL is highly expressed in the brain, particularly, in presyn-
aptic nerve terminals, suggesting that MAGL plays an important role
in terminating 2-AG signaling to precisely modulate or tune synaptic
activity (Dinh, Freund, & Piomelli, 2002; Ludányi et al., 2011). Use of
pharmacological and genetic approaches to manipulate MAGL activ-
ity have provided significant insights into 2-AG metabolism in phys-
iology and disease.
While ‘on demand’ synthesis and release of 2-AG are important for
brain homeostasis, 2-AG is rapidly degraded by several enzymes, in-
cluding MAGL, ABHD6/12, or COX-2 upon its formation. Higher levels
of 2-AG can be maintained in the brain by increasing 2-AG synthesis
by increasing DAGLα/β activity or by reducing degradation. However,
increasing 2-AG levels by enhancing its synthesis may accelerate me-
tabolism of 2-AG and release of AA, resulting in elevation of metabolites
of AA. This approach may not achieve ideal beneficial effects as desired
since certain types of AA metabolites such as prostaglandins (i.e., PGE2)
and leukotrienes (LTB4) are proinflammatory mediators and neurotoxic
(Hein & O'Banion, 2009; Henderson Jr., 1994; Ricciotti & FitzGerald,
2011; Salmon & Higgs, 1987; Xu & Chen, 2015; Yao & Narumiya,
2019). Because 2-AG in the brain is predominantly metabolized by
MAGL (Blankman et al., 2007; Long, Nomura, & Cravatt, 2009; Nomura
et al., 2011), inactivation of MAGL would produce “a dual hit,” which
would augment anti-inflammatory and neuroprotective 2-AG signaling,
and concurrently reduce proinflammatory and neurotoxic eicosanoids
(Chen, 2023; Hu et al., 2022). In addition, prolonged inactivation of
MAGL with pharmacological inhibitors or genetic knockout of MAGL
has been shown to enhance LTP and spatial learning and memory
(Lysenko et al., 2014; Pan et al., 2011; Zhang et al., 2015). Studies
using pharmacological or genetic inactivation of MAGL to inhibit 2-AG
metabolism in experimental animal models have provided evidence
suggesting that MAGL is a promising therapeutic target for neurodegen-
erative diseases (Chen, 2016, 2022; Chen et al., 2012; Gil-Ordonez,
Martin-Fontecha, Ortega-Gutierrez, & Lopez-Rodriguez, 2018; Grabner
et al., 2017; Mulvihill & Nomura, 2013; Wenzel & Klegeris, 2018; Xu &
Chen, 2015; Zanfirescu, Ungurianu, Mihai, Radulescu, & Nitulescu,
2021; Zhu, Gao, & Chen, 2021).
4.1. Alzheimer’s disease
Alzheimer’s disease (AD) is the most common cause of dementia
in the elderly. It is a neurodegenerative disease characterized by
accumulation and deposition of extracellular Aβ plaques and intra-
cellular hyperphosphorylated tau proteins that form neurofibrillary
tangles, sustained neuroinflammation, synaptic malfunction, pro-
gressive deterioration of cognitive function, and loss of memory in
association with widespread neuronal death. No effective therapies
are currently available for preventing or treating AD or delaying pro-
gression of the disease. This lack is largely attributed to our limited
understanding of the mechanisms underlying development of AD.
While the etiology of AD is multifactorial and complex and is linked
to multiple mechanisms and signaling pathways, it is generally ac-
cepted that chronic inflammation as a root cause significantly con-
tributes to pathogenesis of AD (Akiyama et al., 2000; Heneka et al.,
2015; Kwon & Koh, 2020). Since 2-AG displays profound anti-
inflammatory and neuroprotective properties and its hydrolytic
C. Chen
metabolites are proinflammatory and neurotoxic (X. Chen et al.,
2011; Du et al., 2011; Henderson Jr., 1994; Mulvihill & Nomura,
2013; Panikashvili et al., 2006; Panikashvili et al., 2001; Ricciotti &
FitzGerald, 2011; Salmon & Higgs, 1987; Yao & Narumiya, 2019;
Zhang & Chen, 2008; Zhang et al., 2014), investigators have asked
whether inhibition of 2-AG degradation by inactivation of MAGL
would prevent or modify AD neuropathology in experimental animal
models of AD. Systemic administration of JZL184, a potent and irre-
versible MAGL inhibitor (Long et al., 2009; Long, Nomura, &
Cravatt, 2009), resulted in of 6 to 7-fold increases in 2-AG levels in
the brain, while AA and PGE 2 were reduced by roughly 75% and
50%, respectively in 5xFAD mice (Chen et al., 2012), a widely used
animal model of AD (Oakley et al., 2006). Of significance, production
and accumulation of total Aβ and Aβ42 peptides and expression of β-
site amyloid precursor protein cleaving enzyme 1 (BACE1), a key en-
zyme responsible for synthesis of Aβ, were significantly reduced in
5xFAD mice (Chen et al., 2012). Chronic inhibition of MAGL also de-
creases reactivity of astrocytes and microglia and reduces the num-
ber of degenerating neurons. Importantly, AD mice treated with
JZL184 display improved long-term synaptic plasticity in terms of
long-term potentiation (LTP), spatial learning and memory. These
synaptic and cognitive protective effects of MAGL inhibition are
likely associated with the rescue of the reduced expression of gluta-
mate receptor subunits and density of dendritic spines (Chen et al.,
2012). At the same time, another group observed similar anti-
inflammation and neuroprotective effects following genetic deletion
of mgll (the gene encoding MAGL) in PS1/APP+ mice. Genetic inacti-
vation of mgll reduces total Aβ, Aβ40 and Aβ42, cytokine production,
including IL-1β, IL-6, and TNFα, and expression of astrocyte and mi-
croglia markers (Piro et al., 2012). These beneficial effects are similar
to those of pharmacological inactivation of MAGL (Chen et al., 2012).
Several other studies also provided evidence that pharmacological
inactivation of MAGL reduces neuroinflammation and Aβ and im-
proves learning and memory in APP TG mice (Pihlaja et al., 2015;
Zhang et al., 2014; Zhang & Chen, 2018). Since accumulation and de-
position of extracellular Aβ plaques are one of the neuropathological
hallmarks in AD, the early studies were primarily focused on resolu-
tion of neuroinflammation and reduction of amyloidosis by inactiva-
tion of MAGL in animal models of Aβ pathology (Chen et al., 2012;
Pihlaja et al., 2015; Piro et al., 2012; Zhang & Chen, 2018; Zhang
et al., 2014). However, intracellular accumulation of neurofibrillary
tangles consisting primarily of hyperphosphorylated tau (p-tau)
proteins is another important neuropathological hallmark of AD.
Using the P301S/PS19 mice, a widely used tau mouse model of AD
(Yoshiyama et al., 2007), a recent study provided evidence that phar-
macological inactivation of MAGL also mitigates neuroinflammation,
including reduced expression of cytokines, reduced reactivity of as-
trocytes and microglia, and reduced phosphorylated NF-κB. These ef-
fects might lead to decreases in tauopathies, including decreases in
phosphorylated GSK3β, p-tau Thr181, and p-tau Ser202/Thr205
(AT8) (Hashem, Hu, Zhang, Gao, & Chen, 2021). Importantly, inacti-
vation of MAGL reduces cell apoptosis and prevents losses in expres-
sion of synaptic proteins, including PSD-95 and glutamate receptor
subunits, and prevents deterioration in cognitive function in PS19
tau TG mice (Hashem et al., 2021). Alleviation of both Aβ and tau pa-
thologies in APP and tau mouse models of AD by inactivation of
MAGL suggests that MAGL is a promising therapeutic target for AD
(Chen, 2022; Chen et al., 2012; Gil-Ordonez et al., 2018; Grabner
et al., 2017; Hashem et al., 2021; Mulvihill & Nomura, 2013; Zhang
et al., 2014).
Other studies also provide evidence to support MAGL as a therapeu-
tic target for AD. Immunoblot analysis shows that expression of MAGL
in the post-mortem hippocampus from patients with AD is significantly
elevated and the expression level exhibits a positive correlation with
the Braak stage, which represents AD progression (Mulder et al.,
2011), suggesting that 2-AG degradation is escalated in the brain of
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Pharmacology & Therapeutics 244 (2023) 108394
patients with AD at advanced stages. However, 2-AG signaling and the
levels of DAGLα, which synthesizes 2-AG, are increased in the vicinity
of Aβ plaques in the brains of AD patients (Mulder et al., 2011). This
might be a homeostatic defense mechanism as infusion of Aβ into the
brain or brain trauma has been observed to trigger release of 2-AG,
which might protect the brain from injury and insults (Panikashvili
et al., 2001; van der Stelt et al., 2006). Elevated expression or activity
of MAGL in the hippocampus of patients with AD and of animal models
of AD has also been reported and elevation of MAGL proceeds in an age-
dependent manner (Farooqui, Liss, & Horrocks, 1988; Syal et al., 2020).
Given the role of MAGL in degradation of 2-AG, the observation of in-
creased expression of MAGL in aging and AD suggests that 2-AG degra-
dation in the brain is also increased in aging and AD as MAGL is the main
enzyme hydrolyzing 2-AG (Blankman et al., 2007; Dinh, Carpenter,
et al., 2002; Dinh, Freund, & Piomelli, 2002; Long, Nomura, & Cravatt,
2009; Nomura et al., 2011). This remains speculative, however, due to
the difficulty in obtaining brain tissues or cerebrospinal fluid from pa-
tients with AD for analysis. The levels of plasma 2-AG in patients with
AD have been reported previously, but the results are inconsistent.
One study showed increased plasma levels of 2-AG, and one did not
(Altamura et al., 2015; Koppel et al., 2009). Studies that assessed brain
2-AG in AD animals also arrived at conflicting results. Brain 2-AG levels
were not altered in 5xFAD TG mice (Vázquez et al., 2015), but in the
AβPPswe/PS1ΔE9 mouse model of AD, there are no differences in 2-
AG levels in the hippocampus and frontal cortex between WT and APP
TG mice. However, 2-AG was significantly reduced in the striatum of
8-month-old mice (Maroof, Ravipati, Pardon, Barrett, & Kendall,
2014). Another study provided evidence that there is an age-related de-
cline in 2-AG but not AEA in the hippocampus of CD1 and C57BL/6
(Piyanova et al., 2015). Thus, the status of 2-AG in the brains of patients
with AD and animal models of AD remain uncertain.
4.2. Parkinson’s disease
Parkinson’s disease (PD) is another devastating neurodegenerative
disease resulting from loss of neurons that produce dopamine in the
substantia nigra. Neuroinflammation and immune dysfunctions are
well recognized as prominent features in PD (Tansey et al., 2022).
While only a few studies involving MAGL in PD have been reported,
these studies provide clear evidence that limiting 2-AG degradation by
inactivation of MAGL is neuroprotective in animal models of PD. Using
the 1-methyl-4-phenyl-tetrahydropyridine (MPTP) mouse model of
PD, it was found that pharmacological or genetic inactivation of MAGL
reduces MPTP-induced dopaminergic neurodegeneration and elevates
dopamine levels in the striatum and substantia nigra (Nomura et al.,
2011). Chronic treatment with MAGL inhibitor JZL184 prevents MPTP-
induced motor impairment and preserves the nigrostriatal pathway
(Fernández-Suárez et al., 2014). Increasing levels of 2-AG by direct ad-
ministration of exogenous 2-AG or by pharmacological inactivation of
MAGL to restrain endogenous 2-AG degradation provide neuroprotec-
tion against MPTP-induced cell death (Mounsey et al., 2015). In addition,
pharmacological inhibition of MAGL, but not of FAAH, attenuates MPTP-
induced effects on striatal dopamine levels, which is accompanied by an
increase in 2-AG levels (Pasquarelli et al., 2017). The neuroprotective ef-
fects of MAGL inactivation are likely associated with neuroprotective and
anti-inflammatory factors released from astrocytes and microglial cells,
and CB1R and CB2R in astrocytes and microglial cells may be involved
in mediating these effects (Bernal-Chico et al., 2023; Fernández-Suárez
et al., 2014). The results from these studies suggest that modulation of
2-AG levels by manipulation of MAGL may provide an approach for pre-
vention and treatment of this movement disorder.
4.3. Traumatic brain injury
TBI is a temporary or permanent disruption of brain function caused
by external forces. TBI has been recognized as an important risk factor
C. Chen
for development of AD and dementia later in life (Dams-O'Connor,
Guetta, Hahn-Ketter, & Fedor, 2016; Fleminger, Oliver, Lovestone,
Rabe-Hesketh, & Giora, 2003; Graves et al., 1990; Johnson, Stewart, &
Smith, 2010; Mortimer, French, Hutton, & Schuman, 1985; Zhu et al.,
2021). Single severe or repeated TBI may induce chronic traumatic en-
cephalopathy (CTE), a long-term progressive AD-like neurodegenera-
tive disease, which includes hyperphosphorylated tau, aggregation
and translocation of transactive response DNA binding protein 43
(TDP-43), persistent neuroinflammation, neurodegeneration, and syn-
aptic and cognitive declines (Al-Dahhak, Khoury, Qazi, & Grossberg,
2018; Blennow, Hardy, & Zetterberg, 2012; DeKosky, Blennow,
Ikonomovic, & Gandy, 2013; Gao, Hu, Zhang, Hashem, & Chen, 2022;
Li, Liang, & Fu, 2021; McKee et al., 2013; Turner, Lucke-Wold, Robson,
Lee, & Bailes, 2016; Wu et al., 2021). However, no effective therapies
are currently available for prevention or treatment of TBI-induced neu-
rodegenerative disease. The acute brain damage after TBI results not
only from the primary injury, which is the result of an external mechan-
ical force, but also from the secondary injury associated with a complex
cascade of molecular, cellular and immune responses (Zhu et al., 2021).
Neuroinflammation plays a critical role in causing secondary brain in-
jury following TBI (Simon et al., 2017). The extent of the neuroinflam-
matory response is closely correlated with the outcome following TBI
(Woodcock & Morganti-Kossmann, 2013). The implication of this is
that while the primary injury from TBI may not be preventable, appro-
priate and timely intervention to resolve neuroinflammation following
the primary injury would be key to preventing further brain damage,
neuropathological changes, and synaptic and cognitive declines (Xu &
Chen, 2015; Zhang, Teng, et al., 2015; Zhu et al., 2021). Because of the
profound anti-inflammatory and neuroprotective property of 2-AG, a
boost of endogenous 2-AG or administration of exogenous 2-AG
would likely ameliorate TBI-induced neuroinflammation. Indeed, early
studies showed that application of synthetic 2-AG produces CB1R-
dependent maintenance of the integrity of the blood-brain barrier
(BBB), reduction of proinflammatory cytokines, and suppression of
NF-κB activation, providing neuroprotection against CHI (Panikashvili
et al., 2001; Panikashvili et al., 2005; Panikashvili et al., 2006). These
studies provided evidence that 2-AG signaling plays an important role
in protecting the brain from trauma by resolving TBI-induced neuroin-
flammation (Mechoulam et al., 2002; Shohami et al., 2011).
As 2-AG is subject to rapid degradation, a good strategy to enhance
2-AG signaling is to inhibit its degradation. It has been shown that a sin-
gle injection of JZL184 following TBI in rats improves neurological and
behavioral functions and protects the integrity of BBB assessed 24
hours after lateral fluid percussion (Katz et al., 2015). In a mouse
model of repeated mild CHI, it was found that multiple injections of
JZL184 following the impact promoted neurologic recovery, reduced ex-
pression of proinflammatory cytokines, and reduced the reactivity of
astroglial cells (Zhang, Teng, et al., 2015). Importantly, pharmacological
inactivation of MAGL significantly suppressed TBI-induced increases in
expression of BACE1, neurodegeneration, aberrant production of TDP-
43 protein, and phosphorylated tau. Inhibition of 2-AG degradation
also prevents TBI-induced decreases in expression of glutamate recep-
tor subunits and reduces impairments in basal synaptic transmission,
long-term synaptic plasticity, and spatial learning and memory in ani-
mals exposed to repeated mild CHI (Zhang, Teng, et al., 2015). These
studies provide evidence that pharmacological inactivation of MAGL
produces neuroprotection against TBI-induced neuroinflammation, dis-
ruption of BBB integrity, neuropathology, and synaptic and cognitive
impairments (Katz et al., 2015; Xu & Chen, 2015; Zhang, Teng, et al.,
2015; Zhu et al., 2021). Several recent studies provide further evidence
that pharmacological modulation of 2-AG metabolism by different
MAGL inhibitors ameliorates TBI-induced neuronal and synaptic alter-
ations, production of inflammatory cytokines, reactivity of astrocytes
and microglia, glutamate dyshomeostasis, and impairments in spatial
learning and memory (Fucich et al., 2020; Mayeux, Katz, Edwards,
Middleton, & Molina, 2017; Selvaraj, Tanaka, Wen, & Zhang, 2021).
9
Pharmacology & Therapeutics 244 (2023) 108394
These neuroprotective effects produced by MAGL inhibitors likely result
from enhanced 2-AG signaling and concurrently decreased eicosanoid
levels, suggesting that control of 2-AG degradation by MAGL is an im-
portant mechanism in maintaining brain homeostasis and in terminat-
ing neuroinflammation that occurs in TBI.
Pharmacological inactivation of MAGL resolves neuroinflammation,
reduces neuropathology, and improves synaptic and cognitive functions
in TBI. However, it remained unclear whether genetic inactivation of
MAGL would produce neuroprotective effects similar to those of phar-
macological inhibition. A recent study by Hu and colleagues has filled
this gap (Hu et al., 2022). In their study, an mgllflox/flox knockout (KO)
mouse model was used to generate total (tKO), neuronal (nKO), and as-
trocytic (aKO) MAGL KO mice. In wild-type (WT) mice, repeated mild
CHI resulted in chronic neuroinflammation, excessive production of
TDP-43 and phosphorylated tau, neurodegeneration, deterioration in
expression of synaptic proteins, and impairments in LTP and cognitive
function. These TBI-induced changes were diminished in tKO and aKO
mice. However, inactivation of MAGL in neurons did not produce
these neuroprotective effects (Hu et al., 2022). These findings suggest
that previously observed neuroprotective effects produced by pharma-
cological inactivation of MAGL in TBI result largely from restraining 2-
AG degradation in astrocytes, rather than in neurons (Chen, 2023;
Fucich et al., 2020; Hu et al., 2022; Katz et al., 2015; Mayeux et al.,
2017; Selvaraj et al., 2021; Zhang, Teng, et al., 2015). Moreover, the au-
thors observed that expression of MAGL in astrocytes was significantly
increased in hippocampal astrocytes following TBI, suggesting that 2-
AG degradation was likely increased, promoting neuroinflammation
and neuropathology (Hu et al., 2022).
4.4. Multiple sclerosis
Multiple sclerosis (MS) is an incurable, chronic inflammatory disor-
der of the central nervous system. It is traditionally considered to be an
autoimmune demyelinating disease. A 2020 study estimated that more
than 2.8 million people are living with MS worldwide (Walton et al.,
2020). In consideration of the anti-inflammatory properties of 2-AG,
several studies have been conducted to assess the effect of inactivation
of MAGL on MS (Brindisi et al., 2016; Chiurchiù, van der Stelt, Centonze,
& Maccarrone, 2018; Punt, van der Vliet, & van der Stelt, 2022; van
Egmond, Straub, & van der Stelt, 2021). It was found that administration
of JZL184 under a therapeutic regimen decreased clinical severity,
prevented demyelination, and reduced inflammation in chronic exper-
imental autoimmune encephalomyelitis (Bernal-Chico et al., 2015). In
addition, MAGL inactivation also robustly preserved myelin integrity
and suppressed microglial activation in the cuprizone-induced model
of T-cell-independent demyelination (Bernal-Chico et al., 2015). Inacti-
vation of MAGL with different inhibitors also reduces neuroinflamma-
tion, decreases chondroitin sulfate proteoglycan deposition around
demyelinated lesions in the spinal cord of Theiler's murine encephalo-
myelitis virus-infected mice, and ameliorates the clinical progression
in a MS mouse model (Feliú et al., 2017; Hernández-Torres et al.,
2014). The protective effects of MAGL inactivation are apparently asso-
ciated with increased 2-AG tone, which promotes remyelination to
ameliorate motor dysfunction in a model of progressive multiple sclero-
sis. These studies provide evidence that modulation of 2-AG signaling by
inactivating MAGL attenuates symptoms and promotes remyelination
in experimental models of MS, providing evidence supporting MAGL
as a target for treatment of MS.
4.5. Other brain disorders
Inactivation of MAGL is beneficial for other neurodegenerative dis-
eases (e.g., amyotrophic lateral sclerosis), and other neurological or neu-
ropsychiatric disorders, including seizure/epilepsy and mental
disorders (Bedse, Hill, & Patel, 2020; Colangeli et al., 2023; Naidoo
et al., 2012; Pan et al., 2011; Pasquarelli et al., 2017; Ratano et al.,
C. Chen
2018; Shonesy et al., 2014; Silveira, Wegener, & Joca, 2021; Terrone
et al., 2018; Vickstrom et al., 2021; von Ruden, Bogdanovic, Wotjak, &
Potschka, 2015; Zhang, Wang, et al., 2015; Zhong et al., 2014), which
are not discussed here.
5. Signaling pathways mediating neuroprotection following
inactivation of MAGL
As 2-AG displays profound anti-inflammatory and neuroprotective
properties, it is reasonable to ask whether augmentation of 2-AG signal-
ing by inactivating MAGL would resolve inflammatory responses,
thereby preventing or treating some brain disorders. Not surprisingly,
MAGL has been proposed as a therapeutic target for treating neurode-
generative diseases (Baggelaar et al., 2018; Bajaj, Jain, Vyas, Bawa, &
Vohora, 2021; Chen, 2022; Chen et al., 2012; Gil-Ordonez et al., 2018;
Hashem et al., 2021; M. Hu et al., 2022; Mulvihill & Nomura, 2013;
Nomura et al., 2011; Piro et al., 2012; Ren, Wang, Zhang, & Chen,
2020; Xu & Chen, 2015; Zhang & Chen, 2018; Zhang et al., 2014;
Zhang, Teng, et al., 2015; Zhu et al., 2021). However, the molecular
mechanisms underlying the neuroprotective effects of MAGL inactiva-
tion in neurodegenerative diseases remain to be defined. Inflammation
has been recognized as a common mechanism of disease (Chen, 2010),
and neuroinflammation is a known root cause of neurodegenerative
diseases (Heneka et al., 2015; McGeer, Rogers, & McGeer, 2016;
Ransohoff, 2016). Therefore, strategies to resolve neuroinflammation
represent promising avenues toward preventing development of neu-
rodegenerative diseases. Because 2-AG displays anti-inflammatory and
neuroprotective properties (Chen, 2015, 2023; Du et al., 2011;
Panikashvili et al., 2005; Panikashvili et al., 2006; Panikashvili et al.,
2001; Song et al., 2015; Sugiura et al., 2006; Zhang & Chen, 2008;
Zhang et al., 2014), but its metabolites (e.g., PGE2 and LTB4) are
proinflammatory and neurotoxic and contribute to neurodegenerative
diseases (Hein & O'Banion, 2009; Henderson Jr., 1994; Ricciotti &
FitzGerald, 2011; Salmon & Higgs, 1987; Xu & Chen, 2015; Yao &
Narumiya, 2019), inactivation of MAGL may provide the means to pro-
duce anti-inflammatory and neuroprotective effects through multiple
signaling pathways in neurodegenerative diseases based on the proper-
ties of its substrate 2-AG and the proinflammatory and neurotoxic prop-
erties of 2-AG hydrolytic metabolites.
Early studies showed that 2-AG functions as an endogenous neuro-
protective mediator against brain trauma by a CB1R-dependent mecha-
nism of resolution of inflammatory responses and by maintenance of
BBB integrity. It was shown that neuroprotective effects mediated by
2-AG were attenuated by a selective CB1R antagonist or by genetic de-
letion of CB1R (Panikashvili et al., 2001; Panikashvili et al., 2005;
Panikashvili et al., 2006). The CB1R-mediated anti-inflammatory and
neuroprotective effects in TBI have been confirmed by a recent study
in which pharmacological inactivation of MAGL in CB1R knockout
mice failed to produce neuroprotection in TBI (Hu et al., 2022). These
studies provide evidence that 2-AG- or MAGL inactivation-induced neu-
roprotection in TBI is mediated via CB1R. However, alleviation of neuro-
inflammation in an LPS-induced animal model of inflammation and
neuronal loss in an MPTP-induced animal model of PD by pharmacolog-
ical or genetic inactivation of MAGL appeared to not involve 2-AG sig-
naling to activate CB1R or CB2R; instead, these effects were mediated
through prostaglandin signaling as a result of decreases in AA and PGs
(Nomura et al., 2011). Consistent with these observations, anti-
inflammatory and neuroprotective effects by pharmacological or ge-
netic inactivation of MAGL in animal models of AD are also not mediated
via CB1R nor via CB2R (Chen et al., 2012; Piro et al., 2012; Zhang & Chen,
2018). There are reports that restorative astroglia and microglia activa-
tion and the release of neuroprotective and anti-inflammatory mole-
cules may contribute to MAGL inactivation-produced neuroprotection
in PD animals (Fernández-Suárez et al., 2014). In an animal model of
MS, MAGL inactivation-induced protection of oligodendrocytes was as-
sociated with activation of CB1R (Bernal-Chico et al., 2015). It appears
10
Pharmacology & Therapeutics 244 (2023) 108394
from these studies that the signaling pathways that mediate MAGL
inactivation-induced neuroprotective effects are complex, and the sig-
naling pathways involved in the protective events likely depend on
the disease context (e.g., AD versus TBI).
Peroxisome proliferator-activated receptor-γ (PPARγ), a member of
nuclear receptors, displays anti-inflammatory and neuroprotective ef-
fects through interaction with NF-κB, resulting in reductions in tran-
scription and expression of genes involved in inflammation and
neurodegeneration (Bensinger & Tontonoz, 2008; Bright, Kanakasabai,
Chearwae, & Chakraborty, 2008; Heneka et al., 2005; Khan et al., 2019;
Villapol, 2018). Earlier studies showed that PPARγ is a target of canna-
binoids via CB1R- or CB2R-dependent and -independent pathways
(O'Sullivan, 2007, 2016). It has been shown that 2-AG suppression of
IL-1 in Jurkat T cells is not mediated via CB1R or CB2R but via activation
of PPARγ (Rockwell et al., 2006). Du et al., reported that PPARγ is a tar-
get of 2-AG in resolving neuroinflammation and neuroprotection
(Du et al., 2011). Administration of 2-AG or MAGL inhibitors reduces
LPS- or cytokine-induced increases in expression of COX-2, phosphory-
lated NF-κB, and excitatory synaptic transmission in cultured hippo-
campal neurons, and these effects are blocked by a CB1R antagonist or
PPARγ antagonist but mimicked by 15d-PGJ2, an endogenous PPARγ
agonist (Du et al., 2011). The authors also observed that treatment of
the cultures with LPS or cytokines resulted in a decrease in expression
of PPARγ, but the decrease was prevented by 2-AG or inactivation of
MAGL. These results provide evidence that the anti-inflammatory ef-
fects of 2-AG or of MAGL inactivation, at least in vitro, are mediated
via CB1R and PPARγ signaling. Although anti-inflammatory and neuro-
protective effects of pharmacological or genetic inactivation of MAGL in
animal models of AD are not mediated via CB1R or CB2R (Chen et al.,
2012; Piro et al., 2012; Zhang & Chen, 2018), the MAGL inactivation-
induced neuroprotective effects are eliminated by antagonism of
PPARγ in 5xFAD APP mice (Zhang et al., 2014). This study also provides
evidence that 2-AG is an endogenous PPARγ agonist, as 2-AG increases
PPARγ luciferase activity, a finding which has been further supported by
a study showing that the 2-AG-mediated increase in activity of PPARγ
luciferase is blocked by a CB1R or PPARγ antagonist (Hu et al., 2022).
Importantly, the authors discovered that inactivation of MAGL in astro-
cytes prevents TBI-induced neuropathology, as well as synaptic and
cognitive impairments and that the neuroprotective effects are dimin-
ished by silencing of PPARγ in astrocytes (Hu et al., 2022). They also ob-
served that TBI-induced neuropathology and deficits in learning and
memory in WT animals can be averted by overexpression of human
PPARγ in astrocytes. These studies provide evidence that PPARγ likely
acts downstream of CB1R in mediating 2-AG- or MAGL inactivation-
produced anti-inflammatory and neuroprotective effects in neurode-
generative diseases (Chen, 2023; Du et al., 2011; Hu et al., 2022;
Zhang et al., 2014). However, the precise mechanisms of how CB1R
interacts with PPARγ remain unclear, which warrant further
investigation.
Single cell transcriptomic analysis has shown that genetic inactiva-
tion of MAGL alters expression of immune- and inflammation-related
genes in microglia and astrocytes and enhances immune/inflammatory
vigilance in these glial cells (Zhu, Zhang, Hashem, Gao, & Chen, 2023).
This has been confirmed by showing that TBI-upregulated expression
of genes associated with inflammation is significantly reduced in mice
lacking MAGL in astrocytes, while TBI-downregulated expression of
genes associated with anti-inflammation or maintaining brain homeo-
stasis is not significantly changed in astrocytic mgll KO mice (Hu et al.,
2022). Of note, TBI-upregulated expression of genes associated with in-
flammation in astrocytic MAGL knockout mice is robustly reduced in
microglia, and TBI-increased microglial reactivity is also reduced, sug-
gesting that 2-AG generated in astrocytes is an important signaling me-
diator that interacts with microglia to terminate microglia-mediated
inflammatory responses. These observations provide evidence that
restraining 2-AG metabolism in astrocytes enhances resilience to brain
trauma by suppressing TBI-induced upregulation of genes associated
C. Chen Pharmacology & Therapeutics 244 (2023) 108394

with inflammation and reducing TBI-induced downregulation of genes
with anti-inflammatory properties or genes involved in maintenance
of brain homeostasis. In line with these observations, a previous study
demonstrated that AA and PGs derived from 2-AG metabolism primar-
ily result from 2-AG synthesized in astrocytes but not in neurons
(Nomura et al., 2011), which might be one of the mechanisms underly-
ing astrocytic MAGL inactivation-produced anti-inflammatory and neu-
roprotective effects in neurodegenerative diseases (Fig. 6). This suggests
that MAGL in astrocytes controls 2-AG signaling in neurodegenerative
diseases and inactivation of astrocytic MAGL resolves neuroinflamma-
tion and protects neurons by enhancement of 2-AG signaling and lower-
ing of the levels of 2-AG hydrolytic metabolites eicosanoids in astrocytes
(Fig. 6).
6. MAGL inhibitors
Giving that, in the brain, MAGL is the main enzyme that hydrolyzes
2-AG, and 2-AG exhibits profound anti-inflammatory and neuroprotec-
tive properties, while its hydrolytic metabolites are proinflammatory
and neurotoxic, MAGL has emerged as an attractive drug target for
brain disorders (Alhouayek et al., 2014; Baggelaar et al., 2018; Bajaj
et al., 2021; Gil-Ordonez et al., 2018; Grabner et al., 2017; Mulvihill &
Nomura, 2013; van Egmond et al., 2021; Xu & Chen, 2015; Zhu et al.,
2021). This has led to identification and development of several com-
pounds that inhibit activity of MAGL. MAGL inhibitors are classified as
reversible or irreversible based on their mechanisms of action (Gil-
Ordonez et al., 2018; Scalvini et al., 2016). URB602 and N-arachidonyl
maleimide (NAM) were the earliest identified MAGL inhibitors
(Blankman et al., 2007; Burston et al., 2008; Hohmann et al., 2005;
King et al., 2007; Saario et al., 2005). However, JZL184, which was
invented by the Benjamin Cravatt’s group (Long, Li, et al., 2009; Long,
Nomura, & Cravatt, 2009; Schlosburg et al., 2010; Schlosburg et al.,
2014), is the most widely used MAGL inhibitor in experimental animals
because of its high selectivity and potency (Long, Li, et al., 2009; Long,
Nomura, & Cravatt, 2009; Schlosburg et al., 2010; Schlosburg et al.,
2014). Although many MAGL inhibitors have been identified, currently
only ABX-1431 (Lu AG06466), which is an irreversible inhibitor for
MAGL, is in clinical trials (Cisar et al., 2018; Jiang & van der Stelt,
2018; Müller-Vahl et al., 2021; Punt et al., 2022). It is imperative to iden-
tify and develop novel MAGL inhibitors, especially reversible inhibitors,
that can be used for neurodegenerative diseases. MAGL inhibitors are
more thoroughly discussed in several reviews (Alhouayek et al., 2014;
Bajaj et al., 2021; Bononi et al., 2021; Deng & Li, 2020; Gil-Ordonez
et al., 2018; Scalvini et al., 2016; van Egmond et al., 2021).
7. Perspective
Since 2-AG displays profound anti-inflammatory and neuroprotec-
tive properties and 2-AG hydrolytic metabolites are proinflammatory
and neurotoxic, restraint of 2-AG degradation to enhance 2-AG signal-
ing and to reduce its metabolites appear to provide a mechanism to ter-
minate inflammatory responses, thereby preventing or treating brain
disorders. Thus, MAGL has been proposed as a therapeutic target for
neurodegenerative diseases (Alhouayek et al., 2014; Baggelaar et al.,
2018; Bajaj et al., 2021; Brindisi et al., 2016; Chen, 2022; Chen et al.,
2012; Cisar et al., 2018; Gil-Ordonez et al., 2018; Grabner et al., 2017;

Fig. 6. Signaling pathways that mediate astrocytic MAGL inactivation-produced neuroprotection in neurodegenerative diseases. Pharmacological or genetic inactivation of MAGL in astro-
cytes boosts 2-AG levels and reduces its immediate metabolite AA, leading to reduction of the levels of prostaglandins (PGs) and leukotrienes (LT4s). Enhanced 2-AG signaling activates
PPARγ directly or indirectly through binding to CB1R as well as increases expression of PPARγ. PPARγ interacts with NF-κB to inhibit its transcription and expression of genes involved in
inflammatory responses in astrocytes. Reduced release of inflammatory factors from astrocytes alleviates NF-κB-mediated neuropathology in neurons, including phosphorylated tau (p-
tau), synthesis of Aβ, and production of TDP-43. Reduced release of inflammatory factors from astrocytes also decreases NF-κB-mediated inflammatory cascades in microglia to suppress
production and release of cytokines, chemokines, complements, and prostaglandins (PGs) from microglia. It is still not clear whether increased 2-AG levels in astrocytes could activate
PPARγ directly or indirectly through binding to CB2R in microglial cells, leading to reduction of NF-κB-mediated transcription and expression of genes involved in inflammatory responses
in microglia. Reduced neuroinflammation, astrogliosis, and microgliosis by inactivation of MAGL in astrocytes prevent or ameliorate neuropathology, synaptic dysfunction, neurodegen-
eration, impairments in learning and memory through maintaining the brain in homeostasis (Chen, 2023).

11
C. Chen
Hashem et al., 2021; Hu et al., 2022; Mulvihill & Nomura, 2013;
Pasquarelli, Engelskirchen, et al., 2017; Piomelli & Mabou Tagne, 2022;
Wenzel & Klegeris, 2018; Zhang & Chen, 2018; Zhang et al., 2014;
Zhang, et al., 2015; Zhu et al., 2022). However, recent studies have
shown that global inactivation of MAGL induces some adverse effects,
including an increased incidence of lung adenocarcinoma, worsened
heart function after acute myocardial infarction, impaired fine motor
coordination, and bone loss (R. Liu et al., 2018; Marino et al., 2020;
Marino et al., 2019; Martinez-Torres et al., 2019; Schloss et al., 2019).
In addition, early studies also demonstrated that chronic inactivation
of MAGL causes functional antagonism of the endocannabinoid system,
primarily resulting from functional tolerance of CB1R (Chanda et al.,
2010; Imperatore et al., 2015; Schlosburg et al., 2010), which may
reduce the effectiveness of MAGL inhibitors. A recent study by Hu
et al. revealed that inactivation of MAGL in neurons does not prevent
TBI-induced neuropathology or deficits in synaptic plasticity, learning
and memory (Hu et al., 2022). In contrast, inactivation of MAGL in astro-
cytes produces anti-inflammatory and neuroprotective effects in TBI
(Hu et al., 2022). Mass spectrometry analysis in global and cell type-
specific mgll KO mice has demonstrated that most 2-AG in the brain is
generated in neurons, and only small amounts of 2-AG are synthesized
in astrocytes (Hu et al., 2022; Viader et al., 2015). However, 2-AG syn-
thesized in astrocytes produces profound anti-inflammatory and neuro-
protective effects despite the small amounts of 2-AG generated in
astrocytes (Hu et al., 2022). A previous study also reported that inactiva-
tion of MAGL in astrocytes attenuates LPS-induced production of proin-
flammatory PGE2 and cytokines without causing cannabinoid receptor
desensitization (Grabner et al., 2016). In addition, a recent study
showed that overexpression of miR-30b, which targets molecules im-
portant for synapses (Song, Hu, Zhang, Teng, & Chen, 2019), alters syn-
aptic transmission and impairs LTP, and these changes are reversed by
inactivation of MAGL in astrocytes, but not in neurons (Zhu et al.,
2023). The findings from these studies suggest that neuroprotective
effects of global inactivation of MAGL by pharmacological inhibitors or
genetic deletion of mgll observed previously result primarily from
restraining degradation of 2-AG in astrocytes rather than in neurons
(Hu et al., 2022). Thus, global inactivation of MAGL might not be an op-
timal approach to achieving ideal therapeutic goals for neurodegenera-
tive diseases. Perhaps targeting astroglial cells would be an ideal
therapeutic strategy for neurological disorders (Lee, Wheeler, &
Quintana, 2022; Santello, Toni, & Volterra, 2019). However, current
pharmacotherapies do not have capacity to target a molecule in a spe-
cific type of cells. Thus, development of nanoparticle-, exosome-, or
viral vector-mediated therapies might be approaches to target MAGL
in specific type of cells. While inhibiting 2-AG degradation, which aug-
ments 2-AG signaling and reduces hydrolytic metabolites of 2-AG, is be-
lieved to provide a therapeutic strategy for treating neurodegenerative
diseases, deciphering the cell type-specific roles of 2-AG metabolism
will enable us to develop more comprehensive therapeutic strategies
for treating brain disorders (Chen, 2023).
Declaration of Competing Interest
The authors declare that there are no conflicts of interest.
Acknowledgement
This work was supported by National Institutes of Health grants
RF1NS076815 from NINDS and NIA, R01MH113535 from NIMH, and
R01AG058621 from NIA.
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