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. Author manuscript; available in PMC: 2023 Apr 24.
Published in final edited form as: Pharmacol Ther. 2023 Mar 24;244:108394. doi: 10.1016/j.pharmthera.2023.108394

Inhibiting degradation of 2-arachidonoylglycerol as a therapeutic strategy for neurodegenerative diseases

Chu Chen 1
PMCID: PMC10123871  NIHMSID: NIHMS1887859  PMID: 36966972

Abstract

Endocannabinoids are endogenous lipid signaling mediators that participate in a variety of physiological and pathological processes. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid and is a full agonist of G-protein-coupled cannabinoid receptors (CB1R and CB2R), which are targets of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive ingredient in cannabis. While 2-AG has been well recognized as a retrograde messenger modulating synaptic transmission and plasticity at both inhibitory GABAergic and excitatory glutamatergic 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 arachidonic acid (AA), a precursor of prostaglandins (PGs) and leukotrienes. Several lines of evidence indicate that pharmacological or genetic inactivation of MAGL, which boosts 2-AG levels and reduces its hydrolytic metabolites, resolves neuroinflammation, mitigates neuropathology, and improves synaptic and cognitive functions in animal models of neurodegenerative diseases, including Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease (PD), and traumatic brain injury (TBI)-induced neurodegenerative disease. Thus, it has been proposed that MAGL is a potential therapeutic target for treatment of neurodegenerative diseases. As the 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 neurodegenerative 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.

Keywords: Endocannabinoid, 2-Arachidonoylglycerol, Monoacylglycerol lipase, Neurodegenerative disease, Alzheimer’s disease, Traumatic brain injury

1. Introduction

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 psychoactive 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 functions, and side effects (Stella, 2023). CBD has been thought non-psychotropic and fewer side effects. However, recent studies suggested 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; R. 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; R. Chen, et al., 2013; Fitzgerald, Bronstein, & Newquist, 2013; Hoffman, et al., 2007; Messinis, Kyprianidou, Malefaki, & Papathanasopoulos, 2006; Pope & 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 identified, of which more than 100 are chemically and biosynthetically related cannabinoids (Ligresti, De Petrocellis, & Di Marzo, 2016). Synthetic cannabinoids, including CP-55940, Hu-210, and Win55,212–2, emerged from the identification of Δ9-THC (Figure 1). In the mid-1980s, the groundbreaking 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, 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., 1991; Herkenham, et al., 1990; 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 pharmacological and biochemical properties, coupling to GTP binding proteins to inhibit activity of AC (Figure 2) (Felder, et al., 1995; Howlett & Abood, 2017). While CB1R is primarily expressed in the brain, CB2R is 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).

Figure 1.

Figure 1.

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

Figure 2.

Figure 2.

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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. Dissociated 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.

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 activate 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 second endocannabinoid, 2-arachidonoylglycerol (2-AG), was independently identified by two groups of investigators, Drs. Mechoulam and Sugiura (Mechoulam, et al., 1995; Sugiura, Kishimoto, Oka, & Gokoh, 2006; Sugiura, et al., 1995). These discoveries were soon confirmed by other groups (Gonsiorek, et al., 2000; Hillard, 2000; Stella, Schweitzer, & Piomelli, 1997) and several putative endogenous cannabinoids have been identified (Figure 3). AEA and 2-AG have been investigated most thoroughly and they differ in several aspects in terms of binding activity for CB1R or CB2R. For instance, 2-AG is the most abundant 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).

Figure 3.

Figure 3.

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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).

It has been almost six decades since the Mechoulam’s group isolated and identified Δ9-THC as the primary psychoactive constituent of cannabis (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 cannabinoid research and greatly enhanced our understanding of the ingredients of marijuana and actions of cannabinoids. Their research promoted and facilitated discovery of the endogenous cannabinoid system. 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 (H. C. Lu & Mackie, 2021). The endocannabinoid system consists of cannabinoid receptors (CB1R and CB2R), endocannabinoids (e.g., AEA and 2-AG), transporters, and the enzymes that synthesize and degrade endocannabinoids (Figure 4). In addition, there are a few additional putative cannabinoid receptors, one of which is GPR55 (Kano, et al., 2009; Ligresti, et al., 2016; H. C. Lu & Mackie, 2021). Recent evidence shows that fatty acid-binding protein 5 (FABP5) is an important transporter 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 physiological 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, 2020; Freund, Katona, & Piomelli, 2003; Howlett, et al., 2004; Kaczocha & Haj-Dahmane, 2022; Kano, et al., 2009; Katona & Freund, 2012; Ligresti, et al., 2016; H. C. Lu & Mackie, 2021; Mechoulam, et al., 2014; Mechoulam & Parker, 2013; Pertwee, 2006, 2015). This review 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, Carpenter, et al., 2002; Dinh, Freund, & Piomelli, 2002; Long, Nomura, & Cravatt, 2009; Viader, et al., 2015).

Figure 4.

Figure 4.

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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: prostaglandin ethanolamine glycerol; TRPV1: transient receptor potential vanilloid 1

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 transmission and plasticity at both GABAergic and glutamatergic synapses has been extensively studied. It has been recognized that 2-AG is released 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 concomitant increase in K+ channel conductance in presynaptic nerve terminals (Alger, 2002; Castillo, et al., 2012; Chevaleyre & Castillo, 2003, 2004; Freund & Hajos, 2003; Y. 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). Accumulating evidence indicates that 2-AG possesses anti-inflammatory and neuroprotective effects in response to proinflammatory, neurotoxic, and mechanical insults and maintains brain homeostasis (C. 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 recognized as a true natural ligand for both CB1R and CB2R (Sugiura, et al., 2006). 2-AG is generated from membrane phospholipids (e.g., phosphatidylinositol, phosphatidylinositol 4,5-bisphosphate, triacylglycerol, or lysophosphatidylinositol) through multiple pathways (Murataeva, Straiker, & Mackie, 2014). However, the primary pathway of biosynthesis 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) (Figure 5). Diacylglycerol lipases were cloned in 2003 (Bisogno, et al., 2003), advancing our understanding of the key pathway for biosynthesis of 2-AG. There is evidence that DAGLα is the major biosynthetic enzyme for 2-AG in neurons and astrocytes in the brain, while DAGLβ is responsible for synthesis of 2-AG in microglia (Y. 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; Y. 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).

Figure 5.

Figure 5.

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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).

Like the synthesis of 2-AG, there are several pathways involving enzymes that degrade 2-AG (Figure 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 hydrolyzing 2-AG by the Piomelli’s lab where they found that MAGL participates in inactivation of 2-AG (Dinh, Carpenter, et al., 2002; Dinh, Freund, et al., 2002). While MAGL is expressed in most cells, its hydrolysis of 2-AG displays tissue-specificity. For example, systemic administration 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, et al., 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, et al., 2002; Fiskerstrand, et al., 2010; Labar, Wouters, & Lambert, 2010; Long, Nomura, et al., 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 identified 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 demonstrated 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 involvement 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 inflammation (Kingsley, Rouzer, Morgan, Patel, & Marnett, 2019; Morgan, 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 constitutively expressed in all tissues and functions as a housekeeper. However, COX-2 is inducible and its expression is immediately upregulated in response to infection or insults (C. 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 metabolized 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, Gamble-George, Marnett, & Patel, 2014; Hermanson, et al., 2013; 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 neuroinflammation, and protects neurons from harmful insults, suggesting that the effects of COX-2 metabolites of 2-AG are opposite to that of 2-AG (X. 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; S. S. 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, including lung, spleen, and macrophages (B. Szafran, Borazjani, Lee, Ross, & Kaplan, 2015; B. N. 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 (Figure 5). AA is an important lipid mediator that participates 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 oxidases (CYP), respectively (Figure 5). Certain metabolites of AA (e.g., PGE2 and LTB4) are proinflammatory mediators (Henderson, 1994; Ricciotti & FitzGerald, 2011; Salmon & Higgs, 1987; Xu & Chen, 2015; Yao & Narumiya, 2019). It has long been thought that AA is primarily derived 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 significant impact on AA-mediated signaling cascades in physiology and diseases (Alhouayek, et al., 2014; Baggelaar, et al., 2018; Grabner, Zimmermann, Schicho, & Taschler, 2017).

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), specifically a closed head injury (Panikashvili, et al., 2001). The authors observed 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., 2005; Panikashvili, et al., 2001). They provided further evidence that 2-AG-produced neuroprotection in TBI is a consequence of CB1R-mediated inhibition of nuclear 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., 2005; Panikashvili, et al., 2006; Panikashvili, et al., 2001; 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 neuroprotective effects of 2-AG are largely associated with suppression of neuroinflammatory responses following TBI, suggesting that 2-AG is an endogenous terminator of inflammation in response to harmful insults that elicit inflammatory responses (C. Chen, 2023). This assumption has been supported by several studies. For example, 2-AG produces a dose-dependent suppression of proinflammatory factor lipopolysaccharide (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). Apparently, 2-AG inhibition of COX-2 is primarily restricted to glial cells. However, 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 inhibitor 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 endogenous 2-AG degradation by MAGL inhibitors URB602 or JZL184 attenuate β-amyloid (Aβ)-induced neuronal apoptosis and degeneration via CB1R-mediated suppression of extracellular signal-regulated kinases 1 and 2 (ERK1/2), NF-κB, and COX-2 in cultured hippocampal neurons (X. Chen, et al., 2011). Other studies also found similar neuroprotective 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 evidence 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 synaptic 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, expression 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; M. Hu, et al., 2022; Zhang, et al., 2014). It was also observed that direct administration 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). However, 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 (C. Chen, 2023; R. Chen, et al., 2012; Du, et al., 2011; M. Hu, et al., 2022; Xu & Chen, 2015; Zhang, et al., 2014).

Several previous studies revealed that 2-AG, but not AEA, is released 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 augmentation of 2-AG levels by inactivation of MAGL to prevent 2-AG breakdown attenuates TBI-induced neuroinflammation and neuropathology (M. Hu, et al., 2022; Katz, et al., 2015; Panikashvili, et al., 2001; Piro, et al., 2018; Zhang, Teng, Song, Hu, & Chen, 2015), suggesting that release of 2-AG is an endogenous defense mechanism to increase resilience 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 modulating synaptic transmission and plasticity, resolving neuroinflammation, and protecting neurons from harmful insults (C. Chen, 2015, 2023; Mulvihill & Nomura, 2013; Xu & Chen, 2015).

4. MAGL in neurodegenerative diseases

MAGL was originally purified from adipose tissues and recognized as the rate-limiting enzyme involved in the last step of hydrolyzing 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 converted by hormone-sensitive lipase (HSL) into monoacylglycerols. Finally, monoacylglycerols are hydrolyzed by MAGL to fatty acid and glycerol. MAGL was cloned in 1997 (Karlsson, Contreras, Hellman, Tornqvist, & Holm, 1997; Karlsson, et al., 2001). It has a molecular 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, et al., 2002; Long & Cravatt, 2011; Long, Nomura, et al., 2009; Nomura, et al., 2011; Scalvini, et al., 2016; Schlosburg, et al., 2010). MAGL is highly expressed in the brain, particularly, in presynaptic nerve terminals, suggesting that MAGL plays an important role in terminating 2-AG signaling to precisely modulate or tune synaptic activity (Dinh, Freund, et al., 2002; Ludányi, et al., 2011). Use of pharmacological and genetic approaches to manipulate MAGL activity have provided significant insights into 2-AG metabolism in physiology and disease.

While ‘on demand’ synthesis and release of 2-AG are important for brain homeostasis, 2-AG is rapidly degraded by several enzymes, including 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 through increasing DAGLα/β activity or by reducing degradation. However, increasing 2-AG levels by enhancing its synthesis may accelerate metabolism 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, 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, et al., 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 (C. Chen, 2023; M. 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; Z. 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 neurodegenerative diseases (C. Chen, 2016, 2022; R. 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 intracellular hyperphosphorylated tau proteins that form neurofibrillary tangles, sustained neuroinflammation, synaptic malfunction, progressive 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 progression 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 accepted that chronic inflammation as a root cause significantly contributes 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 metabolites are proinflammatory and neurotoxic (X. Chen, et al., 2011; Du, et al., 2011; Henderson, 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 irreversible MAGL inhibitor (Long, Li, et al., 2009; Long, Nomura, et al., 2009), resulted in of 6 to 7-fold increases in 2-AG levels in the brain, while AA and PGE2 were reduced by roughly 75% and 50%, respectively in 5xFAD mice (R. 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 enzyme responsible for synthesis of Aβ, were significantly reduced in 5xFAD mice (R. Chen, et al., 2012). Chronic inhibition of MAGL also decreases reactivity of astrocytes and microglia and reduces the number 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 inactivation are likely associated with the rescue of the reduced expression of glutamate receptor subunits and density of dendritic spines (R. 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 inactivation of mgll reduces total Aβ, Aβ40 and Aβ42, cytokine production, including IL-1β, IL-6, and TNFα, and expression of astrocyte and microglia markers (Piro, et al., 2012). These beneficial effects are similar to those of pharmacological inactivation of MAGL (R. Chen, et al., 2012). Several other studies also provided evidence that pharmacological inactivation of MAGL reduces neuroinflammation and Aβ and improves learning and memory in APP TG mice (Pihlaja, et al., 2015; Zhang & Chen, 2018; Zhang, et al., 2014). Since accumulation and deposition of extracellular Aβ plaques are one of the neuropathological hallmarks in AD, the early studies were primarily focused on resolution of neuroinflammation and reduction of amyloidosis by inactivation of MAGL in animal models of Aβ pathology (R. 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 pharmacological inactivation of MAGL also mitigates neuroinflammation, including reduced expression of cytokines, reduced reactivity of astrocytes and microglia, and reduced phosphorylated NF-κB. These effects 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, inactivation of MAGL reduces cell apoptosis and prevents losses in expression 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 pathologies in APP and tau mouse models of AD by inactivation of MAGL suggests that MAGL is a promising therapeutic target for AD (C. Chen, 2022; R. 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 therapeutic 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 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 increased expression of MAGL in aging and AD suggests that 2-AG degradation 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, et al., 2002; Long, Nomura, et al., 2009; Nomura, et al., 2011). This remains speculative, however, due to the difficulty in obtaining brain tissues or cerebrospinal fluid from patients 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 decline 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 administration of exogenous 2-AG or by pharmacological inactivation of MAGL to restrain endogenous 2-AG degradation provide neuroprotection 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, Porazik, et al., 2017). The neuroprotective effects of MAGL inactivation are likely associated with the release of neuroprotective and anti-inflammatory factors 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 prevention 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 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 encephalopathy (CTE), a long-term progressive AD-like neurodegenerative disease, which includes hyperphosphorylated tau, aggregation and translocation of transactive response DNA binding protein 43 (TDP-43), persistent neuroinflammation, neurodegeneration, and synaptic and cognitive declines (Al-Dahhak, Khoury, Qazi, & Grossberg, 2018; Blennow, Hardy, & Zetterberg, 2012; DeKosky, Blennow, Ikonomovic, & Gandy, 2013; F. 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 neurodegenerative disease. The acute brain damage after TBI results not only from the primary injury, which is the result of an external mechanical 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 injury following TBI (Simon, et al., 2017). The extent of the neuroinflammatory 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, appropriate 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; J. Zhang, 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., 2005; Panikashvili, et al., 2006; Panikashvili, et al., 2001). These studies provided evidence that 2-AG signaling plays an important role in protecting the brain from trauma by resolving TBI-induced neuroinflammation (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 single 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 expression of proinflammatory cytokines, and reduced the reactivity of astroglial cells (J. Zhang, 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 receptor subunits and reduces impairments in basal synaptic transmission, long-term synaptic plasticity, and spatial learning and memory in animals exposed to repeated mild CHI (J. Zhang, et al., 2015). These studies provide evidence that pharmacological inactivation of MAGL produces neuroprotection against TBI-induced neuroinflammation, disruption of BBB integrity, neuropathology, and synaptic and cognitive impairments (Katz, et al., 2015; Xu & Chen, 2015; J. Zhang, 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 alterations, 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). 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 important mechanism in maintaining brain homeostasis and in terminating 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 pharmacological inhibition. A recent study by Hu and colleagues has filled this gap (M. Hu, et al., 2022). In their study, an mgllflox/flox knockout (KO) mouse model was used to generate total (tKO), neuronal (nKO), and astrocytic (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 (M. Hu, et al., 2022). These findings suggest that previously observed neuroprotective effects produced by pharmacological inactivation of MAGL in TBI result largely from restraining 2-AG degradation in astrocytes, rather than in neurons (C. Chen, 2023; Fucich, et al., 2020; M. Hu, et al., 2022; Katz, et al., 2015; Mayeux, et al., 2017; Selvaraj, et al., 2021; J. Zhang, et al., 2015). Moreover, the authors 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 (M. Hu, et al., 2022).

4.4. Multiple sclerosis

Multiple sclerosis (MS) is an incurable, chronic inflammatory disorder 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 experimental 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). Inactivation of MAGL with different inhibitors also reduces neuroinflammation, decreases chondroitin sulfate proteoglycan deposition around demyelinated lesions in the spinal cord of Theiler’s murine encephalomyelitis 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 associated with increased 2-AG tone, which promotes remyelination to ameliorate motor dysfunction in a model of progressive multiple sclerosis. 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 diseases (e.g., amyotrophic lateral sclerosis), and other neurological or neuropsychiatric disorders, including seizure/epilepsy and mental disorders (Bedse, Hill, & Patel, 2020; Colangeli, et al., 2023; Naidoo, et al., 2012; Pan, et al., 2011; Pasquarelli, Engelskirchen, et al., 2017; Ratano, et al., 2018; Shonesy, et al., 2014; Silveira, Wegener, & Joca, 2021; Terrone, et al., 2018; Vickstrom, et al., 2021; von Ruden, Bogdanovic, Wotjak, & Potschka, 2015; Z. Zhang, 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 signaling 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 neurodegenerative diseases (Baggelaar, et al., 2018; Bajaj, Jain, Vyas, Bawa, & Vohora, 2021; C. Chen, 2022; R. 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; J. Zhang, et al., 2015; Zhu, et al., 2021). However, the molecular mechanisms underlying the neuroprotective effects of MAGL inactivation in neurodegenerative diseases remain to be defined. Inflammation has been recognized as a common mechanism of disease (C. 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 neurodegenerative diseases. Because 2-AG displays anti-inflammatory and neuroprotective properties (C. 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, 1994; Ricciotti & FitzGerald, 2011; Salmon & Higgs, 1987; Xu & Chen, 2015; Yao & Narumiya, 2019), inactivation of MAGL may provide the means to produce anti-inflammatory and neuroprotective effects through multiple signaling pathways in neurodegenerative diseases based on the properties of its substrate 2-AG and the proinflammatory and neurotoxic properties of 2-AG hydrolytic metabolites.

Early studies showed that 2-AG functions as an endogenous neuroprotective mediator against brain trauma by a CB1R-dependent mechanism 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 deletion of CB1R (Panikashvili, et al., 2005; Panikashvili, et al., 2006; Panikashvili, et al., 2001). 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 (M. Hu, et al., 2022). These studies provide evidence that 2-AG- or MAGL inactivation-induced neuroprotection in TBI is mediated via CB1R. However, alleviation of neuroinflammation in an LPS-induced animal model of inflammation and neuronal loss in an MPTP-induced animal model of PD by pharmacological or genetic inactivation of MAGL appeared to not involve 2-AG signaling 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 genetic inactivation of MAGL in animal models of AD are also not mediated via CB1R nor via CB2R (R. Chen, et al., 2012; Piro, et al., 2012; Zhang & Chen, 2018). There are reports that restorative astroglia and microglia activation and the release of neuroprotective and anti-inflammatory molecules 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 associated with activation of CB1R (Bernal-Chico, et al., 2015). It appears from these studies that the signaling pathways that mediate MAGL inactivation-induced neuroprotective effects are complex, and the signaling 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 effects through interaction with NF-κB, resulting in reductions in transcription 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 cannabinoids 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 target 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, phosphorylated NF-κB, and excitatory synaptic transmission in cultured hippocampal 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 effects of 2-AG or of MAGL inactivation, at least in vitro, are mediated via CB1R and PPARγ signaling. Although anti-inflammatory and neuroprotective effects of pharmacological or genetic inactivation of MAGL in animal models of AD are not mediated via CB1R or CB2R (R. 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 (M. Hu, et al., 2022). Importantly, the authors discovered that inactivation of MAGL in astrocytes prevents TBI-induced neuropathology, as well as synaptic and cognitive impairments and that the neuroprotective effects are diminished by silencing of PPARγ in astrocytes (M. Hu, et al., 2022). They also observed 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 neurodegenerative diseases (C. Chen, 2023; Du, et al., 2011; M. 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 inactivation 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 homeostasis is not significantly changed in astrocytic mgll KO mice (M. Hu, et al., 2022). Of note, TBI-upregulated expression of genes associated with inflammation in astrocytic MAGL knockout mice is robustly reduced in microglia, and TBI-increased microglial reactivity is also reduced, suggesting that 2-AG generated in astrocytes is an important signaling mediator 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 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 primarily result from 2-AG synthesized in astrocytes but not in neurons (Nomura, et al., 2011), which might be one of the mechanisms underlying astrocytic MAGL inactivation-produced anti-inflammatory and neuroprotective effects in neurodegenerative diseases (Figure 6). This suggests that MAGL in astrocytes controls 2-AG signaling in neurodegenerative diseases and inactivation of astrocytic MAGL resolves neuroinflammation and protects neurons by enhancement of 2-AG signaling and lowering of the levels of 2-AG hydrolytic metabolites eicosanoids in astrocytes (Figure 6).

Figure 6.

Figure 6.

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Signaling pathways that mediate astrocytic MAGL inactivation-produced neuroprotection in neurodegenerative diseases. Pharmacological or genetic inactivation of MAGL in astrocytes 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, neurodegeneration, impairments in learning and memory through maintaining the brain in homeostasis (C. Chen, 2023).

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 neuroprotective 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 compounds 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, et al., 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, et al., 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 identify 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 neuroprotective properties and 2-AG hydrolytic metabolites are proinflammatory and neurotoxic, restraint of 2-AG degradation to enhance 2-AG signaling and to reduce its metabolites appear to provide a mechanism to terminate 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; C. Chen, 2022; R. Chen, et al., 2012; Cisar, et al., 2018; Gil-Ordonez, et al., 2018; Grabner, et al., 2017; Hashem, et al., 2021; M. 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; J. 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 (M. Hu, et al., 2022). In contrast, inactivation of MAGL in astrocytes produces anti-inflammatory and neuroprotective effects in TBI (M. 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 (M. Hu, et al., 2022; Viader, et al., 2015). However, 2-AG synthesized in astrocytes produces profound anti-inflammatory and neuroprotective effects despite the small amounts of 2-AG generated in astrocytes (M. Hu, et al., 2022). A previous study also reported that inactivation of MAGL in astrocytes attenuates LPS-induced production of proinflammatory 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 important for synapses (Song, Hu, Zhang, Teng, & Chen, 2019), alters synaptic transmission and impairs LTP, and these changes are reversed by inactivation of MAGL in astrocytes, but not in neurons (Zhu, Zhang, Gao, 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 (M. Hu, et al., 2022). Thus, global inactivation of MAGL might not be an optimal approach to achieving ideal therapeutic goals for neurodegenerative 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 specific 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 augments 2-AG signaling and reduces hydrolytic metabolites of 2-AG, is believed 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 (C. Chen, 2023).

Acknowledgement:

This work was supported by National Institutes of Health grants RF1NS076815 from NINDS and NIA, R01MH113535 from NIMH, and R01AG058621 from NIA.

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

cyclooxygenase-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

Footnotes

Conflict of interest statement

The authors declare that there are no conflicts of interest.

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