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

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 Δ-tetrahydrocannabinol (Δ-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.