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. Author manuscript; available in PMC: 2022 Aug 1.
Published in final edited form as: Mol Neurobiol. 2021 May 3;58(8):4122–4133. doi: 10.1007/s12035-021-02400-2

Figure 7. Signaling pathways mediating the beneficial effects produced by inhibition of 2-AG metabolism.

Figure 7.

Inactivation of monoacylglycerol lipase (MAGL) by JZL184 augments 2-AG signaling and decreases 2-AG immediate metabolite arachidonic acid (AA) and AA-derived prostaglandins (PGs) through cyclooxygenase 1 and 2 (COX-1/2) and leukotrienes (LT4s) through 5-lipoxygenase (LOX). 2-AG possesses anti-inflammatory and neuroprotective properties, while prostaglandins and leukotrienes are proinflammatory and neurotoxic. Enhanced 2-AG by inactivation of MAGL stimulates expression and activity PPARγ through CB1/2-dependent and independent pathways, resulting in inhibition of NF-κB. Reduced NF-kB transcriptional activity and the amount of prostaglandins and leukotrienes decrease proinflammatory cytokines and chemokines and neuroinflammation as well as apoptosis, which in turn suppress tau phosphorylation and tauopathies. These events may benefit to maintaining brain homeostasis and the integrity of synapses, and thus improving synaptic and cognitive functions.