Endocannabinoid Hydrolysis Generates Brain Prostaglandins That Promote Neuroinflammation

Abstract

Phospholipase A2 (PLA2) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)-mediated biosynthesis of prostaglandins. Here, we show that a distinct pathway exists in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins. MAGL-disrupted animals show neuroprotection in a parkinsonian mouse model. These animals are spared the hemorrhaging caused by COX inhibitors in the gut, where prostaglandins are instead regulated by cytosolic-PLA2. These findings identify MAGL as a distinct metabolic node that couples endocannabinoid to prostaglandin signaling networks in the nervous system and suggest that inhibition of this enzyme may be a new and potentially safer way to suppress the proinflammatory cascades that underlie neurodegenerative disorders.

Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

“…Recent studies show that the anti-inflammatory and neuroprotective effects by inhibition of MAGL are not mediated by CB1 or by CB2 receptors. 19,21,27 In addition, inhibition of CB1 receptors only partly blocks 2-AG-produced neuroprotective effects in TBI. 22 This suggests that there may be other mechanisms mediating the anti-neuroinflammatory and neuroprotective effects produced by inhibition of 2-AG metabolism.…”

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

“…The moderate dose employed here should also be devoid of the decreased CB1 receptor function observed at high doses of the drug (Schlosburg et al, 2010;Kinsey et al, 2013), although, differently from these previous reports, in our case the duration of the treatment was longer. As JZL184-induced increase in 2-AG levels is dependent on the dose as well as the duration of the treatment (Kinsey et al, 2013), one possibility is that in healthy mice (controls) chronic administration of JZL184 may have exacerbated the 2-AG-signaling, along with an eventual loss of MAGL activity-dependent neuroprotective mechanisms (Nomura et al, 2011), to an extent sufficient to produce the behavioral responses observed, and which usually occur at high doses of CB1 receptor agonists (Rey et al, 2012). Indeed, JZL184 and combo treatments induced a statistically significant higher increase in 2-AG level in controls as compared with CUS animals ( Figure 5).…”

A quantitiative LC-MS/MS method for the measurement of arachidonic acid, prostanoids, endocannabinoids, N-acylethanolamines and steroids in human plasma

“…Recently, the levels of 2-AG and AA were shown to inversely correlate with the free AA generated upon hydrolysis of 2-AG which was shown to act as precursor for eicosanoid biosynthesis [4]. Prostanoids are a family of lipid mediators that play key roles in both inflammatory and neuropsychiatric processes.…”