Monoacylglycerol lipase (MAGL) is an enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol and regulates production of arachidonic acid and prostaglandins, substances that mediate tissue inflammatory response. Here, we have studied the effects of the selective MAGL inhibitors JZL184 and MJN110 and their underlying molecular mechanisms on 3 different experimental models of focal cerebral ischemia.
Spontaneously hypertensive rats and normotensive Wistar-Kyoto rats were subject to an intracortical injection of the potent vasoconstrictor endothelin-1, permanent occlusion of a distal segment of the middle cerebral artery (MCA) via craniectomy, or transient occlusion of the MCA by the intraluminal suture method. JZL184 or MJN110 were administered 60 min after focal cerebral ischemia. Infarct volumes, hemispheric swelling, and functional outcomes were assessed between day 1 to day 28 by magnetic resonance imaging, histology, and behavioral tests.
Pharmacological inhibition of MAGL significantly attenuated infarct volume and hemispheric swelling. MAGL inhibition also ameliorated sensorimotor deficits, suppressed inflammatory response, and decreased the number of degenerating neurons. These beneficial effects of MAGL inhibition were not fully abrogated by selective antagonists of cannabinoid receptors, indicating that the anti-inflammatory effects are caused by inhibition of eicosanoid production rather than by activation of cannabinoid receptors.