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      Neuroprotective effects of monoacylglycerol lipase inhibitors in experimental ischemic stroke

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          Abstract

          Background and Purpose

          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.

          Methods

          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.

          Results

          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.

          Conclusions

          Our results suggest that MAGL may contribute to the pathophysiology of focal cerebral ischemia and is thus a promising therapeutic target for the treatment of ischemic stroke.

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          Author and article information

          Journal
          0235266
          7613
          Stroke
          Stroke
          Stroke
          0039-2499
          1524-4628
          25 January 2018
          13 February 2018
          March 2018
          01 March 2019
          : 49
          : 3
          : 718-726
          Affiliations
          [1 ]Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging
          [2 ]Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 USA
          [3 ]College of Veterinary Medicine, Chungbuk National University, Cheongju, Republic of Korea
          Author notes
          [* ]Corresponding author: Afonso C. Silva, Ph.D. Chief, Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health. 49 Convent Drive MSC 4478, Building 49 Room 3A72, Bethesda, MD 20892-4478 USA. silvaa@ 123456ninds.nih.gov . Telephone: 301-402-9703. Fax: 301-480-2558
          Article
          PMC5829008 PMC5829008 5829008 nihpa935345
          10.1161/STROKEAHA.117.019664
          5829008
          29440474
          358f1e6b-f2c5-4d9e-82ee-ad5891cf413f
          History
          Categories
          Article

          neuroprotection,MAGL,JZL184,MJN110,endocannabinoid,ischemic stroke

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