title: The monoacylglycerol lipase inhibitor JZL184 attenuates LPS-induced increases in cytokine expression in the rat frontal cortex and plasma: differential mechanisms of action.
abstract: OBJECTIVE
  JZL184 is a selective inhibitor of monoacylglycerol lipase (MAGL), the enzyme that preferentially catabolizes the endocannabinoid 2-arachidonoyl glycerol (2-AG). Here, we have studied the effects of JZL184 on inflammatory cytokines in the brain and plasma following an acute immune challenge and the underlying receptor and molecular mechanisms involved.
  
  
  METHODS
  JZL184 and/or the CB₁ receptor antagonist, AM251 or the CB₂ receptor antagonist, AM630 were administered to rats 30 min before lipopolysaccharide (LPS). 2 h later cytokine expression and levels, MAGL activity, 2-AG, arachidonic acid and prostaglandin levels were measured in the frontal cortex, plasma and spleen.
  
  
  RESULTS
  JZL184 attenuated LPS-induced increases in IL-1β, IL-6, TNF-α and IL-10 but not the expression of the inhibitor of NFkB (IκBα) in rat frontal cortex. AM251 attenuated JZL184-induced decreases in frontal cortical IL-1β expression. Although arachidonic acid levels in the frontal cortex were reduced in JZL184-treated rats, MAGL activity, 2-AG, PGE₂ and PGD₂ were unchanged. In comparison, MAGL activity was inhibited and 2-AG levels enhanced in the spleen following JZL184. In plasma, LPS-induced increases in TNF-α and IL-10 levels were attenuated by JZL184, an effect partially blocked by AM251. In addition, AM630 blocked LPS-induced increases in plasma IL-1β in the presence, but not absence, of JZL184.
  
  
  CONCLUSIONS
  Inhibition of peripheral MAGL in rats by JZL184 suppressed LPS-induced circulating cytokines that in turn may modulate central cytokine expression. The data provide further evidence for the endocannabinoid system as a therapeutic target in treatment of central and peripheral inflammatory disorders.
authors.affiliation: Physiology, School of Medicine, National University of Ireland, Galway, Ireland.
authors.forename: D M
authors.initials: DM
authors.lastname: Kerr
authors.forename: B
authors.initials: B
authors.lastname: Harhen
authors.forename: B N
authors.initials: BN
authors.lastname: Okine
authors.forename: L J
authors.initials: LJ
authors.lastname: Egan
authors.forename: D P
authors.initials: DP
authors.lastname: Finn
authors.forename: M
authors.initials: M
authors.lastname: Roche
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D001095:Arachidonic Acids / Q000097:blood / Q000378:metabolism; D052117:Benzodioxoles / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D063387:Cannabinoid Receptor Antagonists / Q000737:chemistry / Q000627:therapeutic use*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D004660:Encephalitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D063388:Endocannabinoids / Q000097:blood / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D005625:Frontal Lobe / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D005989:Glycerides / Q000097:blood / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D010538:Peritonitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D011453:Prostaglandins / Q000097:blood / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D052117:Benzodioxoles; D063387:Cannabinoid Receptor Antagonists; C543264:Cnr1 protein, rat; C469526:Cnr2 protein, rat; D016207:Cytokines; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; C534333:JZL 184; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D010880:Piperidines; D011453:Prostaglandins; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C440499:lipopolysaccharide, Escherichia coli O111 B4; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases