title: Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model.
abstract: OBJECTIVE
  Cannabinoids, such as Δ9-THC, act through an endogenous signaling system in the vertebrate eye that reduces IOP via CB1 receptors. Endogenous cannabinoid (eCB) ligand, 2-arachidonoyl glycerol (2-AG), likewise activates CB1 and is metabolized by monoacylglycerol lipase (MAGL). We investigated ocular 2-AG and its regulation by MAGL and the therapeutic potential of harnessing eCBs to lower IOP.
  
  
  METHODS
  We tested the effect of topical application of 2-AG and MAGL blockers in normotensive mice and examined changes in eCB-related lipid species in the eyes and spinal cord of MAGL knockout (MAGL-/-) mice using high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). We also examined the protein distribution of MAGL in the mouse anterior chamber.
  
  
  RESULTS
  2-Arachidonoyl glycerol reliably lowered IOP in a CB1- and concentration-dependent manner. Monoacylglycerol lipase is expressed prominently in nonpigmented ciliary epithelium. The MAGL blocker KML29, but not JZL184, lowered IOP. The ability of CB1 to lower IOP is not desensitized in MAGL-/- mice. Ocular monoacylglycerols, including 2-AG, are elevated in MAGL-/- mice but, in contrast to the spinal cord, arachidonic acid and prostaglandins are not changed.
  
  
  CONCLUSIONS
  Our data confirm a central role for MAGL in metabolism of ocular 2-AG and related lipid species, and that endogenous 2-AG can be harnessed to reduce IOP. The MAGL blocker KML29 has promise as a therapeutic agent, while JZL184 may have difficulty crossing the cornea. These data, combined with the relative specificity of MAGL for ocular monoacylglycerols and the lack of desensitization in MAGL-/- mice, suggest that the development of an optimized MAGL blocker offers therapeutic potential for treatment of elevated IOP.
authors.affiliation: Department of Psychological and Brain Sciences Indiana University, Bloomington, Indiana, United States.
authors.forename: Sally
authors.initials: S
authors.lastname: Miller
authors.affiliation: Department of Psychological and Brain Sciences Indiana University, Bloomington, Indiana, United States.
authors.forename: Emma
authors.initials: E
authors.lastname: Leishman
authors.affiliation: Department of Psychology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Sherry Shujung
authors.initials: SS
authors.lastname: Hu
authors.affiliation: Department of Psychological and Brain Sciences Indiana University, Bloomington, Indiana, United States.
authors.forename: Alhasan
authors.initials: A
authors.lastname: Elghouche
authors.affiliation: Department of Psychological and Brain Sciences Indiana University, Bloomington, Indiana, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Daily
authors.affiliation: Department of Psychological and Brain Sciences Indiana University, Bloomington, Indiana, United States.
authors.forename: Natalia
authors.initials: N
authors.lastname: Murataeva
authors.affiliation: Department of Psychological and Brain Sciences Indiana University, Bloomington, Indiana, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Bradshaw
authors.affiliation: Department of Psychological and Brain Sciences Indiana University, Bloomington, Indiana, United States.
authors.forename: Alex
authors.initials: A
authors.lastname: Straiker
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000867:Anterior Chamber / Q000378:metabolism; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D052117:Benzodioxoles; D002924:Ciliary Body / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D063388:Endocannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D005989:Glycerides / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D007150:Immunohistochemistry; D007429:Intraocular Pressure / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D050178:Monoglycerides / Q000378:metabolism; D010880:Piperidines; D011817:Rabbits; D053719:Tandem Mass Spectrometry
chemical_list: D001095:Arachidonic Acids; D052117:Benzodioxoles; D063388:Endocannabinoids; D005989:Glycerides; C534333:JZL 184; D050178:Monoglycerides; D010880:Piperidines; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases