Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model

PURPOSE: Cannabinoids, such as Δ(9)-THC, act through an endogenous signaling system in the vertebrate eye that reduces IOP via CB(1) receptors. Endogenous cannabinoid (eCB) ligand, 2-arachidonoyl glycerol (2-AG), likewise activates CB(1) 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 CB(1)- 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 CB(1) 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.