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.