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

Abstract

PurposeCannabinoids, 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.MethodsWe 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.Results2-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.ConclusionsOur 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.

Controlled-Deactivation CB1 Receptor Ligands as a Novel Strategy to Lower Intraocular Pressure

“…The mouse is an established model system for the study of IOP [ 22 , 23 ], offering access to assorted genetic mutants such as CB1 knockout mice, among other things. We have made use of this system in several studies of the regulation of ocular pressure by endocannabinoids [ 5 , 24 ].…”

“…However, the initial promise of CB1 as a target for treating glaucoma has not thus far translated into a credible therapeutic strategy. We have recently shown that blocking monoacylglycerol lipase (MAGL), an enzyme that breaks the endocannabinoid 2-arachidonoyl glycerol (2-AG), substantially lowers IOP for 8 h [ 5 ]. Another strategy is to develop cannabinoid CB1 receptor agonists that are optimized for topical application to the eye.…”

Subcellular Localization of a 2-Arachidonoyl Glycerol Signaling Cassette in Retinal Ganglion Cell Axonal Growth In Vitro

“…The ECS participates in diverse functions of the adult visual system ranging from corneal endothelial cell chemotaxis to retinal processing of visual information and the regulation of intraocular pressure. [46][47][48][49] The ECS also modulates visual system development by way of retinofugal projection growth and target selection. [16][17][18] In this context, there are several outstanding questions about the ECS with significant therapeutic implications that should be addressed by future studies.…”

Potential for endocannabinoid system modulation in ocular pain and inflammation: filling the gaps in current pharmacological options

“…Along a similar line of investigation, Crowe et al [240] assessed the combination of the NSAID diclofenac with JZL184, finding additive attenuation of cold allodynia, as well as synergistic reduction of mechanical allodynia, which was blocked with CB1R antagonist treatment. Also examining KLM29, Miller et al [241] observed an ocular hypotensive effect in a mouse model, while JZL184 did not have an effect on IOP.…”