Endocannabinoid metabolism and transport as targets to regulate intraocular pressure. (December 2020)

• Record Type: Journal Article
• Authors: Miller, Sally; Daily, Laura; Dharla, Vijai; Gertsch, Juerg; Malamas, Michael S.; Ojima, Iwao; Kaczocha, Martin; Ogasawara, Daisuke; Straiker, Alex
• Is Part Of: Experimental eye research. Volume 201(2020)
• Publication Date: 2020-12
• Subjects: Cannabinoid -- FAAH -- COX2 -- ABHD12 -- NAAA -- Transporter -- Anandamide -- Glaucoma -- Ocular pressure; 2-AG 2-arachidonoul glycerol -- COX2 cyclooxygenase 2 -- CB1 cannabinoid receptor 1 -- CB2 cannabinoid receptor 2 -- FAAH fatty acid amide hydrolase -- GPR18 G protein receptor 18 -- GPR119 G protein receptor 119 -- IOP intraocular pressure -- MAGL monoacylglycerol lipase -- ABHD12 a/b containing hydrolase domain 12 -- NAAA N-acylethanolamine-hydrolyzing acid amidase; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2020.108266
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Cannabinoids are part of an endogenous signaling system found throughout the body, including the eye. Hepler and Frank showed in the early 1970s that plant cannabinoids can lower intraocular pressure (IOP), an effect since shown to occur via cannabinoid CB1 and GPR18 receptors. Endocannabinoids are synthesized and metabolized enzymatically. Enzymes implicated in endocannabinoids breakdown include monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), but also ABHD12, NAAA, and COX-2. Inhibition of MAGL activity raises levels of the endocannabinoid 2-arachidonoyl glycerol and substantially lowers IOP. Blocking other cannabinoid metabolizing enzymes or cannabinoid transporters may similarly contribute to lowering IOP and so serve as therapeutic targets for treating glaucoma. We have tested blockers for several cannabinoid-metabolizing enzymes and transporters (FABP5 and membrane reuptake) for their ability to alter ocular pressure in a murine model of IOP. Of FAAH, ABHD12, NAAA, and COX2, only FAAH was seen to play a role in regulation of IOP. Only the FAAH blocker URB597 lowered IOP, but in a temporally, diurnally, and sex-specific manner. We also tested two blockers of cannabinoid transport (SBFI-26 and WOBE437), finding that each lowered IOP in a CB1-dependent manner. Though we see a modest, limited role for FAAH, our results suggest that MAGL is the primary cannabinoid-metabolizing enzyme in regulating ocular pressure, thus pointing towards a role of 2-arachidonoyl glycerol. Interestingly, inhibition of cannabinoid transport mechanisms independent of hydrolysis may prove to be an alternative strategy to lower ocular pressure. Highlights: Endocannabinoid metabolizing enzymes and transporters may offer an attractive target to regulate ocular pressure. Blocking either of the hypothesized endocannabinoid transporters lowers ocular pressure. Fatty acid amide hydrolase (FAAH) appears to play a complex, sex- and time-dependent role in regulating endocannabinoids. COX2, ABHD12, and NAAA do not appear to contribute to endocannabinoid metabolism in the context of regulation of ocular pressure.