Endocannabinoid metabolism and transport as targets to regulate intraocular pressure.

Miller S; Daily L; Dharla V; Gertsch J; Malamas MS; Ojima I; Kaczocha M; Ogasawara D; Straiker A

doi:10.1016/j.exer.2020.108266

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Journal article

Endocannabinoid metabolism and transport as targets to regulate intraocular pressure.

Miller S The Gill Center for Biomolecular Science, Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405, USA.
Daily L The Gill Center for Biomolecular Science, Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405, USA.
Dharla V The Gill Center for Biomolecular Science, Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405, USA.
Gertsch J Institute of Biochemistry and Molecular Medicine, NCCR TransCure, University of Bern, Bühlstrasse 28, 3012, Bern, Switzerland.
Malamas MS Center for Drug Discovery and Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA.
Ojima I Department of Chemistry, USA; Institute of Chemical Biology and Drug Discovery, USA.
Kaczocha M Institute of Chemical Biology and Drug Discovery, USA; Department of Anesthesiology, Stony Brook University, Stony Brook, NY, 11794, USA.
Ogasawara D Department of Chemistry, Scripps Research Institute, La Jolla, CA, 92037, USA.
Straiker A The Gill Center for Biomolecular Science, Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, 47405, USA. Electronic address: straiker@indiana.edu.

2020-09-26

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Experimental eye research. - 2020

English 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.

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