Endocannabinoid metabolism and transport as targets to regulate intraocular pressure.

Miller, Sally; Daily, Laura; Dharla, Vijai; Gertsch, Jürg; Malamas, Michael S; Ojima, Iwao; Kaczocha, Martin; Ogasawara, Daisuke; Straiker, Alex (2020). Endocannabinoid metabolism and transport as targets to regulate intraocular pressure. Experimental eye research, 201, p. 108266. Elsevier 10.1016/j.exer.2020.108266

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
04 Faculty of Medicine > Faculty Institutions > NCCR TransCure

UniBE Contributor:

Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0014-4835

Publisher:

Elsevier

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

18 Mar 2021 10:02

Last Modified:

18 Mar 2021 13:17

Publisher DOI:

10.1016/j.exer.2020.108266

PubMed ID:

32979397

Uncontrolled Keywords:

ABHD12 Anandamide COX2 Cannabinoid FAAH Glaucoma NAAA Ocular pressure Transporter

BORIS DOI:

10.48350/154256

URI:

https://boris.unibe.ch/id/eprint/154256

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