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Philipp Steven, Daniela Heß, Horstmann Jens, Frank M Dautzenberg, Michael E Stern, Uta Gehlsen; Application of a Cannabinoid-Receptor Agonist in a Mouse Model of Desiccating Stress. Invest. Ophthalmol. Vis. Sci. 2019;60(9):273.
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The endocannabinoid systems (ECS) is physiologically involved in regulating inflammation, nociception and wound healing. As pathologic inflammation, pain and impaired wound healing are key features of dry eye disease, simultaneously targeting these mechanisms could improve therapeutic success. However, little is known about the ECS and the eye in this context. This project was set up to test the hypothesis, that the genes encoding cannabinoid receptors 1 and 2 (CB1, CB2 ) are expressed in the murine eye and that topical application of the cannabinoid receptor ligand Δ9-Tetrahydrocannabinol (THC) formulated in a semifluorinated alkane (SFA) as delivery platform would improve dry eye disease in a desiccating mouse model.
Quantitative PCR was performed to detect mRNA from CB1 and CB2 in cornea, conjunctiva and lacrimal glands (LG) of naïve B6 mice. Experimental dry eye disease was induced by scopolamine and desiccating stress. 0.1 % or 0.5 % THC in the SFA F4H5 were applied TID during or following desiccating stress. Clinical readouts included corneal fluorescein staining, corneal sensitivity, tear production (TP) and behavioral monitoring. Corneal nerves were analyzed in corneal whole mounts. T-cell response was determined using FACS analysis.
CCB1 and CB2 mRNA was expressed in all ocular tissues tested with strongest relative expression in LG. Application of THC/F4H5 demonstrated dose-dependent improvement of experimental dry-eye by significant decrease of corneal staining by two grades (p<0.001) and increase of TP in comparison to controls. THC/F4H5 did not induce anesthesia. Nerve fiber quantification demonstrated higher nerve fiber length (71 mm/mm2) in treated animals compared to control (39 mm/mm2) (p=0.03). Number of CD4+ T-cells was lower by 5 % (p=0.03) and CD4:CD8 ratio in lymph nodes was 1.2 in THC/F4H5 treated animals in comparison to controls (1.4, p=0.05). No behavioral abnormalities were noted.
The presence of CB1 and CB2 receptors in ocular tissues implicate a role in maintaining ocular surface health. Disruption of the ECS may therefore be part of dry eye disease, however this has not been shown so far. This study demonstrates that applying the partial agonist THC in a water-free delivery platform improves certain features of experimental desiccating stress and could evolve into a novel treatment concept.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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