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M. E. Kelly, A. Dong, S. E. Howlett, M. Almasieh, A. Wilson, A. Di Polo; Vasoactive and Neuroprotective Actions of a Non-Pyschotropic Atypical Cannabinoid in the Retina. Invest. Ophthalmol. Vis. Sci. 2009;50(13):87.
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© ARVO (1962-2015); The Authors (2016-present)
Cannabinoids have vasoactive and neuroprotective actions in the eye, however, their therapeutic use is limited by behavioral side-effects. Abnormal cannabidiol (Abn-CBD), is a non-pyschotropic, atypical cannabinoid that produces vasodilation. We examined the in vitro vasoactive actions of Abn-CBD in retinal arterioles and determined if Abn-CBD was neuroprotective in vivo following optic nerve axotomy.
Retinal arterioles were isolated from retinal tissue, plated on poly-D-lysine in an experimental bath and superfused at 37°C. Drugs were locally applied and changes in arteriole diameter were measured with a video edge detector. For studies of neuroprotection, retinal ganglion cells (RGCs) were retrogradely labeled in vivo with fluorogold (FG). 7 days post-labeling, the optic nerve was transected 1 mm behind the globe. Abn-CBD (100 µM) was injected intravitreally at 0 and 7 days post-axotomy. At 14 days post-axotomy, animals were sacrificed, eyes enucleated and fixed with 4% paraformaldehyde. Retinas were flat-mounted and analyzed for FG-labeled RGC densities and the presence of phagocytic microglial (MG) cells.
Abn-CBD (10 µM) caused relaxation of endothelin-1 vasoconstricted arterioles (43% relaxation, n=10). Abn-CBD-mediated vasorelaxation was not inhibited by antagonists of cannabinoid 1 (CB1) or cannabinoid 2 (CB2) receptors, but was completely blocked by O-1918 (108% inhibition, n=5), an antagonist of the novel endothelial cannabinoid (CBx) receptor and reduced by L-NAME (31% inhibition, n=6, 100 µM), a nitric oxide synthase (NOS) blocker. Examination of the neuroprotective effects of Abn-CBD at 14 days post-axotomy revealed marked RGC survival (28%, n=4) compared to the saline-treated controls (9%, n=4). Phagocytic MG cells were reduced in Abn-CBD-treated axotomized eyes compared to saline-treated eyes.
Abn-CBD produced vasorelaxation of retinal arterioles via activation of a novel vascular cannabinoid receptor(s). Abn-CBD also produced neuroprotection of RGCs and a reduction in the presence of phagocytic MG following axotomy, suggesting additional actions on non-vascular targets. The vasorelaxant and neuroprotective properties of the behaviorally-inactive cannabinoid, Abn-CBD, may indicate therapeutic potential for treatment of retinopathies.
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