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dc.contributor.authorEl-Remessy, Azza B.
dc.contributor.authorTang, Y
dc.contributor.authorZhu, G
dc.contributor.authorMatragoon, Suraporn
dc.contributor.authorKhalifa, Yousef
dc.contributor.authorLiu, E K
dc.contributor.authorLiu, J-Y
dc.contributor.authorHanson, E
dc.contributor.authorMian, S
dc.contributor.authorFatteh, Nadeem
dc.contributor.authorLiou, Gregory I.
dc.date.accessioned2010-09-24T22:03:22Z
dc.date.available2010-09-24T22:03:22Z
dc.date.issued2008-12-04en_US
dc.identifier.citationMol Vis. 2008 Dec 3; 14:2190-2203en_US
dc.identifier.issn1090-0535en_US
dc.identifier.pmid19052649en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/114
dc.description.abstractPURPOSE: Degenerative retinal diseases are characterized by inflammation and microglial activation. The nonpsychoactive cannabinoid, cannabidiol (CBD), is an anti-inflammatory in models of diabetes and glaucoma. However, the cellular and molecular mechanisms are largely unknown. We tested the hypothesis that retinal inflammation and microglia activation are initiated and sustained by oxidative stress and p38 mitogen-activated protein kinase (MAPK) activation, and that CBD reduces inflammation by blocking these processes. METHODS: Microglial cells were isolated from retinas of newborn rats. Tumor necrosis factor (TNF)-alpha levels were estimated with ELISA. Nitric oxide (NO) was determined with a NO analyzer. Superoxide anion levels were determined by the chemiluminescence of luminol derivative. Reactive oxygen species (ROS) was estimated by measuring the cellular oxidation products of 2', 7'-dichlorofluorescin diacetate. RESULTS: In retinal microglial cells, treatment with lipopolysaccharide (LPS) induced immediate NADPH oxidase-generated ROS. This was followed by p38 MAPK activation and resulted in a time-dependent increase in TNF-alpha production. At a later phase, LPS induced NO, ROS, and p38 MAPK activation that peaked at 2-6 h and was accompanied by morphological change of microglia. Treatment with 1 microM CBD inhibited ROS formation and p38 MAPK activation, NO and TNF-alpha formation, and maintained cell morphology. In addition, LPS-treated rat retinas showed an accumulation of macrophages and activated microglia, significant levels of ROS and nitrotyrosine, activation of p38 MAPK, and neuronal apoptosis. These effects were blocked by treatment with 5 mg/kg CBD. CONCLUSIONS: Retinal inflammation and degeneration in uveitis are caused by oxidative stress. CBD exerts anti-inflammatory and neuroprotective effects by a mechanism that involves blocking oxidative stress and activation of p38 MAPK and microglia.
dc.rightsThe PMC Open Access Subset is a relatively small part of the total collection of articles in PMC. Articles in the PMC Open Access Subset are still protected by copyright, but are made available under a Creative Commons or similar license that generally allows more liberal redistribution and reuse than a traditional copyrighted work. Please refer to the license statement in each article for specific terms of use. The license terms are not identical for all articles in this subset.en_US
dc.subject.meshAnimalsen_US
dc.subject.meshCannabidiol / pharmacologyen_US
dc.subject.meshCell Death / drug effectsen_US
dc.subject.meshEndotoxins / pharmacologyen_US
dc.subject.meshEnzyme Activation / drug effectsen_US
dc.subject.meshEnzyme Inhibitors / pharmacologyen_US
dc.subject.meshLipopolysaccharides / pharmacologyen_US
dc.subject.meshMacrophages / enzymology / pathologyen_US
dc.subject.meshMaleen_US
dc.subject.meshMicroglia / drug effects / enzymology / pathologyen_US
dc.subject.meshModels, Biologicalen_US
dc.subject.meshNADPH Oxidase / antagonists & inhibitors / metabolismen_US
dc.subject.meshNeuroprotective Agents / pharmacologyen_US
dc.subject.meshNitric Oxide / metabolismen_US
dc.subject.meshOxidative Stress / drug effectsen_US
dc.subject.meshPeroxynitrous Acid / metabolismen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Sprague-Dawleyen_US
dc.subject.meshRetina / drug effects / enzymology / pathologyen_US
dc.subject.meshSuperoxides / metabolismen_US
dc.subject.meshTumor Necrosis Factor-alpha / secretionen_US
dc.subject.meshUveitis / chemically induced / enzymologyen_US
dc.subject.meshp38 Mitogen-Activated Protein Kinases / metabolismen_US
dc.titleNeuroprotective effects of cannabidiol in endotoxin-induced uveitis: critical role of p38 MAPK activation.en_US
dc.typeJournal Articleen_US
dc.typeResearch Support, Non-U.S. Gov'ten_US
dc.identifier.pmcidPMC2592995en_US
dc.contributor.corporatenameDepartment of Ophthalmologyen_US
refterms.dateFOA2019-04-09T16:23:48Z
html.description.abstractPURPOSE: Degenerative retinal diseases are characterized by inflammation and microglial activation. The nonpsychoactive cannabinoid, cannabidiol (CBD), is an anti-inflammatory in models of diabetes and glaucoma. However, the cellular and molecular mechanisms are largely unknown. We tested the hypothesis that retinal inflammation and microglia activation are initiated and sustained by oxidative stress and p38 mitogen-activated protein kinase (MAPK) activation, and that CBD reduces inflammation by blocking these processes. METHODS: Microglial cells were isolated from retinas of newborn rats. Tumor necrosis factor (TNF)-alpha levels were estimated with ELISA. Nitric oxide (NO) was determined with a NO analyzer. Superoxide anion levels were determined by the chemiluminescence of luminol derivative. Reactive oxygen species (ROS) was estimated by measuring the cellular oxidation products of 2', 7'-dichlorofluorescin diacetate. RESULTS: In retinal microglial cells, treatment with lipopolysaccharide (LPS) induced immediate NADPH oxidase-generated ROS. This was followed by p38 MAPK activation and resulted in a time-dependent increase in TNF-alpha production. At a later phase, LPS induced NO, ROS, and p38 MAPK activation that peaked at 2-6 h and was accompanied by morphological change of microglia. Treatment with 1 microM CBD inhibited ROS formation and p38 MAPK activation, NO and TNF-alpha formation, and maintained cell morphology. In addition, LPS-treated rat retinas showed an accumulation of macrophages and activated microglia, significant levels of ROS and nitrotyrosine, activation of p38 MAPK, and neuronal apoptosis. These effects were blocked by treatment with 5 mg/kg CBD. CONCLUSIONS: Retinal inflammation and degeneration in uveitis are caused by oxidative stress. CBD exerts anti-inflammatory and neuroprotective effects by a mechanism that involves blocking oxidative stress and activation of p38 MAPK and microglia.


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