Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6156077 | Translational Research | 2016 | 46 Pages |
Abstract
Glaucoma is a leading cause of vision loss and blindness worldwide, characterized by chronic and progressive neuronal loss. Reactive microglial cells have been recognized as a neuropathologic feature, contributing to local inflammation and retinal neurodegeneration. In a recent in vitro work (organotypic cultures), we demonstrated that blockade of adenosine A2A receptor (A2AR) prevents the neuroinflammatory response and affords protection to retinal ganglion cells (RGCs) against exposure to elevated hydrostatic pressure (EHP), to mimic elevated intraocular pressure (IOP), the main risk factor for glaucoma development. Herein, we investigated whether a selective A2AR antagonist (SCH 58261) could modulate retinal microglia reactivity and their inflammatory response. Furthermore, we took advantage of the high IOP-induced transient ischemia (ischemia-reperfusion, I-R) animal model to evaluate the protective role of A2AR blockade in the control of retinal neuroinflammation and neurodegeneration. Primary microglial cell cultures were challenged either with lipopolysaccharide or with EHP, in the presence or absence of A2AR antagonist SCH 58261 (50 nM). In addition, I-R injury was induced in adult Wistar rats after intravitreal administration of SCH 58261 (100 nM, 5 μL). Our results showed that SCH 58261 attenuated microglia reactivity and the increased expression and release of proinflammatory cytokines. Moreover, intravitreal administration of SCH 58261 prevented I-R-induced cell death and RGC loss, by controlling microglial-mediated neuroinflammatory response. These results prompt the proposal that A2AR blockade may have great potential in the management of retinal neurodegenerative diseases characterized by microglia reactivity and RGC death, such as glaucoma and ischemic diseases.
Keywords
TNFIPLiOpGCLINLiNOSRGCOPLONLEGTAmRNAHEPESPBSA2ARLPSEHPFBSI-RCTCFM-CSF4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidmessenger RNAEDTAethylene glycol tetraacetic acidethylenediamine tetraacetic acidischemia-reperfusioninterleukinCNSfetal bovine serumretinal ganglion cellinducible nitric oxide synthasecentral nervous systemtumor necrosis factorIntraocular pressurecorrected total cell fluorescenceouter plexiform layerouter nuclear layerinner plexiform layerinner nuclear layerganglion cell layerlipopolysaccharidemacrophage colony–stimulating factorPhosphate-buffered salineNitric oxidepolymerase chain reactionPCRAdenosine A2A receptor
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Authors
Maria H. Madeira, Raquel Boia, Filipe Elvas, Tiago Martins, Rodrigo A. Cunha, António Francisco Ambrósio, Ana Raquel Santiago,