title: Selective A2A receptor antagonist prevents microglia-mediated neuroinflammation and protects retinal ganglion cells from high intraocular pressure-induced transient ischemic injury.
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.
authors.affiliation: Faculty of Medicine, Institute for Biomedical Imaging and Life Sciences (IBILI), University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Maria H
authors.initials: MH
authors.lastname: Madeira
authors.affiliation: Faculty of Medicine, Institute for Biomedical Imaging and Life Sciences (IBILI), University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Boia
authors.affiliation: Faculty of Medicine, Institute for Biomedical Imaging and Life Sciences (IBILI), University of Coimbra, Coimbra, Portugal; Association for Innovation and Biomedical Research on Light (AIBILI), Coimbra, Portugal.
authors.forename: Filipe
authors.initials: F
authors.lastname: Elvas
authors.affiliation: Faculty of Medicine, Institute for Biomedical Imaging and Life Sciences (IBILI), University of Coimbra, Coimbra, Portugal; Association for Innovation and Biomedical Research on Light (AIBILI), Coimbra, Portugal.
authors.forename: Tiago
authors.initials: T
authors.lastname: Martins
authors.affiliation: CNC.IBILI, University of Coimbra, Coimbra, Portugal; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: Faculty of Medicine, Institute for Biomedical Imaging and Life Sciences (IBILI), University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal; Association for Innovation and Biomedical Research on Light (AIBILI), Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: António Francisco
authors.initials: AF
authors.lastname: Ambrósio
authors.affiliation: Faculty of Medicine, Institute for Biomedical Imaging and Life Sciences (IBILI), University of Coimbra, Coimbra, Portugal; CNC.IBILI, University of Coimbra, Coimbra, Portugal; Association for Innovation and Biomedical Research on Light (AIBILI), Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address: asantiago@fmed.uc.pt.
authors.forename: Ana Raquel
authors.initials: AR
authors.lastname: Santiago
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D007249:Inflammation / Q000517:prevention & control*; D007511:Ischemia / Q000517:prevention & control*; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000187:drug effects*
chemical_list: D058917:Adenosine A2 Receptor Antagonists