title: Adenosine A2A receptor antagonism reverses inflammation-induced impairment of microglial process extension in a model of Parkinson's disease.
abstract: Microglia, the immune cells of the central nervous system, constantly survey the parenchyma in the healthy brain to maintain homeostasis. When a disturbance, such as cell death, results in ATP release in vivo, microglial processes respond by utilizing P2Y12 purinergic receptors to trigger extension toward the site of damage. Processes ultimately surround the injury site, preventing the spread of harmful cellular constituents and assisting with tissue repair. In contrast to the healthy brain, many neurodegenerative diseases, including Parkinson's disease, are characterized by the presence of neuroinflammation. Yet, the ability of microglia to respond to tissue damage under pro-inflammatory conditions has not been well studied. To assess the ability of microglia to respond to tissue injury and localized cell death in the context of Parkinson's disease, we performed confocal imaging of acute brain slices from mice with microglia-specific green fluorescent protein expression. Microglia in coronal slices containing the substantia nigra extend processes toward a mechanical injury in a P2Y12 receptor-dependent manner. However, microglia in mice treated for 5days with 20mg/kg/day 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) show significantly reduced process displacement toward the injury compared to microglia in control animals. Pre-treatment of slices from MPTP-injected mice with the A2A receptor-selective antagonist preladenant restores the ability of activated microglia to respond to tissue damage. These data support the hypothesis that chronic inflammation impedes microglial motility in response to further injury, such as cell death, and suggest that some aspects of the neuroprotection observed with adenosine A2A receptor antagonists may involve direct or indirect actions at microglia.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA; Graduate Division of Biological and Biomedical Sciences, Molecular and Systems Pharmacology Program, Emory University, Atlanta, GA 30322, USA. Electronic address: stefka.gyoneva@gmail.com.
authors.forename: Stefka
authors.initials: S
authors.lastname: Gyoneva
authors.affiliation: Graduate Division of Biological and Biomedical Sciences, Molecular and Systems Pharmacology Program, Emory University, Atlanta, GA 30322, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Shapiro
authors.affiliation: School of Public Health, Environmental Health, Emory University, Atlanta, GA 30322, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lazo
authors.affiliation: Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: Ethel
authors.initials: E
authors.lastname: Garnier-Amblard
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Yoland
authors.initials: Y
authors.lastname: Smith
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA; School of Public Health, Environmental Health, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Miller
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020267:MPTP Poisoning / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D008070:Lipopolysaccharides
keywords: Acute brain slice; Adenosine A(2A) receptor; Imaging; Microglia; Neuroinflammation; Parkinson's disease; Preladenant