title: Dopamine modulates astroglial and microglial activity via glial renin-angiotensin system in cultures.
abstract: Dopamine is an immunomodulatory molecule that acts on immune effector cells both in the CNS and peripheral tissues. However, the role of changes in dopamine levels in the neuroinflammatory response is controversial. The local/paracrine renin-angiotensin system (RAS) plays a major role in inflammatory processes in peripheral tissues and brain. In the present study, we investigated the possible role of the brain RAS in the effects of dopamine on the glial inflammatory responses. Astrocytes are the major source of the precursor protein angiotensinogen and angiotensin II (AII) in the brain. Neurotoxins such as MPP+(1-methyl-4-phenylpyridinium) can act directly on astrocytes to increase levels of angiotensinogen and AII. Conversely, dopamine, via type-2 (D2) receptors, inhibited production of angiotensinogen, decreased expression of angiotensin type-1 (AT1) receptors and increased expression of AT2 receptors. In microglia, dopamine and dopamine agonists also regulated RAS activity. First, indirectly, via downregulation of the astrocyte-derived AII. Second, via dopamine-induced regulation of microglial angiotensin receptors. Dopamine decreased the microglial AT1/AT2 ratio leading to inhibition of the pro-inflammatory AT1/NADPH-oxidase/superoxide axis. D2 receptors were particularly responsible for microglial RAS inhibition in basal culture conditions. However, both D1 and D2 agonists inhibited the AT1/NADPH-oxidase axis in lipopolysaccharide-treated (LPS; i.e. activated) microglia. The results indicate that the decrease in dopamine levels observed in early stages of Parkinson's disease and aging may promote neuroinflammation and disease progression via glial RAS exacerbation.
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Dominguez-Meijide
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rodriguez-Perez
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Diaz-Ruiz
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Guerra
authors.affiliation: Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain. Electronic address: joseluis.labandeira@usc.es.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Labandeira-Garcia
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000808:Angiotensinogen / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001552:Benzazepines / Q000494:pharmacology; D002478:Cells, Cultured; D004298:Dopamine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012457:Salicylamides / Q000494:pharmacology
chemical_list: D001552:Benzazepines; D018492:Dopamine Antagonists; C534628:SCH 23390; D012457:Salicylamides; D000808:Angiotensinogen; C045989:eticlopride; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine
keywords: Aging; Angiotensin; Astrocytes; Dopaminergic; Immunomodulation; Microglia; NADPH-oxidase; Neuroinflammation; Parkinson