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Dopamine Quinones Activate Microglia and Induce a Neurotoxic Gene Expression Profile
Author(s) -
KUHN DONALD M.,
FRANCESCUTTIVERBEEM DINA M.,
THOMAS DAVID M.
Publication year - 2006
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1369.003
Subject(s) - neurotoxicity , meth , microglia , methamphetamine , neuroinflammation , gene expression , inflammation , biology , microbiology and biotechnology , dopamine , gene knockdown , chemistry , neuroscience , pharmacology , gene , immunology , biochemistry , toxicity , monomer , organic chemistry , acrylate , polymer
Methamphetamine (METH) intoxication leads to persistent damage of dopamine (DA) nerve endings of the striatum. Recently, we and others have suggested that the neurotoxicity associated with METH is mediated by extensive microglial activation. DA itself has been shown to play an obligatory role in METH neurotoxicity, possibly through the formation of quinone species. We show presently that DA‐quinones (DAQ) cause a time‐dependent activation of cultured microglial cells. Microarray analysis of the effects of DAQ on microglial gene expression revealed that 101 genes were significantly changed in expression, with 73 genes increasing and 28 genes decreasing in expression. Among those genes differentially regulated by DAQ were those often associated with neurotoxic conditions including inflammation, cytokines, chemokines, and prostaglandins. In addition, microglial genes associated with a neuronally protective phenotype were among those that were downregulated by DAQ. These results implicate DAQ as one species that could cause early activation of microglial cells in METH intoxication, manifested as an alteration in the expression of a broad biomarker panel of genes. These results also link oxidative stress, chemical alterations in DA to its quinone, and microglial activation as part of a cascade of glial–neuronal crosstalk that can amplify METH‐induced neurotoxicity.