title: Statin treatment affects cytokine release and phagocytic activity in primary cultured microglia through two separable mechanisms.
abstract: BACKGROUND
  As the primary immune cells of the central nervous system, microglia contribute to development, homeostasis, and plasticity of the central nervous system, in addition to their well characterized roles in the foreign body and inflammatory responses. Increasingly, inappropriate activation of microglia is being reported as a component of inflammation in neurodegenerative and neuropsychiatric disorders. The statin class of cholesterol-lowering drugs have been observed to have anti-inflammatory and protective effects in both neurodegenerative diseases and ischemic stroke, and are suggested to act by attenuating microglial activity.
  
  
  RESULTS
  We sought to investigate the effects of simvastatin treatment on the secretory profile and phagocytic activity of primary cultured rat microglia, and to dissect the mechanism of action of simvastatin on microglial activity. Simvastatin treatment altered the release of cytokines and trophic factors from microglia, including interleukin-1-β, tumour necrosis factor-α, and brain derived neurotrophic factor in a cholesterol-dependent manner. Conversely, simvastatin inhibited phagocytosis in microglia in a cholesterol-independent manner.
  
  
  CONCLUSIONS
  The disparity in cholesterol dependence of cytokine release and phagocytosis suggests the two effects occur through distinct molecular mechanisms. These two pathways may provide an opportunity for further refinement of pharmacotherapies for neuroinflammatory, neurodegenerative, and neuropsychiatric disorders.
authors.affiliation: Neurochemical Research Unit, University of Alberta Faculty of Medicine, Edmonton, AB, Canada, T6G 2R3. churchward@ualberta.ca.|Department of Psychiatry, University of Alberta Faculty of Medicine, Edmonton, AB, Canada, T6G 2R3. churchward@ualberta.ca.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Churchward
authors.affiliation: Neurochemical Research Unit, University of Alberta Faculty of Medicine, Edmonton, AB, Canada, T6G 2R3. kgtodd@ualberta.ca.|Department of Psychiatry, University of Alberta Faculty of Medicine, Edmonton, AB, Canada, T6G 2R3. kgtodd@ualberta.ca.|Neuroscience and Mental Health Institute, University of Alberta Faculty of Medicine, Edmonton, AB, Canada, T6G 2R3. kgtodd@ualberta.ca.
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Todd
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D053583:Interleukin-1beta / Q000378:metabolism; D017628:Microglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; D019821:Simvastatin