title: Minocycline exerts inhibitory effects on multiple mitogen-activated protein kinases and IkappaBalpha degradation in a stimulus-specific manner in microglia.
abstract: CNS inflammation mediated by microglial activation can result in neuronal and glial cell death in a variety of neurodegenerative and demyelinating diseases. Minocycline, a second-generation tetracycline, has profound anti-inflammatory properties in the CNS mediated, in part, by inhibition of microglia. MAPK and nuclear factor-kappaB (NF-kappaB) activation are hallmarks of activated microglia and they are critical for the expression of many inflammatory mediators. In the present study, we investigated minocycline effects on activation of p38, c-Jun-N-terminal activated protein kinase (JNK) 1/2 and extracellular signal regulated kinase (ERK) 1/2 MAPKs and inhibitor alpha of NF-kappaB (IkappaBalpha) degradation in BV-2 and primary microglial cells. Our results demonstrate that minocycline has the ability to inhibit all MAPKs but these effects strongly depend on the stimulus used for MAPK activation. Minocycline significantly decreased activation of all lipopolysaccharide-stimulated MAPKs but it was without effect on MAPKs activated by H2O2. Minocycline inhibited JNK1/2 and ERK1/2 but not p38 when stimulated by 2',3'-O-(4-benzoylbenzoyl)-adenosine 5'-triphosphate, indicating that minocycline affects only certain upstream signaling target(s) that are stimulus-specific. Our data also suggest that protein kinase C (PKC) inhibition may be partially involved in the minocycline mechanism of MAPK inhibition. In addition, minocycline attenuated lipopolysaccharide-stimulated degradation of IkappaBalpha implying a possible inhibitory role on NF-kappaB transcriptional activity.
authors.affiliation: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53706, USA. nikodemova@svm.vetmed.wisc.edu
authors.forename: Maria
authors.initials: M
authors.lastname: Nikodemova
authors.forename: Ian D
authors.initials: ID
authors.lastname: Duncan
authors.forename: Jyoti J
authors.initials: JJ
authors.lastname: Watters
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D020033:Protein Isoforms; D009569:Nitric Oxide; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D008911:Minocycline