Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells.
Nitric oxide (NO) has been implicated in the etiopathology of central nervous system (CNS) diseases such as multiple sclerosis (MS). Inhibition of NO synthesis has been proposed to be a possible mechanism of action of relevance in the treatment of multiple sclerosis and migraine. Here, we investigated the effect of parthenolide on inducible NO synthase (iNOS) synthesis and NO release using primary rat microglia. We found parthenolide to be an inhibitor of iNOS/NO synthesis. Investigating the molecular mechanisms by which parthenolide prevents iNOS/NO synthesis, we found that parthenolide inhibits the activation of p42/44 mitogen-activated protein kinase (MAPK), but not IkBalpha (IkappaBalpha) degradation or nuclear factor-kappaB (NF-kappaB) p65 activation. The data suggest that parthenolide might have a potential in the treatment of CNS diseases where NO is part of the pathophysiology.
Fiebich
Bernd L
BL
Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, D-79104 Freiburg, Germany. bernd_fiebich@psyallg.ukl.uni-freiburg.de
Lieb
Klaus
K
Engels
Stefanie
S
Heinrich
Michael
M
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000494:pharmacology*; D051996:Transcription Factor RelA; D048051:p38 Mitogen-Activated Protein Kinases
D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D012717:Sesquiterpenes; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; C002669:parthenolide; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases