Early steps of microglial activation are directly affected by neuroprotectant FK506 in both in vitro inflammation and in rat model of stroke

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• 作者：Malgorzata Zawadzka (1)
  Michal Dabrowski (1)
  Agata Gozdz (1)
  Barbara Szadujkis (1)
  Marcin Sliwa (1)
  Maciej Lipko (1)
  Bozena Kaminska (1) (2)
  
• 关键词：CNS inflammation ; Microglia activation ; Immunosuppressants ; MAPK signaling ; Gene expression profiling
• 刊名：Journal of Molecular Medicine
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：90
• 期：12
• 页码：1459-1471
• 全文大小：874KB
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• 作者单位：Malgorzata Zawadzka (1)
  Michal Dabrowski (1)
  Agata Gozdz (1)
  Barbara Szadujkis (1)
  Marcin Sliwa (1)
  Maciej Lipko (1)
  Bozena Kaminska (1) (2)
  
  1. Laboratory of Transcription Regulation, Department Cell Biology, Nencki Institute of Experimental Biology, 3 Pasteur Str., 02-093, Warsaw, Poland
  2. Laboratory of Transcription Regulation, Nencki Institute of Experimental Biology, 3 Pasteur Str., 02-093, Warsaw, Poland
  
• ISSN：1432-1440

文摘

Neuroprotective and/or neuroregenerative activity of FK506, its derivatives, and to a lesser extent cyclosporin A (CsA) in animal models of neurodegenerative diseases of different etiology have been reported. Here, we verified a hypothesis that the most likely mechanism of their neuroprotective action is inhibition of the early steps of inflammatory activation of microglia by interference with mitogen-activated protein kinase (MAPK) signaling. The effect of immunosuppressants on lipopolysaccharide (LPS)-induced changes in morphology, proliferation, and motility of rat primary microglial cultures was evaluated. FK506 and CsA directly inhibited LPS-induced microglia activation and inflammatory responses. While both drugs efficiently reduced the expression of iNOS and the release of nitric oxide, only FK506 strongly inhibited the expression of Cox-2 and secretion of the mature form of IL-1β. FK506 strongly reduced LPS-induced activation of MAPK, and its downstream signaling crucial for inflammatory responses. Comparative analysis of global gene expression in rat ischemic brains and in LPS-stimulated microglial cultures revealed many genes and signaling pathways regulated in the same way in both systems. FK506 treatment blocked a majority of genes induced by an ischemic insult in the cortex, in particular inflammatory/innate immunity and apoptosis-related genes. Microglia-mediated inflammation is considered as one of the most important components of brain injury after trauma or stroke; thus, effective and multifaceted blockade of microglial activation by FK506 has clinical relevance and potential therapeutic implications.