Early steps of microglial activation are directly affected by neuroprotectant FK506 in both in vitro inflammation and in rat model of stroke.
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.
Laboratory of Transcription Regulation, Department Cell Biology, Nencki Institute of Experimental Biology, 3 Pasteur Str., 02-093 Warsaw, Poland.
Malgorzata
M
Zawadzka
Michal
M
Dabrowski
Agata
A
Gozdz
Barbara
B
Szadujkis
Marcin
M
Sliwa
Maciej
M
Lipko
Bozena
B
Kaminska
D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases; D051381:Rats; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology* / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D016559:Tacrolimus