Journal
JOURNAL OF NEUROIMMUNOLOGY
Volume 251, Issue 1-2, Pages 65-72Publisher
ELSEVIER
DOI: 10.1016/j.jneuroim.2012.07.006
Keywords
Nicotinic acetylcholine receptor; Inflammation; Neuroinflammation; A beta(1-42); GTS-21; Mitogen-activated protein kinase
Categories
Funding
- Danish Medical Research Council
- Danish Strategic Research Council
- Lundbeck Foundation
- NOVO Nordisk Foundation
- Danish Ministry of Science, Innovation and Higher Education
- Neurosearch A/S
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The anti-inflammatory properties of, particularly the alpha 7, nicotinic acetylcholine receptors (nAChRs) in the peripheral immune system are well documented. There are also reports of anti-inflammatory actions of nicotine in the CNS, but it is unclear, whether this is due to activation or inhibition of nAChRs. Here we investigate the mechanisms behind alpha 7 nAChR-mediated modulation of TNF-alpha release. We show that alpha 7 nAChR agonists or positive allosteric modulators do not affect LPS-induced release of the pro-inflammatory cytokine TNF-alpha from cultured microglia. This suggests that classical activation of, i.e. ion-flux through, the alpha 7 nAChR does not reduce TNF-alpha release from activated microglia. Contrarily, the alpha 7 nAChR antagonist methyllycaconitine and the weak (<10%) agonist NS6740 reduced LPS-induced TNF-alpha release, indicating that alpha 7 nAChR antagonism conveys anti-inflammatory properties on microglia. The effect of methyllycaconitine or NS6740 was not due to changes in MAPK signaling. These results suggest that the anti-inflammatory effects of nicotine seen in vivo are not due to classical activation of the alpha 7 nAChR, and further suggest that antagonism of alpha 7 nAChRs may reduce neuroinflammation. (C) 2012 Elsevier B.V. All rights reserved.
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