title: Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation.
abstract: Previous investigations have demonstrated the anti-inflammatory effects of cholinergic agonists, such as nicotine. In the present study, we investigated the potential anti-inflammatory activity of anatabine, a minor tobacco alkaloid also present in plants of the Solanacea family which displays a chemical structural similarity with nicotine. Our data show that anatabine prevents STAT3 and NFκB phosphorylation induced by lipopolysaccharide (LPS) or TNF-α in SH-SY5Y, HEK293, human microglia and human blood mononuclear cells. Using human whole blood, we found that anatabine prevents IL-1β production induced by LPS. We assessed anatabine's anti-inflammatory activity in vivo using an acute model of inflammation by challenging wild-type mice with LPS. We observed that anatabine reduces pro-inflammatory cytokine production (IL-6, IL-1β and TNF-α) in the plasma, kidney and spleen of the animals following the injection of LPS and concomitantly opposes STAT3 phosphorylation induced by LPS in the spleen and kidney. We also investigated the impact of anatabine on neuroinflammation using a transgenic mouse model of Alzheimer's disease (Tg APPsw) that displays elevated cytokine levels in the brain. Following a chronic oral treatment with anatabine, a reduction in brain TNF-α and IL-6 levels compared to untreated Tg APPsw mice was observed. Moreover, an increased STAT3 phosphorylation was detected in the brains of Tg APPsw mice compared to wild-type littermates and was inhibited by anatabine treatment. Overall our data show that the anti-inflammatory activity of anatabine in vitro and in vivo is mediated in part via an inhibition of STAT3 phosphorylation.
authors.affiliation: The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, Florida 34243, USA. dparis@rfdn.org
authors.forename: Daniel
authors.initials: D
authors.lastname: Paris
authors.forename: David
authors.initials: D
authors.lastname: Beaulieu-Abdelahad
authors.forename: Laila
authors.initials: L
authors.lastname: Abdullah
authors.forename: Corbin
authors.initials: C
authors.lastname: Bachmeier
authors.forename: Ghania
authors.initials: G
authors.lastname: Ait-Ghezala
authors.forename: Jon
authors.initials: J
authors.lastname: Reed
authors.forename: Megha
authors.initials: M
authors.lastname: Verma
authors.forename: Fiona
authors.initials: F
authors.lastname: Crawford
authors.forename: Michael
authors.initials: M
authors.lastname: Mullan
mesh_terms: D000470:Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D011725:Pyridines; D050796:STAT3 Transcription Factor; C012737:anatabine