Anatabine

Anti-inflammatory activity of anatabine via inhibition of STAT3 phosphorylation.[Pubmed:23178521]

Eur J Pharmacol. 2013 Jan 5;698(1-3):145-53.

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 NFkappaB phosphorylation induced by lipopolysaccharide (LPS) or TNF-alpha in SH-SY5Y, HEK293, human microglia and human blood mononuclear cells. Using human whole blood, we found that Anatabine prevents IL-1beta 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-1beta and TNF-alpha) 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-alpha 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.

Anatabine lowers Alzheimer's Abeta production in vitro and in vivo.[Pubmed:21958873]

Eur J Pharmacol. 2011 Nov 30;670(2-3):384-91.

Brain Abeta accumulation represents a key pathological hallmark in Alzheimer's disease. In this study, we investigated the impact of Anatabine, a minor alkaloid present in plants of the Solanacea family on Abeta production in vitro using a cell line overexpressing the human amyloid precursor protein (APP) and in vivo using a transgenic mouse model of Alzheimer's disease. In vitro, Anatabine lowers Abeta(1)(-)(4)(0) and Abeta(1)(-)(4)(2) levels in a dose dependent manner and reduces sAPPbeta production without impacting sAPPalpha levels suggesting that Anatabine lowers Abeta production by mainly impacting the beta-cleavage of APP. Additionally, we show that Anatabine lowers NFkappaB activation at doses that inhibit Abeta production in vitro. Since NFkappaB is known to regulate BACE-1 expression (the rate limiting enzyme responsible for Abeta production), we determined the impact of Anatabine on BACE-1 transcription. We show that Anatabine inhibits BACE-1 transcription and reduces BACE-1 protein levels in human neuronal like SHSY-5Y cells suggesting that the Abeta lowering properties of Anatabine are mediated via a regulation of BACE-1 expression. In vivo, we show that an acute treatment with Anatabine for four days significantly lowers brain soluble Abeta(1)(-)(4)(0) and Abeta(1)(-)(4)(2) levels in a transgenic mouse model of Alzheimer's disease. Altogether our data suggest that Anatabine may represent an interesting compound for regulating brain Abeta accumulation.

Anatabine ameliorates experimental autoimmune thyroiditis.[Pubmed:22807490]

Endocrinology. 2012 Sep;153(9):4580-7.

Tobacco smoking favorably influences the course of Hashimoto thyroiditis, possibly through the antiinflammatory proprieties of nicotine. In this study we tested Anatabine, another tobacco alkaloid, in a model of experimental autoimmune thyroiditis. Experimental autoimmune thyroiditis was induced by different doses of thyroglobulin, to produce a disease of low, moderate, or high severity, in 88 CBA/J female mice: 43 drank Anatabine supplemented water and 45 regular water. Mice were bled after immunization and killed to assess thyroid histopathology, thyroglobulin antibodies, T(4), and thyroid RNA expression of 84 inflammatory genes. We also stimulated in vitro a macrophage cell line with interferon-gamma or lipopolysaccharide plus or minus Anatabine to quantitate inducible nitric oxide synthase and cyclooxygenase 2 protein expression. Anatabine reduced the incidence and severity of thyroiditis in the moderate disease category: only 13 of 21 mice (62%) developed thyroid infiltrates when drinking Anatabine as compared with 22 of 23 (96%) controls (relative risk 0.59, P = 0.0174). The median thyroiditis severity was 0.5 and 2.0 in Anatabine and controls, respectively (P = 0.0007 by Wilcoxon rank sum test). Anatabine also reduced the antibody response to thyroglobulin on d 14 (P = 0.029) and d 21 (P = 0.045) after immunization and improved the recovery of thyroid function on d 21 (P = 0.049). In the thyroid transcriptome, Anatabine restored expression of IL-18 and IL-1 receptor type 2 to preimmunization levels. Finally, Anatabine suppressed in a dose-dependent manner macrophage production of inducible nitric oxide synthase and cyclooxygenase 2. Anatabine ameliorates disease in a model of autoimmune thyroiditis, making the delineation of its mechanisms of action and potential clinical utility worthwhile.