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PubMed: 21958873

Title
Anatabine lowers Alzheimer's Aβ production in vitro and in vivo.
Journal
European journal of pharmacology
Volume
670
Issue
None
Pages
384-91
Date
2011-11-30
Authors
Ait-Ghezala G | Bachmeier C | Beaulieu-Abdelahad D | Bishop A | Chao J | Crawford F | Mathura V | Mullan M | Paris D | Reed J

Evidence c95b7b6f58
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Anatabine dose dependently inhibited Aβ1–40 and Aβ1–42 with an approximate half maximal inhibitory concentration of 640 μg/ml for both Aβ1–40 and Aβ1–42 (Fig. 2).

a(CHEBI:Anatabine) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

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Experimental Factor Ontology (EFO)
CHO cell

a(CHEBI:Anatabine) decreases a(CHEBI:"amyloid-beta polypeptide 40") View Subject | View Object

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Evidence a45b7d7167
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We then tested the impact of anatabine on sAPPα and sAPPβ production using 7W CHO cells and observed that anatabine inhibits sAPPβ secretion without impacting sAPPα suggesting that anatabine is preventing the β-cleavage of APP (Fig. 4).

a(CHEBI:Anatabine) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

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CHO cell

a(CHEBI:Anatabine) decreases a(CHEBI:"amyloid-beta polypeptide 40") View Subject | View Object

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Experimental Factor Ontology (EFO)
CHO cell

a(CHEBI:Anatabine) decreases sec(p(HBP:"sAPP-beta")) View Subject | View Object

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CHO cell

a(CHEBI:Anatabine) causesNoChange sec(p(HBP:"sAPP-alpha")) View Subject | View Object

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Evidence 9981e24f81
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A significant reduction in the accumulation of brain soluble and insoluble Aβ1–40 and Aβ1–42 was observed following four days of treatment with 2 mg/kg of anatabine (Fig. 9).

a(CHEBI:Anatabine) decreases a(CHEBI:"amyloid-beta polypeptide 42") View Subject | View Object

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MeSH
Brain

a(CHEBI:Anatabine) decreases a(CHEBI:"amyloid-beta polypeptide 40") View Subject | View Object

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MeSH
Brain

Evidence 8411a50039
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No cytotoxicity was observed (as measured by the release of lactate dehydrogenase in the culture medium of 7W CHO cells) with the dose range of anatabine tested (data not shown).

a(CHEBI:Anatabine) causesNoChange sec(p(HGNC:LDHA)) View Subject | View Object

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Evidence d978dfee5b
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Contrary to anatabine, (−)-nicotine and other nicotinic acetylcholine receptors agonists and antagonists do not inhibit Aβ production by 7W CHO cells (Fig. 3).

a(CHEBI:Anatabine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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a(CHEBI:nicotine) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

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a(CHEBI:nicotine) increases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

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CHO cell

a(PUBCHEM:11957537) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

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a(PUBCHEM:11957537) decreases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

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CHO cell

a(PUBCHEM:56972222) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

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a(PUBCHEM:56972222) increases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

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CHO cell

a(PUBCHEM:71311633) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

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a(PUBCHEM:71311633) increases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

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CHO cell

p(HBP:"alpha-Bungarotoxin") causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

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CHO cell

p(HBP:"alpha-Bungarotoxin") decreases act(a(MESH:"Receptors, Nicotinic")) View Subject | View Object

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Evidence a6269fbb20
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In addition, a significant decreased in plasma Aβ levels was observed in mice treated with anatabine consistent with an inhibition of Aβ production (Fig. 10).

a(CHEBI:Anatabine) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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MeSH
Plasma

Evidence 348a07f253
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We observed that anatabine dose dependently inhibited NFκB activation by TNFα in HEK293 NFκB luciferase reporter cells (Fig. 5) whereas nicotine was ineffective

a(CHEBI:Anatabine) decreases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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a(CHEBI:nicotine) causesNoChange act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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p(HGNC:TNF) increases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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Evidence afab001781
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In addition, an inhibition of p65 NFκB phosphorylation was observed following treatment with anatabine in 7W CHO overexpressing APP (Fig. 6A), in HEK293 (Fig. 6B) and in human neuronal like SH-SY5Y cells (Fig. 6C) showing that anatabine can prevent NFκB activation in various cell lines.

a(CHEBI:Anatabine) decreases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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Experimental Factor Ontology (EFO)
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Experimental Factor Ontology (EFO)
SH-SY5Y

a(CHEBI:Anatabine) decreases p(HGNC:RELA, pmod(Ph)) View Subject | View Object

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CHO cell
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence a2386a9816
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Since BACE-1 transcription is regulated by NFκB (Buggia-Prevot et al., 2008) and since we have shown that anatabine inhibits NFκB activation, we investigated the effect of anatabine on BACE-1 transcription using human neuronal like SH-SY5Y cells

a(CHEBI:Anatabine) decreases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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complex(GO:"NF-kappaB complex") regulates p(HGNC:BACE1) View Subject | View Object

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Evidence 4adef72fd3
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Since anatabine lowers NFκB activation in vitro, we explored the possibility that anatabine may affect the level of C-reactive protein (CRP) whose expression is NFκB dependent (Karlsen et al., 2010; Yang et al.,2010).

a(CHEBI:Anatabine) decreases act(complex(GO:"NF-kappaB complex")) View Subject | View Object

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complex(GO:"NF-kappaB complex") regulates p(HGNC:CRP) View Subject | View Object

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Evidence ceb828e546
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As expected, TNFα greatly stimulated BACE-1 transcription whereas anatabine fully prevented the increase in BACE-1 mRNA levels induced by TNFα (Fig. 7A).

a(CHEBI:Anatabine) decreases r(HGNC:BACE1) View Subject | View Object

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Experimental Factor Ontology (EFO)
SH-SY5Y

p(HGNC:TNF) increases p(HGNC:BACE1) View Subject | View Object

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SH-SY5Y

Evidence 120fc1cdb3
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Following 24 h of treatment, a dose dependent inhibition of BACE-1 protein levels was observed with anatabine (Fig. 7B)

a(CHEBI:Anatabine) decreases p(HGNC:BACE1) View Subject | View Object

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SH-SY5Y

Evidence 6e1683ef79
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A statistically significant reduction in plasma CRP levels was observed following the 2 mg/kg treatment with anatabine showing that at this dosage anatabine displays an anti-inflammatory activity in vivo (Fig. 11).

a(CHEBI:Anatabine) decreases p(HGNC:CRP) View Subject | View Object

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MeSH
Plasma

Evidence ab52e2e232
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Nicotine does not appear to affect sAPPβ and sAPPα secretion in 7W CHO contrary to anatabine (Fig. 4)

a(CHEBI:nicotine) causesNoChange sec(p(HBP:"sAPP-beta")) View Subject | View Object

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Experimental Factor Ontology (EFO)
CHO cell

a(CHEBI:nicotine) causesNoChange sec(p(HBP:"sAPP-alpha")) View Subject | View Object

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