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PubMed: 23383175

Title
Amelioration of experimental autoimmune encephalomyelitis by anatabine.
Journal
PloS one
Volume
8
Issue
None
Pages
e55392
Date
2013-01-01
Authors
Mullan MJ | Mathura V | Ait-Ghezala G | Bachmeier C | Beaulieu-Abdelahad D | Crawford F | Mullan M | Paris D

Evidence 5e44e6c9e2
JSON

However, a significant reduction in IL-17 was observed in the spleen of EAE anatabine treated mice compared to EAE placebo mice (Fig. 2C)

a(CHEBI:Anatabine) decreases p(MGI:Il17a) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen
MeSH
Encephalomyelitis

Evidence bc560719c4
JSON

This particular dosage was selected from a previous study showing that this dosage is efficient at lowering brain cytokine levels in a mouse model of Alzheimer’s disease displaying chronic neuroinflammation

a(CHEBI:Anatabine) decreases a(MESH:Cytokines) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Alzheimer Disease

Evidence 24c583ecd2
JSON

Clinical signs of EAE became apparent by day 6 following the immunization in the placebo group but were delayed to day 11 in the anatabine treatment group (Fig. 1A)

a(CHEBI:Anatabine) negativeCorrelation path(MESH:Encephalomyelitis) View Subject | View Object

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path(MESH:Encephalomyelitis) negativeCorrelation a(CHEBI:Anatabine) View Subject | View Object

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Evidence d627687ff0
JSON

The average clinical severity of EAE was also significantly reduced by the anatabine treatment (Fig. 1B)

a(CHEBI:Anatabine) decreases path(MESH:Encephalomyelitis) View Subject | View Object

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Evidence 3b2d7f232e
JSON

Importantly, approximately 70% of the mice in the placebo group developed hind-limb weakness or paralysis compared to only 20% in the anatabine treatment group (Fig. 1C) showing that the mice treated with anatabine displayed significantly milder disease symptoms than the placebo group

a(CHEBI:Anatabine) decreases path(MESH:Paralysis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Encephalomyelitis

a(CHEBI:Anatabine) decreases path(HP:"Limb muscle weakness") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Encephalomyelitis

Evidence f3f8670bfd
JSON

However, anatabine significantly suppressed the production of IL-1b, IL-6 and IL-17A in the serum of EAE mice (Fig. 2B) but did not significantly impact IFN-gamma and TNF-alpha

a(CHEBI:Anatabine) decreases p(MGI:Il1b) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Serum
MeSH
Encephalomyelitis

a(CHEBI:Anatabine) decreases p(MGI:Il6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Serum
MeSH
Encephalomyelitis

a(CHEBI:Anatabine) decreases p(MGI:Il17a) View Subject | View Object

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Annotations
MeSH
Serum
MeSH
Encephalomyelitis

a(CHEBI:Anatabine) causesNoChange p(MGI:Ifng) View Subject | View Object

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Annotations
MeSH
Serum
MeSH
Encephalomyelitis

a(CHEBI:Anatabine) causesNoChange p(MGI:Tnf) View Subject | View Object

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MeSH
Serum
MeSH
Encephalomyelitis

Evidence b32622908d
JSON

Anatabine appears to fully suppress IL-1b, INF-gamma and TNF-a elevation in the spleen of EAE mice (Fig. 2C).

a(CHEBI:Anatabine) decreases p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen
MeSH
Encephalomyelitis

a(CHEBI:Anatabine) decreases p(MGI:Il1b) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen
MeSH
Encephalomyelitis

a(CHEBI:Anatabine) decreases p(MGI:Ifng) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen
MeSH
Encephalomyelitis

Evidence 1dc845548f
JSON

We have shown previously that anatabine prevents STAT3 and p65 NFkB phosphorylation in various cell types and suggested that anatabine impact cytokine production by this mechanism as both STAT3 and p65 NFkB are known to regulate cytokine production.

a(CHEBI:Anatabine) decreases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

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a(CHEBI:Anatabine) decreases p(MGI:Rela, pmod(Ph)) View Subject | View Object

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p(MGI:Rela) regulates bp(GO:"cytokine production") View Subject | View Object

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p(MGI:Stat3) regulates bp(GO:"cytokine production") View Subject | View Object

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Evidence a76190cd78
JSON

Interestingly, a significant increase in STAT3 phosphorylation was observed in the spleen of EAE mice compared to control non immunized mice and a significant decrease in STAT3 phosphorylation level was detected in EAE mice treated with anatabine (Fig. 3)

a(CHEBI:Anatabine) decreases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen
MeSH
Encephalomyelitis

path(MESH:Encephalomyelitis) increases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen

Evidence 4221a2c4a4
JSON

Additionally, we observed that anatabine significantly prevented STAT3 and p65 NFkB phosphorylation in brain homogenates of EAE mice (Fig. 4)

a(CHEBI:Anatabine) decreases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Encephalomyelitis

a(CHEBI:Anatabine) decreases p(MGI:Rela, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain
MeSH
Encephalomyelitis

Evidence 7282cab4db
JSON

A reduction in the number of phosphorylated STAT3 immunoreactive cells was observed in the cerebral cortex of EAE mice treated with anatabine further confirming the data obtained by western-blotting using brain homogenates (Fig. 5)

a(CHEBI:Anatabine) decreases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Encephalomyelitis

Evidence 6bd6937344
JSON

Similarly, we observed an increased number of phosphorylated STAT3 immunopositive cells in the spinal cord of EAE mice compared to control non-immunized mice and a decreased number of phosphorylated STAT3 immunoreactive cells in EAE mice treated with anatabine (Fig. 6) showing overall that anatabine reduces STAT3 phosphorylation in the brain, spinal cord and spleen of EAE mice.

a(CHEBI:Anatabine) decreases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord
MeSH
Encephalomyelitis

path(MESH:Encephalomyelitis) increases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord

Evidence f0fcd43ae6
JSON

Overall, anatabine did not significantly impact EAE induced astrogliosis for the different areas of the brain examined (Fig. 7)

a(CHEBI:Anatabine) causesNoChange bp(HBP:Astrogliosis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex
MeSH
Hippocampus

Evidence a3889e7c23
JSON

A marked increase in GFAP immunostaining was also observed in the spinal cord of EAE mice and was significantly suppressed by the anatabine treatment showing that anatabine prevents astrogliosis in the spinal cord of EAE mice (Fig. 11)

a(CHEBI:Anatabine) decreases bp(HBP:Astrogliosis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord
MeSH
Encephalomyelitis

path(MESH:Encephalomyelitis) increases bp(HBP:Astrogliosis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord

Evidence 40927a3f9d
JSON

Interestingly, a significant reduction in the number of IBa1 immunopositive microglial cells was found in the hippocampus and medulla of anatabine treated EAE mice (Fig. 8)

a(CHEBI:Anatabine) decreases bp(HBP:Microgliosis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Medulla Oblongata
MeSH
Encephalomyelitis

Evidence 63d402e7e3
JSON

Less cellular infiltration was observed in the spinal cord of anatabine treated mice compared to EAE placebo mice (Fig. 9)

a(CHEBI:Anatabine) decreases tloc(a(MESH:Leukocytes), fromLoc(GO:"extracellular region"), toLoc(MESH:"Spinal Cord")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Encephalomyelitis

Evidence 935f17e9f2
JSON

In addition, anatabine markedly decreased the Iba1 immunostaining in the spinal cord of EAE mice showing that anatabine reduces the infiltration of macrophage/ microglia in the spinal cord of EAE mice (Fig. 10)

a(CHEBI:Anatabine) decreases a(MESH:Microglia) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord
MeSH
Encephalomyelitis

a(CHEBI:Anatabine) decreases tloc(a(MESH:Microglia), fromLoc(GO:"extracellular region"), toLoc(MESH:"Spinal Cord")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord
MeSH
Encephalomyelitis

a(CHEBI:Anatabine) decreases tloc(a(MESH:Macrophages), fromLoc(GO:"extracellular region"), toLoc(MESH:"Spinal Cord")) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord
MeSH
Encephalomyelitis

Evidence c4047ad108
JSON

Interestingly, anatabine significantly prevented demyelination associated with EAE in the spinal cord (Fig. 12)

a(CHEBI:Anatabine) positiveCorrelation a(GO:"myelin sheath") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord
MeSH
White Matter
MeSH
Encephalomyelitis

a(GO:"myelin sheath") positiveCorrelation a(CHEBI:Anatabine) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord
MeSH
White Matter
MeSH
Encephalomyelitis

Evidence 309a84e221
JSON

A statistically significant positive correlation was observed between the amount of GFAP and Iba1 burden in the spinal cord (Pearson correlation = 0.612, P,0.002) whereas negative correlations were observed between the GFAP burden and the Luxol fast blue burden (Pearson correlation =20.525, P= 0.007), and between the IBa1 burden and the Luxol fast blue burden (Pearson correlation =20.609, P =0.001) suggesting that astrogliosis and microgliosis are associated with the loss of myelin in the spinal cord

a(GO:"myelin sheath") negativeCorrelation a(MESH:Astrocytes) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord

a(GO:"myelin sheath") negativeCorrelation a(MESH:Microglia) View Subject | View Object

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Annotations
MeSH
Spinal Cord

a(GO:"myelin sheath") negativeCorrelation bp(HBP:Astrogliosis) View Subject | View Object

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Annotations
MeSH
Spinal Cord

a(GO:"myelin sheath") negativeCorrelation bp(HBP:Microgliosis) View Subject | View Object

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Annotations
MeSH
Spinal Cord

a(MESH:Astrocytes) positiveCorrelation a(MESH:Microglia) View Subject | View Object

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Annotations
MeSH
Spinal Cord

a(MESH:Astrocytes) negativeCorrelation a(GO:"myelin sheath") View Subject | View Object

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Annotations
MeSH
Spinal Cord

a(MESH:Microglia) positiveCorrelation a(MESH:Astrocytes) View Subject | View Object

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Annotations
MeSH
Spinal Cord

a(MESH:Microglia) negativeCorrelation a(GO:"myelin sheath") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord

bp(HBP:Astrogliosis) negativeCorrelation a(GO:"myelin sheath") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord

bp(HBP:Microgliosis) negativeCorrelation a(GO:"myelin sheath") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord

Evidence c6a35f5f23
JSON

The axonal damage in EAE mice leads to well defined clinical signs such as tail paralysis, hind-limb weakness and paralysis

act(a(GO:axon)) decreases path(MESH:Paralysis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Encephalomyelitis

act(a(GO:axon)) decreases path(HP:"Limb muscle weakness") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Encephalomyelitis

Evidence 958929c7e6
JSON

We found that IL-1b, IFN-gamma, TNF-alpha, IL-6 and IL-17A were significantly elevated in the serum of EAE mice compared to control non-immunized mice

p(MGI:Ifng) positiveCorrelation path(MESH:Encephalomyelitis) View Subject | View Object

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Annotations
MeSH
Serum

p(MGI:Il17a) positiveCorrelation path(MESH:Encephalomyelitis) View Subject | View Object

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MeSH
Serum

p(MGI:Il1b) positiveCorrelation path(MESH:Encephalomyelitis) View Subject | View Object

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MeSH
Serum

p(MGI:Il6) positiveCorrelation path(MESH:Encephalomyelitis) View Subject | View Object

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MeSH
Serum

path(MESH:Encephalomyelitis) positiveCorrelation p(MGI:Il1b) View Subject | View Object

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MeSH
Serum

p(MGI:Tnf) positiveCorrelation path(MESH:Encephalomyelitis) View Subject | View Object

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MeSH
Serum

path(MESH:Encephalomyelitis) positiveCorrelation p(MGI:Ifng) View Subject | View Object

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Annotations
MeSH
Serum

path(MESH:Encephalomyelitis) positiveCorrelation p(MGI:Tnf) View Subject | View Object

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Annotations
MeSH
Serum

path(MESH:Encephalomyelitis) positiveCorrelation p(MGI:Il6) View Subject | View Object

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Annotations
MeSH
Serum

path(MESH:Encephalomyelitis) positiveCorrelation p(MGI:Il17a) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Serum

Evidence 44b1f1f1a1
JSON

In addition, we observed a statistically significant correlation between the amount of p65 NFkB phosphorylation and STAT3 phosphorylation in brain homogenates (Pearson Correlation = 0.637, P<0.001)

p(MGI:Rela, pmod(Ph)) positiveCorrelation p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

p(MGI:Stat3, pmod(Ph)) positiveCorrelation p(MGI:Rela, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence d9431dcf06
JSON

Interestingly, a statistically significant correlation was observed between the amount of STAT3 phosphorylation detected in brain homogenates and the clinical severity of EAE (Pearson correlation = 0.653, P<0.001) but not with p65 NFkB phosphorylation (Pearson correlation = 0.371, P= 0.062) suggesting that STAT3 may play a more preponderant role than NFkB in the development of neurological deficits of EAE

p(MGI:Stat3, pmod(Ph)) positiveCorrelation path(MESH:Encephalomyelitis) View Subject | View Object

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Annotations
MeSH
Brain

p(MGI:Stat3, pmod(Ph)) association path(MESH:"Neurologic Manifestations") View Subject | View Object

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MeSH
Brain

path(MESH:"Neurologic Manifestations") association p(MGI:Stat3, pmod(Ph)) View Subject | View Object

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MeSH
Brain

path(MESH:Encephalomyelitis) positiveCorrelation p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence ec0c680175
JSON

A statistically significant correlation was observed between the number of STAT3 phosphorylated cells in the cerebral cortex and the clinical severity of EAE (Pearson Correlation =0.531, P,0.002)

p(MGI:Stat3, pmod(Ph)) positiveCorrelation path(MESH:Encephalomyelitis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

path(MESH:Encephalomyelitis) positiveCorrelation p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence a185de0308
JSON

A statistically significant correlation was also observed between the amount of STAT3 phosphorylated cells in the spinal cord and the clinical severity of EAE (Pearson Correlation = 0.512, P,0.004)

p(MGI:Stat3, pmod(Ph)) positiveCorrelation path(MESH:Encephalomyelitis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord

path(MESH:Encephalomyelitis) positiveCorrelation p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord

Evidence c5d966d530
JSON

A significant elevation of IL-1b, INF-gamma and TNF-alpha was observed in the spleen of EAE mice compared to control non immunized animals

path(MESH:Encephalomyelitis) increases p(MGI:Il1b) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen

path(MESH:Encephalomyelitis) increases p(MGI:Ifng) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen

path(MESH:Encephalomyelitis) increases p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spleen

Evidence 5d2afb574a
JSON

Western-blot experiments using brain homogenates from EAE mice also reveal that both STAT3 and p65 NFkB phosphorylation are significantly elevated in the brain of EAE mice compared to control non immunized mice (Fig. 4)

path(MESH:Encephalomyelitis) increases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:Encephalomyelitis) increases p(MGI:Rela, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence 2de127712f
JSON

We further assessed STAT3 phosphorylation by immunohistochemistry using brain sections of the animals and observed an increased number of phosphorylated STAT3 immunopositive cells in the cortex of EAE mice compared to control non-immunized mice (Fig. 5)

path(MESH:Encephalomyelitis) increases p(MGI:Stat3, pmod(Ph)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence c25f576eed
JSON

A significant increase in astrogliosis revealed by a GFAP immunostaining was observed in the cortex and medulla of EAE mice compared to control non immunized animals (Fig. 7)

path(MESH:Encephalomyelitis) increases bp(HBP:Astrogliosis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Cerebral Cortex

Evidence bcc3f4032a
JSON

A significant increase in the number of microglial cells immunoreactive for Iba1 was observed in the hippocampus and medulla of EAE mice compared to control non-immunized mice (Fig. 8)

path(MESH:Encephalomyelitis) increases bp(HBP:Microgliosis) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Hippocampus
MeSH
Medulla Oblongata

Evidence a39aa3af28
JSON

As shown in Fig. 9, hematoxylin and eosin staining revealed numerous perivascular clusters of mononuclear infiltrating cells in the spinal cord of EAE mice and an absence of these inflammatory cell infiltrates in the spinal cord of control non-immunized mice

path(MESH:Encephalomyelitis) increases tloc(a(MESH:Leukocytes), fromLoc(GO:"extracellular region"), toLoc(MESH:"Spinal Cord")) View Subject | View Object

Appears in Networks:

Evidence d485c04727
JSON

Globally, Iba1 immunostaining is significantly increased in the spinal cord of EAE mice compared to control nonimmunized mice (Fig. 10)

path(MESH:Encephalomyelitis) increases a(MESH:Microglia) View Subject | View Object

Appears in Networks:

Evidence c3c58258a7
JSON

Finally, Luxol Fast Blue staining showed significant myelin loss in the white matter of the spinal cord of EAE mice compared control non-immunized mice (Fig. 12)

path(MESH:Encephalomyelitis) decreases a(GO:"myelin sheath") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Spinal Cord
MeSH
White Matter

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