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Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis.

Levine YA, Koopman FA, Faltys M, Caravaca A, Bendele A, Zitnik R, Vervoordeldonk MJ, Tak PP - PLoS ONE (2014)

Bottom Line: Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study.Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02), a 57% reduction in ankle diameter (area under curve; p = 0.02) and 46% reduction overall histological arthritis score (p = 0.01) with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02), accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance.Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL) from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01).

View Article: PubMed Central - PubMed

Affiliation: SetPoint Medical Corporation, Valencia, California, United States of America.

ABSTRACT

Introduction: The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model.

Methods: Rats implanted with vagus nerve cuff electrodes had collagen-induced arthritis induced and were followed for 15 days. Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study. Joint swelling, histology, and levels of cytokines and bone metabolism mediators were assessed.

Results: Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02), a 57% reduction in ankle diameter (area under curve; p = 0.02) and 46% reduction overall histological arthritis score (p = 0.01) with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02), accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance. Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL) from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01).

Conclusions: The severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders.

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Related in: MedlinePlus

NCAP Reduces Histological Measures of Joint Damage.(A–B) Ankle joints were harvested on study day 16, stained with Toluidine Blue, and scored on a scale of 0-5 for inflammation, pannus formation, cartilage damage and bone resorption (A), with a composite summated score of 0–20 (B). Data are shown as mean+SE score. *p≤0.05 t-test versus CIA/Sham NCAP. (C–D) Representative 50X photomicrographs of ankle joints are shown which have the approximate mean summed score as that of the entire treatment group. Ankle from CIA/Sham NCAP group (C) demonstrates marked inflammation and synovitis (S) and mild cartilage damage (large arrow) and bone resorption (small arrow). Ankle from CIA/NCAP group (D) demonstrates mild inflammation and synovitis (S) and minimal cartilage damage (large arrow) and minimal bone resorption (small arrow).
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pone-0104530-g003: NCAP Reduces Histological Measures of Joint Damage.(A–B) Ankle joints were harvested on study day 16, stained with Toluidine Blue, and scored on a scale of 0-5 for inflammation, pannus formation, cartilage damage and bone resorption (A), with a composite summated score of 0–20 (B). Data are shown as mean+SE score. *p≤0.05 t-test versus CIA/Sham NCAP. (C–D) Representative 50X photomicrographs of ankle joints are shown which have the approximate mean summed score as that of the entire treatment group. Ankle from CIA/Sham NCAP group (C) demonstrates marked inflammation and synovitis (S) and mild cartilage damage (large arrow) and bone resorption (small arrow). Ankle from CIA/NCAP group (D) demonstrates mild inflammation and synovitis (S) and minimal cartilage damage (large arrow) and minimal bone resorption (small arrow).

Mentions: At day 16, joints were assessed histologically in a blinded manner for presence of inflammation, pannus formation, cartilage damage, and bone resorption using a semi-quantitative scoring system (Table 2). Each of these parameters was graded between 0–5, and a composite score summed score was calculated. A 46% reduction in the composite score was observed (4.1±0.9 versus 7.6±0.9 in CIA/NCAP and CIA/Sham NCAP, respectively, p = 0.01, Figure 3A), and there were significant reductions in inflammation (2.2±0.4 versus 3.5±0.4), pannus formation (0.6±0.2 versus 1.2±0.2), cartilage damage (0.8±0.2 versus 1.8±0.2), and bone resorption (0.4±0.2 versus 1.1±0.2), mean±SE, p = 0.01, 0.01, 0.01, 0.02 respectively (Figure 3B). No effects on joint histology were seen in the animals implanted in the absence of CIA induction (Control/No Implant and Control/Implant composite scores were 0.0 and 0.0, respectively). Figures 3C–D illustrate typical histological appearance of joint inflammation and damage in CIA/Sham NCAP group and reductions induced by active treatment in the CIA/NCAP group. Similar effects were seen in the histological scores of the knee joint (data not shown).


Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis.

Levine YA, Koopman FA, Faltys M, Caravaca A, Bendele A, Zitnik R, Vervoordeldonk MJ, Tak PP - PLoS ONE (2014)

NCAP Reduces Histological Measures of Joint Damage.(A–B) Ankle joints were harvested on study day 16, stained with Toluidine Blue, and scored on a scale of 0-5 for inflammation, pannus formation, cartilage damage and bone resorption (A), with a composite summated score of 0–20 (B). Data are shown as mean+SE score. *p≤0.05 t-test versus CIA/Sham NCAP. (C–D) Representative 50X photomicrographs of ankle joints are shown which have the approximate mean summed score as that of the entire treatment group. Ankle from CIA/Sham NCAP group (C) demonstrates marked inflammation and synovitis (S) and mild cartilage damage (large arrow) and bone resorption (small arrow). Ankle from CIA/NCAP group (D) demonstrates mild inflammation and synovitis (S) and minimal cartilage damage (large arrow) and minimal bone resorption (small arrow).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128811&req=5

pone-0104530-g003: NCAP Reduces Histological Measures of Joint Damage.(A–B) Ankle joints were harvested on study day 16, stained with Toluidine Blue, and scored on a scale of 0-5 for inflammation, pannus formation, cartilage damage and bone resorption (A), with a composite summated score of 0–20 (B). Data are shown as mean+SE score. *p≤0.05 t-test versus CIA/Sham NCAP. (C–D) Representative 50X photomicrographs of ankle joints are shown which have the approximate mean summed score as that of the entire treatment group. Ankle from CIA/Sham NCAP group (C) demonstrates marked inflammation and synovitis (S) and mild cartilage damage (large arrow) and bone resorption (small arrow). Ankle from CIA/NCAP group (D) demonstrates mild inflammation and synovitis (S) and minimal cartilage damage (large arrow) and minimal bone resorption (small arrow).
Mentions: At day 16, joints were assessed histologically in a blinded manner for presence of inflammation, pannus formation, cartilage damage, and bone resorption using a semi-quantitative scoring system (Table 2). Each of these parameters was graded between 0–5, and a composite score summed score was calculated. A 46% reduction in the composite score was observed (4.1±0.9 versus 7.6±0.9 in CIA/NCAP and CIA/Sham NCAP, respectively, p = 0.01, Figure 3A), and there were significant reductions in inflammation (2.2±0.4 versus 3.5±0.4), pannus formation (0.6±0.2 versus 1.2±0.2), cartilage damage (0.8±0.2 versus 1.8±0.2), and bone resorption (0.4±0.2 versus 1.1±0.2), mean±SE, p = 0.01, 0.01, 0.01, 0.02 respectively (Figure 3B). No effects on joint histology were seen in the animals implanted in the absence of CIA induction (Control/No Implant and Control/Implant composite scores were 0.0 and 0.0, respectively). Figures 3C–D illustrate typical histological appearance of joint inflammation and damage in CIA/Sham NCAP group and reductions induced by active treatment in the CIA/NCAP group. Similar effects were seen in the histological scores of the knee joint (data not shown).

Bottom Line: Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study.Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02), a 57% reduction in ankle diameter (area under curve; p = 0.02) and 46% reduction overall histological arthritis score (p = 0.01) with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02), accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance.Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL) from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01).

View Article: PubMed Central - PubMed

Affiliation: SetPoint Medical Corporation, Valencia, California, United States of America.

ABSTRACT

Introduction: The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model.

Methods: Rats implanted with vagus nerve cuff electrodes had collagen-induced arthritis induced and were followed for 15 days. Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study. Joint swelling, histology, and levels of cytokines and bone metabolism mediators were assessed.

Results: Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02), a 57% reduction in ankle diameter (area under curve; p = 0.02) and 46% reduction overall histological arthritis score (p = 0.01) with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02), accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance. Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL) from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01).

Conclusions: The severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders.

Show MeSH
Related in: MedlinePlus