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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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NCAP Effect on Mediators of Bone Metabolism.Study day 16 serum was assayed for RANKL (A), and OPG (B), and the ratio of OPG/RANKL group means calculated (C). Data are shown as mean+SE level, *p≤0.05, t-test versus CIA/Sham NCAP. Osteocalcin (D), P1NP (E), TRAP-5b (F) and CTX-1 (G) data are shown as mean+SE level, *p≤0.05 t-test versus CIA/Sham NCAP.
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pone-0104530-g005: NCAP Effect on Mediators of Bone Metabolism.Study day 16 serum was assayed for RANKL (A), and OPG (B), and the ratio of OPG/RANKL group means calculated (C). Data are shown as mean+SE level, *p≤0.05, t-test versus CIA/Sham NCAP. Osteocalcin (D), P1NP (E), TRAP-5b (F) and CTX-1 (G) data are shown as mean+SE level, *p≤0.05 t-test versus CIA/Sham NCAP.

Mentions: Serum levels of RANKL were reduced from 132±13 to 6±2 picograms/mL, OPG increased from 18±4 to 44±10 picograms/mL, and OPG/RANKL ratio increased from 0.1±0.1 to 6.8±1.3 in the CIA/Sham versus CIA/NCAP groups, respectively (p = 0.01, 0.02, 0.01), indicating a marked NCAP-induced reduction in propensity toward bone resorption at day 16 (Figure 5A–C). There were no treatment-induced changes in the bone formation markers osteocalcin and P1NP (Figure 5D–E). Interestingly, despite the greatly reduced levels of RANKL, and the markedly elevated OPG/RANK ligand ratio, which would be expected to drive diminished bone resorption, systemic markers typically indicative of resorption were either not changed (CTX-1), or were increased (TRAP-5b) in the CIA/NCAP group, compared to CIA/Sham NCAP (Figure 5F–G).


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 Effect on Mediators of Bone Metabolism.Study day 16 serum was assayed for RANKL (A), and OPG (B), and the ratio of OPG/RANKL group means calculated (C). Data are shown as mean+SE level, *p≤0.05, t-test versus CIA/Sham NCAP. Osteocalcin (D), P1NP (E), TRAP-5b (F) and CTX-1 (G) data are shown as mean+SE level, *p≤0.05 t-test versus CIA/Sham NCAP.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104530-g005: NCAP Effect on Mediators of Bone Metabolism.Study day 16 serum was assayed for RANKL (A), and OPG (B), and the ratio of OPG/RANKL group means calculated (C). Data are shown as mean+SE level, *p≤0.05, t-test versus CIA/Sham NCAP. Osteocalcin (D), P1NP (E), TRAP-5b (F) and CTX-1 (G) data are shown as mean+SE level, *p≤0.05 t-test versus CIA/Sham NCAP.
Mentions: Serum levels of RANKL were reduced from 132±13 to 6±2 picograms/mL, OPG increased from 18±4 to 44±10 picograms/mL, and OPG/RANKL ratio increased from 0.1±0.1 to 6.8±1.3 in the CIA/Sham versus CIA/NCAP groups, respectively (p = 0.01, 0.02, 0.01), indicating a marked NCAP-induced reduction in propensity toward bone resorption at day 16 (Figure 5A–C). There were no treatment-induced changes in the bone formation markers osteocalcin and P1NP (Figure 5D–E). Interestingly, despite the greatly reduced levels of RANKL, and the markedly elevated OPG/RANK ligand ratio, which would be expected to drive diminished bone resorption, systemic markers typically indicative of resorption were either not changed (CTX-1), or were increased (TRAP-5b) in the CIA/NCAP group, compared to CIA/Sham NCAP (Figure 5F–G).

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