Ligation of the jugular veins does not result in brain inflammation or demyelination in mice

Wendy Atkinson, Reza Forghani, Gregory R. Wojtkiewicz, Benjamin Pulli, Yoshiko Iwamoto, Takuya Ueno, Peter Waterman, Jessica Truelove, Rahmi Oklu, John W. Chen

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

An alternative hypothesis has been proposed implicating chronic cerebrospinal venous insufficiency (CCSVI) as a potential cause of multiple sclerosis (MS). We aimed to evaluate the validity of this hypothesis in a controlled animal model. Animal experiments were approved by the institutional animal care committee. The jugular veins in SJL mice were ligated bilaterally (n = 20), and the mice were observed for up to six months after ligation. Sham-operated mice (n = 15) and mice induced with experimental autoimmune encephalomyelitis (n = 8) were used as negative and positive controls, respectively. The animals were evaluated using CT venography and 99mTc-exametazime to assess for structural and hemodynamic changes. Imaging was performed to evaluate for signs of blood-brain barrier (BBB) breakdown and neuroinflammation. Flow cytometry and histopathology were performed to assess inflammatory cell populations and demyelination. There were both structural changes (stenosis, collaterals) in the jugular venous drainage and hemodynamic disturbances in the brain on Tc99m-exametazime scintigraphy (p = 0.024). In the JVL mice, gadolinium MRI and immunofluorescence imaging for barrier molecules did not reveal evidence of BBB breakdown (p = 0.58). Myeloperoxidase, matrix metalloproteinase, and protease molecular imaging did not reveal signs of increased neuroinflammation (all p>0.05). Flow cytometry and histopathology also did not reveal increase in inflammatory cell infiltration or population shifts. No evidence of demyelination was found, and the mice remained without clinical signs. Despite the structural and hemodynamic changes, we did not identify changes in the BBB permeability, neuroinflammation, demyelination, or clinical signs in the JVL group compared to the sham group. Therefore, our murine model does not support CCSVI as a cause of demyelinating diseases such as multiple sclerosis.

Original languageEnglish (US)
Article numbere33671
JournalPLoS One
Volume7
Issue number3
DOIs
StatePublished - Mar 26 2012
Externally publishedYes

Fingerprint

Jugular Veins
jugular vein
Demyelinating Diseases
Encephalitis
encephalitis
Ligation
Brain
Hemodynamics
Animals
blood-brain barrier
Flow cytometry
mice
hemodynamics
Blood-Brain Barrier
Venous Insufficiency
sclerosis
image analysis
Molecular imaging
Imaging techniques
histopathology

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Atkinson, W., Forghani, R., Wojtkiewicz, G. R., Pulli, B., Iwamoto, Y., Ueno, T., ... Chen, J. W. (2012). Ligation of the jugular veins does not result in brain inflammation or demyelination in mice. PLoS One, 7(3), [e33671]. https://doi.org/10.1371/journal.pone.0033671

Ligation of the jugular veins does not result in brain inflammation or demyelination in mice. / Atkinson, Wendy; Forghani, Reza; Wojtkiewicz, Gregory R.; Pulli, Benjamin; Iwamoto, Yoshiko; Ueno, Takuya; Waterman, Peter; Truelove, Jessica; Oklu, Rahmi; Chen, John W.

In: PLoS One, Vol. 7, No. 3, e33671, 26.03.2012.

Research output: Contribution to journalArticle

Atkinson, W, Forghani, R, Wojtkiewicz, GR, Pulli, B, Iwamoto, Y, Ueno, T, Waterman, P, Truelove, J, Oklu, R & Chen, JW 2012, 'Ligation of the jugular veins does not result in brain inflammation or demyelination in mice', PLoS One, vol. 7, no. 3, e33671. https://doi.org/10.1371/journal.pone.0033671
Atkinson W, Forghani R, Wojtkiewicz GR, Pulli B, Iwamoto Y, Ueno T et al. Ligation of the jugular veins does not result in brain inflammation or demyelination in mice. PLoS One. 2012 Mar 26;7(3). e33671. https://doi.org/10.1371/journal.pone.0033671
Atkinson, Wendy ; Forghani, Reza ; Wojtkiewicz, Gregory R. ; Pulli, Benjamin ; Iwamoto, Yoshiko ; Ueno, Takuya ; Waterman, Peter ; Truelove, Jessica ; Oklu, Rahmi ; Chen, John W. / Ligation of the jugular veins does not result in brain inflammation or demyelination in mice. In: PLoS One. 2012 ; Vol. 7, No. 3.
@article{90122603240b40efba8e6a066f62b1c6,
title = "Ligation of the jugular veins does not result in brain inflammation or demyelination in mice",
abstract = "An alternative hypothesis has been proposed implicating chronic cerebrospinal venous insufficiency (CCSVI) as a potential cause of multiple sclerosis (MS). We aimed to evaluate the validity of this hypothesis in a controlled animal model. Animal experiments were approved by the institutional animal care committee. The jugular veins in SJL mice were ligated bilaterally (n = 20), and the mice were observed for up to six months after ligation. Sham-operated mice (n = 15) and mice induced with experimental autoimmune encephalomyelitis (n = 8) were used as negative and positive controls, respectively. The animals were evaluated using CT venography and 99mTc-exametazime to assess for structural and hemodynamic changes. Imaging was performed to evaluate for signs of blood-brain barrier (BBB) breakdown and neuroinflammation. Flow cytometry and histopathology were performed to assess inflammatory cell populations and demyelination. There were both structural changes (stenosis, collaterals) in the jugular venous drainage and hemodynamic disturbances in the brain on Tc99m-exametazime scintigraphy (p = 0.024). In the JVL mice, gadolinium MRI and immunofluorescence imaging for barrier molecules did not reveal evidence of BBB breakdown (p = 0.58). Myeloperoxidase, matrix metalloproteinase, and protease molecular imaging did not reveal signs of increased neuroinflammation (all p>0.05). Flow cytometry and histopathology also did not reveal increase in inflammatory cell infiltration or population shifts. No evidence of demyelination was found, and the mice remained without clinical signs. Despite the structural and hemodynamic changes, we did not identify changes in the BBB permeability, neuroinflammation, demyelination, or clinical signs in the JVL group compared to the sham group. Therefore, our murine model does not support CCSVI as a cause of demyelinating diseases such as multiple sclerosis.",
author = "Wendy Atkinson and Reza Forghani and Wojtkiewicz, {Gregory R.} and Benjamin Pulli and Yoshiko Iwamoto and Takuya Ueno and Peter Waterman and Jessica Truelove and Rahmi Oklu and Chen, {John W.}",
year = "2012",
month = "3",
day = "26",
doi = "10.1371/journal.pone.0033671",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - Ligation of the jugular veins does not result in brain inflammation or demyelination in mice

AU - Atkinson, Wendy

AU - Forghani, Reza

AU - Wojtkiewicz, Gregory R.

AU - Pulli, Benjamin

AU - Iwamoto, Yoshiko

AU - Ueno, Takuya

AU - Waterman, Peter

AU - Truelove, Jessica

AU - Oklu, Rahmi

AU - Chen, John W.

PY - 2012/3/26

Y1 - 2012/3/26

N2 - An alternative hypothesis has been proposed implicating chronic cerebrospinal venous insufficiency (CCSVI) as a potential cause of multiple sclerosis (MS). We aimed to evaluate the validity of this hypothesis in a controlled animal model. Animal experiments were approved by the institutional animal care committee. The jugular veins in SJL mice were ligated bilaterally (n = 20), and the mice were observed for up to six months after ligation. Sham-operated mice (n = 15) and mice induced with experimental autoimmune encephalomyelitis (n = 8) were used as negative and positive controls, respectively. The animals were evaluated using CT venography and 99mTc-exametazime to assess for structural and hemodynamic changes. Imaging was performed to evaluate for signs of blood-brain barrier (BBB) breakdown and neuroinflammation. Flow cytometry and histopathology were performed to assess inflammatory cell populations and demyelination. There were both structural changes (stenosis, collaterals) in the jugular venous drainage and hemodynamic disturbances in the brain on Tc99m-exametazime scintigraphy (p = 0.024). In the JVL mice, gadolinium MRI and immunofluorescence imaging for barrier molecules did not reveal evidence of BBB breakdown (p = 0.58). Myeloperoxidase, matrix metalloproteinase, and protease molecular imaging did not reveal signs of increased neuroinflammation (all p>0.05). Flow cytometry and histopathology also did not reveal increase in inflammatory cell infiltration or population shifts. No evidence of demyelination was found, and the mice remained without clinical signs. Despite the structural and hemodynamic changes, we did not identify changes in the BBB permeability, neuroinflammation, demyelination, or clinical signs in the JVL group compared to the sham group. Therefore, our murine model does not support CCSVI as a cause of demyelinating diseases such as multiple sclerosis.

AB - An alternative hypothesis has been proposed implicating chronic cerebrospinal venous insufficiency (CCSVI) as a potential cause of multiple sclerosis (MS). We aimed to evaluate the validity of this hypothesis in a controlled animal model. Animal experiments were approved by the institutional animal care committee. The jugular veins in SJL mice were ligated bilaterally (n = 20), and the mice were observed for up to six months after ligation. Sham-operated mice (n = 15) and mice induced with experimental autoimmune encephalomyelitis (n = 8) were used as negative and positive controls, respectively. The animals were evaluated using CT venography and 99mTc-exametazime to assess for structural and hemodynamic changes. Imaging was performed to evaluate for signs of blood-brain barrier (BBB) breakdown and neuroinflammation. Flow cytometry and histopathology were performed to assess inflammatory cell populations and demyelination. There were both structural changes (stenosis, collaterals) in the jugular venous drainage and hemodynamic disturbances in the brain on Tc99m-exametazime scintigraphy (p = 0.024). In the JVL mice, gadolinium MRI and immunofluorescence imaging for barrier molecules did not reveal evidence of BBB breakdown (p = 0.58). Myeloperoxidase, matrix metalloproteinase, and protease molecular imaging did not reveal signs of increased neuroinflammation (all p>0.05). Flow cytometry and histopathology also did not reveal increase in inflammatory cell infiltration or population shifts. No evidence of demyelination was found, and the mice remained without clinical signs. Despite the structural and hemodynamic changes, we did not identify changes in the BBB permeability, neuroinflammation, demyelination, or clinical signs in the JVL group compared to the sham group. Therefore, our murine model does not support CCSVI as a cause of demyelinating diseases such as multiple sclerosis.

UR - http://www.scopus.com/inward/record.url?scp=84863353672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863353672&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0033671

DO - 10.1371/journal.pone.0033671

M3 - Article

C2 - 22457780

AN - SCOPUS:84863353672

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

M1 - e33671

ER -