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Molecular Neurobiology

, Volume 55, Issue 5, pp 3642–3659 | Cite as

Blood-Brain Barrier Permeability Is Exacerbated in Experimental Model of Hepatic Encephalopathy via MMP-9 Activation and Downregulation of Tight Junction Proteins

  • Saurabh Dhanda
  • Rajat Sandhir
Article

Abstract

The present study was designed to investigate the mechanisms involved in blood-brain barrier (BBB) permeability in bile duct ligation (BDL) model of chronic hepatic encephalopathy (HE). Four weeks after BDL surgery, a significant increase was observed in serum bilirubin levels. Masson trichrome staining revealed severe hepatic fibrosis in the BDL rats. 99mTc-mebrofenin retention was increased in the liver of BDL rats suggesting impaired hepatobiliary transport. An increase in permeability to sodium fluorescein, Evans blue, and fluorescein isothiocyanate (FITC)-dextran along with increase in water and electrolyte content was observed in brain regions of BDL rats suggesting disrupted BBB. Increased brain water content can be attributed to increase in aquaporin-4 mRNA and protein expression in BDL rats. Matrix metalloproteinase-9 (MMP-9) mRNA and protein expression was increased in brain regions of BDL rats. Additionally, mRNA and protein expression of tissue inhibitor of matrix metalloproteinases (TIMPs) was also increased in different regions of brain. A significant decrease in mRNA expression and protein levels of tight junction proteins, viz., occludin, claudin-5, and zona occluden-1 (ZO-1) was observed in different brain regions of BDL rats. VCAM-1 mRNA and protein expression was also found to be significantly upregulated in different brain regions of BDL animals. The findings from the study suggest that increased BBB permeability in HE involves activation of MMP-9 and loss of tight junction proteins.

Keywords

Aquaporins Bile duct ligation Blood-brain barrier Hepatic encephalopathy Matrix metalloproteinases Tight junction proteins 

Abbreviations

BBB

Blood-brain barrier

BDL

Bile duct ligation

FITC

Fluorescein isothiocyanate

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

HE

Hepatic encephalopathy

HEPES

4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

HRP

Horse radish peroxidase

ICAM-1

Intercellular adhesion molecule-1

IgG

Immunoglobulin G

LPS

Lipolysaccharide

MMPs

Matrix metalloproteinases

MMP-2

Matrix metalloproteinase-2

MMP-9

Matrix metalloproteinase-9

NKCC1

Sodium potassium chloride-cotransporter 1

PBS

Phosphate buffer saline

PMSF

Phenylmethylsulfonyl fluoride

PVDF

Polyvinylidene difluoride

SC

Sham control

SDS-PAGE

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

SEM

Standard error mean

TCA

Trichloroacetic acid

99mTc

Technetium 99m

TIMPs

Tissue inhibitor of matrix metalloproteinases

TIMP-1

Tissue inhibitor of matrix metalloproteinase-1

TIMP-2

Tissue inhibitor of matrix metalloproteinase-2

VCAM-1

Vascular cell adhesion molecule-1

ZO-1

Zona occluden-1

Notes

Acknowledgements

This work was supported by financial assistance provided from the Department of Science and Technology (DST), New Delhi, under the Promotion of University Research and Scientific Excellence (PURSE) grant and University Grants Commission-Special Assistance Programme (UGC-SAP) Departmental Research Support-II (DRS-II).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Biochemistry, Basic Medical Science Block-II, Sector-25Panjab UniversityChandigarhIndia

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