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

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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.

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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

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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).

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  1. Department of Biochemistry, Basic Medical Science Block-II, Sector-25, Panjab University, Chandigarh, 160014, India

    Saurabh Dhanda & Rajat Sandhir

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Dhanda, S., Sandhir, R. Blood-Brain Barrier Permeability Is Exacerbated in Experimental Model of Hepatic Encephalopathy via MMP-9 Activation and Downregulation of Tight Junction Proteins. Mol Neurobiol 55, 3642–3659 (2018). https://doi.org/10.1007/s12035-017-0521-7

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