Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat: Contribution of hyperglycaemia and matrix metalloproteinases

B. T. Hawkins, T. F. Lundeen, K. M. Norwood, Heddwen L Brooks, R. D. Egleton

Research output: Contribution to journalArticle

186 Citations (Scopus)

Abstract

Aims/hypothesis: Although diabetes mellitus is associated with peripheral microvascular complications and increased risk of neurological events, the mechanisms by which diabetes disrupts the blood-brain barrier (BBB) are not known. Matrix metalloproteinase (MMP) activity is increased in diabetic patients, is associated with degradation of tight junction proteins, and is a known mediator of BBB compromise. We hypothesise that diabetes leads to compromise of BBB tight junctions via stimulation of MMP activity. Materials and methods: Diabetes was induced in the rat with streptozotocin. At 14 days after injection, BBB function was assessed by in situ brain perfusion. Tight junction proteins were assessed by immunoblot and immunofluorescence. Plasma MMP activity was quantified by fluorometric gelatinase assay and gel zymography. Results: In streptozotocin-treated animals, permeability to [14C]sucrose increased concurrently with decreased production of BBB tight junction proteins occludin (also known as OCLN) and zona occludens 1 (ZO-1, also known as tight junction protein 1 or TJP1). Insulin treatment, begun on day 7, normalised blood glucose levels and attenuated BBB hyperpermeability to [14C]sucrose. Neither acute hyperglycaemia in naive animals nor acute normalisation of blood glucose in streptozotocin-treated animals altered BBB permeability to [ 14C]sucrose. Plasma MMP activity was increased in streptozotocin-treated animals. Conclusions/interpretation: These data indicate that diabetes increases BBB permeability via a loss of tight junction proteins, and that increased BBB permeability in diabetes does not result from hyperglycaemia alone. Increased plasma MMP activity is implicated in degradation of BBB tight junction proteins and increased BBB permeability in diabetes. Peripheral MMP activity may present a novel target for protection of the BBB and prevention of neurological complications in diabetes.

Original languageEnglish (US)
Pages (from-to)202-211
Number of pages10
JournalDiabetologia
Volume50
Issue number1
DOIs
StatePublished - Jan 2007

Fingerprint

Tight Junctions
Blood-Brain Barrier
Matrix Metalloproteinases
Hyperglycemia
Permeability
Tight Junction Proteins
Streptozocin
Sucrose
Blood Glucose
Zonula Occludens-1 Protein
Occludin
Gelatinases
Herpes Zoster
Diabetes Complications
Fluorescent Antibody Technique
Diabetes Mellitus
Perfusion
Gels
Insulin

Keywords

  • Blood-brain barrier
  • Diabetes
  • In situ brain perfusion
  • Matrix metalloproteinase
  • Occludin
  • OCLN
  • Rat
  • Streptozotocin
  • TJP1
  • ZO-1
  • Zymography

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat : Contribution of hyperglycaemia and matrix metalloproteinases. / Hawkins, B. T.; Lundeen, T. F.; Norwood, K. M.; Brooks, Heddwen L; Egleton, R. D.

In: Diabetologia, Vol. 50, No. 1, 01.2007, p. 202-211.

Research output: Contribution to journalArticle

@article{591174b437cc451fa2949b561af44db3,
title = "Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat: Contribution of hyperglycaemia and matrix metalloproteinases",
abstract = "Aims/hypothesis: Although diabetes mellitus is associated with peripheral microvascular complications and increased risk of neurological events, the mechanisms by which diabetes disrupts the blood-brain barrier (BBB) are not known. Matrix metalloproteinase (MMP) activity is increased in diabetic patients, is associated with degradation of tight junction proteins, and is a known mediator of BBB compromise. We hypothesise that diabetes leads to compromise of BBB tight junctions via stimulation of MMP activity. Materials and methods: Diabetes was induced in the rat with streptozotocin. At 14 days after injection, BBB function was assessed by in situ brain perfusion. Tight junction proteins were assessed by immunoblot and immunofluorescence. Plasma MMP activity was quantified by fluorometric gelatinase assay and gel zymography. Results: In streptozotocin-treated animals, permeability to [14C]sucrose increased concurrently with decreased production of BBB tight junction proteins occludin (also known as OCLN) and zona occludens 1 (ZO-1, also known as tight junction protein 1 or TJP1). Insulin treatment, begun on day 7, normalised blood glucose levels and attenuated BBB hyperpermeability to [14C]sucrose. Neither acute hyperglycaemia in naive animals nor acute normalisation of blood glucose in streptozotocin-treated animals altered BBB permeability to [ 14C]sucrose. Plasma MMP activity was increased in streptozotocin-treated animals. Conclusions/interpretation: These data indicate that diabetes increases BBB permeability via a loss of tight junction proteins, and that increased BBB permeability in diabetes does not result from hyperglycaemia alone. Increased plasma MMP activity is implicated in degradation of BBB tight junction proteins and increased BBB permeability in diabetes. Peripheral MMP activity may present a novel target for protection of the BBB and prevention of neurological complications in diabetes.",
keywords = "Blood-brain barrier, Diabetes, In situ brain perfusion, Matrix metalloproteinase, Occludin, OCLN, Rat, Streptozotocin, TJP1, ZO-1, Zymography",
author = "Hawkins, {B. T.} and Lundeen, {T. F.} and Norwood, {K. M.} and Brooks, {Heddwen L} and Egleton, {R. D.}",
year = "2007",
month = "1",
doi = "10.1007/s00125-006-0485-z",
language = "English (US)",
volume = "50",
pages = "202--211",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat

T2 - Contribution of hyperglycaemia and matrix metalloproteinases

AU - Hawkins, B. T.

AU - Lundeen, T. F.

AU - Norwood, K. M.

AU - Brooks, Heddwen L

AU - Egleton, R. D.

PY - 2007/1

Y1 - 2007/1

N2 - Aims/hypothesis: Although diabetes mellitus is associated with peripheral microvascular complications and increased risk of neurological events, the mechanisms by which diabetes disrupts the blood-brain barrier (BBB) are not known. Matrix metalloproteinase (MMP) activity is increased in diabetic patients, is associated with degradation of tight junction proteins, and is a known mediator of BBB compromise. We hypothesise that diabetes leads to compromise of BBB tight junctions via stimulation of MMP activity. Materials and methods: Diabetes was induced in the rat with streptozotocin. At 14 days after injection, BBB function was assessed by in situ brain perfusion. Tight junction proteins were assessed by immunoblot and immunofluorescence. Plasma MMP activity was quantified by fluorometric gelatinase assay and gel zymography. Results: In streptozotocin-treated animals, permeability to [14C]sucrose increased concurrently with decreased production of BBB tight junction proteins occludin (also known as OCLN) and zona occludens 1 (ZO-1, also known as tight junction protein 1 or TJP1). Insulin treatment, begun on day 7, normalised blood glucose levels and attenuated BBB hyperpermeability to [14C]sucrose. Neither acute hyperglycaemia in naive animals nor acute normalisation of blood glucose in streptozotocin-treated animals altered BBB permeability to [ 14C]sucrose. Plasma MMP activity was increased in streptozotocin-treated animals. Conclusions/interpretation: These data indicate that diabetes increases BBB permeability via a loss of tight junction proteins, and that increased BBB permeability in diabetes does not result from hyperglycaemia alone. Increased plasma MMP activity is implicated in degradation of BBB tight junction proteins and increased BBB permeability in diabetes. Peripheral MMP activity may present a novel target for protection of the BBB and prevention of neurological complications in diabetes.

AB - Aims/hypothesis: Although diabetes mellitus is associated with peripheral microvascular complications and increased risk of neurological events, the mechanisms by which diabetes disrupts the blood-brain barrier (BBB) are not known. Matrix metalloproteinase (MMP) activity is increased in diabetic patients, is associated with degradation of tight junction proteins, and is a known mediator of BBB compromise. We hypothesise that diabetes leads to compromise of BBB tight junctions via stimulation of MMP activity. Materials and methods: Diabetes was induced in the rat with streptozotocin. At 14 days after injection, BBB function was assessed by in situ brain perfusion. Tight junction proteins were assessed by immunoblot and immunofluorescence. Plasma MMP activity was quantified by fluorometric gelatinase assay and gel zymography. Results: In streptozotocin-treated animals, permeability to [14C]sucrose increased concurrently with decreased production of BBB tight junction proteins occludin (also known as OCLN) and zona occludens 1 (ZO-1, also known as tight junction protein 1 or TJP1). Insulin treatment, begun on day 7, normalised blood glucose levels and attenuated BBB hyperpermeability to [14C]sucrose. Neither acute hyperglycaemia in naive animals nor acute normalisation of blood glucose in streptozotocin-treated animals altered BBB permeability to [ 14C]sucrose. Plasma MMP activity was increased in streptozotocin-treated animals. Conclusions/interpretation: These data indicate that diabetes increases BBB permeability via a loss of tight junction proteins, and that increased BBB permeability in diabetes does not result from hyperglycaemia alone. Increased plasma MMP activity is implicated in degradation of BBB tight junction proteins and increased BBB permeability in diabetes. Peripheral MMP activity may present a novel target for protection of the BBB and prevention of neurological complications in diabetes.

KW - Blood-brain barrier

KW - Diabetes

KW - In situ brain perfusion

KW - Matrix metalloproteinase

KW - Occludin

KW - OCLN

KW - Rat

KW - Streptozotocin

KW - TJP1

KW - ZO-1

KW - Zymography

UR - http://www.scopus.com/inward/record.url?scp=33845915580&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33845915580&partnerID=8YFLogxK

U2 - 10.1007/s00125-006-0485-z

DO - 10.1007/s00125-006-0485-z

M3 - Article

C2 - 17143608

AN - SCOPUS:33845915580

VL - 50

SP - 202

EP - 211

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 1

ER -