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, H L Brooks, R D Egleton
Diabetologia 2007, 50 (1): 202-11

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 [(14)C]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 [(14)C]sucrose. Neither acute hyperglycaemia in naive animals nor acute normalisation of blood glucose in streptozotocin-treated animals altered BBB permeability to [(14)C]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.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"