Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat: contribution of hyperglycaemia and matrix metalloproteinases
Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat: contribution of hyperglycaemia and matrix metalloproteinases
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DOI：
10.1007/s00125-006-0485-z
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发表时间：
2007-01-01
期刊：
影响因子：
8.2
通讯作者：
Egleton, R. D.
中科院分区：
文献类型：
--
作者：
Hawkins, B. T.;Lundeen, T. F.;Egleton, R. D.
虽然糖尿病与外周微血管并发症和神经事件风险增加有关，但糖尿病破坏血脑屏障(BBB)的机制尚不清楚。基质金属蛋白酶(MMPs)活性在糖尿病患者中升高，与紧密连接蛋白的降解有关，是血脑屏障损害的已知介体。我们假设糖尿病通过刺激基质金属蛋白酶活性导致血脑屏障紧密连接受损。糖尿病是用链脲佐菌素诱导的。注射后第14天，用脑原位灌注法评价血脑屏障功能。用免疫印迹和免疫荧光法检测紧密连接蛋白。在用链脲佐菌素处理的动物中，对[C-14]蔗糖的通透性增加的同时，血脑屏障紧密连接蛋白阻断素(也称为OCLN)和封闭带1(ZO-1，也称为紧密连接蛋白1或TJP1)的产生减少。胰岛素治疗从第7天开始，使血糖水平正常化，并减轻了血脑屏障对[C-14]蔗糖的高通透性。幼稚动物的急性高血糖和链脲佐菌素治疗的动物的血糖急性正常化都不会改变血脑屏障对[C-14]蔗糖的通透性。在用链脲佐菌素治疗的动物中，血浆基质金属蛋白酶活性增加。这些数据表明，糖尿病通过丢失紧密连接蛋白来增加血脑屏障通透性，糖尿病患者血脑屏障通透性增加不仅仅是高血糖引起的。糖尿病患者血浆基质金属蛋白酶活性升高与血脑屏障紧密连接蛋白降解和血脑屏障通透性增加有关。外周血中基质金属蛋白酶活性可能为糖尿病血脑屏障的保护和神经并发症的预防提供新的靶点。
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.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.In streptozotocin-treated animals, permeability to [C-14]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 [C-14]sucrose. Neither acute hyperglycaemia in naive animals nor acute normalisation of blood glucose in streptozotocin-treated animals altered BBB permeability to [C-14]sucrose. Plasma MMP activity was increased in streptozotocin-treated animals.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.