Increased blood–brain barrier permeability and altered tight junctions in experimental diabetes in the rat: contribution of hyperglycaemia and matrix metalloproteinases
Tóm tắt
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 [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. 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.
Tài liệu tham khảo
Hawkins BT, Davis TP (2005) The blood–brain barrier/neurovascular unit in health and disease. Pharm Rev 57:173–185
Yamagishi S, Imaizumi T (2005) Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des 11:2279–2299
Kadoglou NP, Daskalopoulou SS, Perrea D, Liapis CD (2005) Matrix metalloproteinases and diabetic vascular complications. Angiology 56:173–189
Ristow M (2004) Neurodegenerative disorders associated with diabetes mellitus. J Mol Med 82:510–529
Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P (2006) Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 5:64–74
Starr JM, Wardlaw J, Ferguson K, MacLullich A, Deary IJ, Marshall I (2003) Increased blood–brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. J Neurol Neurosurg Psychiatry 74:70–76
Iwata A, Koike F, Arasaki K, Tamaki M (1999) Blood brain barrier destruction in hyperglycemic chorea in a patient with poorly controlled diabetes. J Neurol Sci 163:90–93
Hovsepyan MR, Haas MJ, Boyajyan AS et al (2004) Astrocytic and neuronal biochemical markers in the sera of subjects with diabetes mellitus. Neurosci Lett 369:224–227
Mooradian AD, Haas MJ, Batejko O, Hovsepyan M, Feman SS (2005) Statins ameliorate endothelial barrier permeability changes in the cerebral tissue of streptozotocin-induced diabetic rats. Diabetes 54:2977–2982
Dai J, Vrensen GF, Schlingemann RO (2002) Blood–brain barrier integrity is unaltered in human brain cortex with diabetes mellitus. Brain Res 954:311–316
Rechthand E, Smith QR, Latker CH, Rapoport SI (1987) Altered blood–nerve barrier permeability to small molecules in experimental diabetes mellitus. J Neuropathol Exp Neurol 46:302–314
Ennis SR, Betz AL (1986) Sucrose permeability of the blood–retinal and blood–brain barriers. Effects of diabetes, hypertonicity, and iodate. Invest Ophthalmol Vis Sci 27:1095–1102
Chehade JM, Haas MJ, Mooradian AD (2002) Diabetes-related changes in rat cerebral occludin and zonula occludens-1 (ZO-1) expression. Neurochem Res 27:249–252
Antonetti DA, Barber AJ, Khin S, Lieth E, Tarbell JM, Gardner TW (1998) Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Penn State Retina Research Group. Diabetes 47:1953–1959
Giebel SJ, Menicucci G, McGuire PG, Das A (2005) Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood–retinal barrier. Lab Invest 85:597–607
Derosa G, Avanzini MA, Geroldi D et al (2005) Matrix metalloproteinase 2 may be a marker of microangiopathy in children and adolescents with type 1 diabetes mellitus. Diabetes Res Clin Pract 70:119–125
Signorelli SS, Malaponte G, Libra M et al (2005) Plasma levels and zymographic activities of matrix metalloproteinases 2 and 9 in type II diabetics with peripheral arterial disease. Vasc Med 10:1–6
Rosenberg GA, Estrada EY, Dencoff JE (1998) Matrix metalloproteinases and TIMPs are associated with blood–brain barrier opening after reperfusion in rat brain. Stroke 29:2189–2195
Mun-Bryce S, Rosenberg GA (1998) Gelatinase B modulates selective opening of the blood–brain barrier during inflammation. Am J Physiol 274:R1203–R1211
Wachtel M, Frei K, Ehler E, Fontana A, Winterhalter K, Gloor SM (1999) Occludin proteolysis and increased permeability in endothelial cells through tyrosine phosphatase inhibition. J Cell Sci 112( Pt 23):4347–4356
Williams SA, Abbruscato TJ, Hruby VJ, Davis TP (1996) Passage of a delta-opioid receptor selective enkephalin, [d-penicillamine2,5] enkephalin, across the blood–brain and the blood–cerebrospinal fluid barriers. J Neurochem 66:1289–1299
Hawkins BT, Abbruscato TJ, Egleton RD et al (2004) Nicotine increases in vivo blood–brain barrier permeability and alters cerebral microvascular tight junction protein distribution. Brain Res 1027:48–58
Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386
McReynolds MR, Taylor-Garcia KM, Greer KA, Hoying JB, Brooks HL (2005) Renal medullary gene expression in aquaporin-1 null mice. Am J Physiol Renal Physiol 288:F315–F321
Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic, New York
Willis CL, Leach L, Clarke GJ, Nolan CC, Ray DE (2004) Reversible disruption of tight junction complexes in the rat blood–brain barrier, following transitory focal astrocyte loss. Glia 48:1–13
Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH (2000) Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab 20:1681–1689
Hawkins BT, Egleton RD, Davis TP (2005) Modulation of cerebral microvascular permeability by endothelial nicotinic acetylcholine receptors. Am J Physiol, Heart Circ Physiol 289:H212–H219
Wang FQ, So J, Reierstad S, Fishman DA (2005) Matrilysin (MMP-7) promotes invasion of ovarian cancer cells by activation of progelatinase. Int J Cancer 114:19–31
Like AA, Rossini AA (1976) Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science 193:415–417
Rakieten N, Rakieten ML, Nadkarni MR (1963) Studies on the diabetogenic action of streptozotocin (NSC-37917). Cancer Chemother Rep 29:91–98
Winer N, Sowers JR (2004) Epidemiology of diabetes. J Clin Pharmacol 44:397–405
Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK (1990) Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA 263:2893–2898
Bickel U (2005) How to measure drug transport across the blood–brain barrier. NeuroRx 2:15–26
Preston JE, al-Sarraf H, Segal MB (1995) Permeability of the developing blood–brain barrier to 14C-mannitol using the rat in situ brain perfusion technique. Brain Res Dev Brain Res 87:69–76
Witt KA, Mark KS, Hom S, Davis TP (2003) Effects of hypoxia-reoxygenation on rat blood–brain barrier permeability and tight junctional protein expression. Am J Physiol, Heart Circ Physiol 285:H2820–H2831
Maepea O, Karlsson C, Alm A (1984) Blood–ocular and blood–brain barrier function in streptozocin-induced diabetes in rats. Arch Ophthalmol 102:1366–1369
Lorenzi M, Healy DP, Hawkins R, Printz JM, Printz MP (1986) Studies on the permeability of the blood–brain barrier in experimental diabetes. Diabetologia 29:58–62
Hawkins BT, Fleegal MA, McCaffery G, Egleton RD (2006) Contributions of hyperglycaemia and gelatinase activity to increased blood–brain barrier permeability in experimental diabetes. Society for Neuroscience, Annual Meeting (Abstract)
Bazzoni G, Dejana E (2004) Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 84:869–901
Penes MC, Li X, Nagy JI (2005) Expression of zonula occludens-1 (ZO-1) and the transcription factor ZO-1-associated nucleic acid-binding protein (ZONAB)-MsY3 in glial cells and colocalization at oligodendrocyte and astrocyte gap junctions in mouse brain. Eur J Neurosci 22:404–418
Harkness KA, Adamson P, Sussman JD, Davies-Jones GA, Greenwood J, Woodroofe MN (2000) Dexamethasone regulation of matrix metalloproteinase expression in CNS vascular endothelium. Brain 123:698–709
Jacqueminet S, Ben Abdesselam O, Chapman MJ et al (2006) Elevated circulating levels of matrix metalloproteinase-9 in type 1 diabetic patients with and without retinopathy. Clin Chim Acta 367:103–107
Nguyen JH, Yamamoto S, Steers J et al (2005) Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice. J Hepatol 44:1105–1114
Nakaya R, Uzui H, Shimizu H et al (2005) Pravastatin suppresses the increase in matrix metalloproteinase-2 levels after acute myocardial infarction. Int J Cardiol 105:67–73
Nomura S, Yoshimura K, Akiyama N et al (2005) HMG-CoA reductase inhibitors reduce matrix metalloproteinase-9 activity in human varicose veins. Eur Surg Res 37:370–378
Couture R, Harrisson M, Vianna RM, Cloutier F (2001) Kinin receptors in pain and inflammation. Eur J Pharmacol 429:161–176
Huber JD, Hau VS, Borg L, Campos CR, Egleton RD, Davis TP (2002) Blood–brain barrier tight junctions are altered during a 72-h exposure to lambda-carrageenan-induced inflammatory pain. Am J Physiol, Heart Circ Physiol 283:H1531–H1537
Banks WA, Jaspan JB, Kastin AJ (1997) Effect of diabetes mellitus on the permeability of the blood–brain barrier to insulin. Peptides 18:1577–1584
Mooradian AD (1987) Blood–brain barrier choline transport is reduced in diabetic rats. Diabetes 36:1094–1097