Effects of 17β-Estradiol on Blood-Brain Barrier Disruption During Focal Ischemia in Rats

Summary

This study was performed to test whether 17β-estradiol could attenuate the blood-brain barrier disruption caused by middle cerebral artery occlusion in the ovariectomized rats. Rats aged twelve to fourteen weeks were used in this study. Their ovaries were removed one week prior to the implantation of the pellets. For the 17β-estradiol group, a 500 µg 17β-estradiol 21 day-release pellet was implanted and for the control group, a vehicle pellet was implanted 21 days before the experiments. One hour after middle cerebral artery occlusion under isoflurane anesthesia, the transfer coefficient of ¹⁴C-α-aminoisobutyric acid (104 Daltons) and the volume of ³H-dextran (70 000 Daltons) distribution were determined to represent the degree of blood-brain barrier disruption. Blood pressures and blood gases were similar between controls and 17β-estradiol-treated rats. In both groups, the transfer coefficient of the ischemic cortex was higher than that of the corresponding contralateral cortex (control: Ischemic Cortex 12.5 ± 5.9 µl/g/min, Contralateral Cortex 3.0 ± 1.6, p < 0.001; 17β-estradiol: Ischemic Cortex 6.7 ± 3.3 µl/g/min, Contralateral Cortex 2.2 ± 0.9, p < 0.01). There was no significant difference in the transfer coefficient of the contralateral cortex between these two groups. However, the transfer coefficient of the Ischemic Cortex of the 17β-estradiol-treated animals was 46 % lower than that of the control, vehicle-treated rats (p < 0.05). The increase of the volume of ³H-dextran distribution with middle cerebral artery occlusion was significant in the vehicle-treated rats (Ischemic Cortex: 6.4 ± 2.7 ml/100 g, Contralateral Cortex: 3.8 ± 0.8, p < 0.01) but not in the 17β-estradiol-treated animals. Our data suggest that chronic 17β-estradiol treatment was effective in reducing blood-brain barrier disruption during focal ischemia in the ovariectomized rats.

Key words

Brain - Capillary Permeability - Estrogen - Stroke

References

• 1 Murakami K, Kondo T, Chan P H. Blood-brain barrier disruption, edema formation and apoptotic neuronal death following cold injury.  Acta Neurochir Suppl (Wien). 1997;  70 234-236
• 2 Albayrak S, Zhao O, Siesjo B K, Smith M L. Effect of transient focal ischemia on BBB permeability in the rat: correlation to cell injury.  Acta Neuropathol (Berl). 1997;  94 158-163
• 3 Chi O Z, Wei H M, Lu X, Weiss H R. Increased blood-brain barrier permeability with hyperosmolar mannitol increases cerebral O₂ consumption and O2 supply/consumption heterogeneity.  J Cereb Blood Flow Metab. 1996;  16 327-333
• 4 Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia.  JAMA. 1998;  279 688-695
• 5 Fung M M, Barrett-Connor E, Bettencourt R R. Hormone replacement therapy and stroke risk in older women.  J Womens Health. 1999;  8 359-364
• 6 Paganini-Hill A, Ross R K, Henderson B E. Postmenopausal oestrogen treatment and stroke: a prospective study.  BMJ. 1988;  297 519-522
• 7 Rusa R, Alkayed N J, Crain B J, Traystman R J, Kimes A S, London E D, Klaus J A, Hurn P D. 17beta-estradiol reduces stroke injury in estrogen-deficient female animals.  Stroke. 1999;  30 1665-1670
• 8 Dubal D B, Shughrue P J, Wilson M E, Merchenthaler I, Wise P M. Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors.  J Neurosci. 1999;  19 6385-6393
• 9 Toung T J, Traystman R J, Hurn P D. Estrogen-mediated neuroprotection after experimental stroke in male rats.  Stroke. 1998;  29 1666-1670
• 10 Gardner G, Banka C L, Roberts K A, Mullick A E, Rutledge J C. Modified LDL-mediated increases in endothelial layer permeability are attenuated with 17 beta-estradiol.  Arterioscler Thromb Vasc Biol. 1999;  19 854-861
• 11 Nishino H, Nakajima K, Kumazaki M, Fukuda A, Muramatsu K, Deshpande S B, Inubushi T, Morikawa S, Borlongan C V, Sanberg P R. Estrogen protects against while testosterone exacerbates vulnerability of the lateral striatal artery to chemical hypoxia by 3-nitropropionic acid.  Neurosci Res. 1998;  30 303-312
• 12 Oztas B, Kaya M. Influence of orchidectomy and ovariectomy on the blood-brain barrier permeability during bicuculline-induced seizures.  Horm Metab Res. 1998;  30 500-503
• 13 Cullinan-Bove K, Koos R D. Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth.  Endocrinology. 1993;  133 829-837
• 14 Chi O Z, Wei H M, Sinha A K, Weiss H R. Effects of inhibition of nitric oxide synthase on blood-brain barrier transport in focal cerebral ischemia.  Pharmacology. 1994;  48 367-373
• 15 Gross P M, Blasberg R G, Fenstermacher J D, Patlak C S. The microcirculation of rat circumventricular organs and pituitary gland.  Brain Res Bull. 1987;  18 73-85
• 16 Saija A, Princi P, de Pasquale R, Costa G. High intensity light exposure increases blood-brain barrier transport in rats.  Pharmacol Res Commun. 1988;  20 553-559
• 17 Saija A, Princi P, de Pasquale R, Costa G. Modifications of the permeability of the blood-brain barrier and local cerebral metabolism in pentobarbital and ketamine-anesthetized rats.  Neuropharmacology. 1989;  28 997-1002
• 18 Sharma H S, Dey P K. Impairment of blood-brain barrier (BBB) in rat by immobilization stress: role of serotonin (5-HT).  Indian J Physiol Pharmacol. 1981;  25 111-122
• 19 Chi O Z, Chang Q, Weiss H R. Effects of topical N-methyl-D-aspartate on blood-brain barrier permeability in the cerebral cortex of normotensive and hypertensive Rats.  Neurol Res. 1997;  19 539-544
• 20 Losordo D W, Kearney M, Kim E A, Jekanowski J, Isner J M. Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women.  Circulation. 1994;  89 1501-1510
• 21 Lin A L, Shain S A. Estrogen mediated cytoplasmic and nuclear distribution of rat cardiovascular estrogen receptors.  Arteriosclerosis. 1985;  5 668-677
• 22 McNeill A M, Kim N, Duckles S P, Krause D N. Chronic estrogen treatment increases levels of endothelial nitric oxide synthase protein in rat cerebral microvessels.  Stroke. 1999;  30 2186-2190
• 23 Komesaroff P A, Black C V, Westerman R A. A novel, nongenomic action of estrogen on the cardiovascular system.  J Clin Endocrinol Metab. 1998;  83 2313-2316
• 24 Caulin-Glaser T, Garcia-Cardena G, Sarrel P, Sessa W C, Bender J R. Beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca²⁺ mobilization.  Circ Res. 1997;  81 885-892
• 25 Kubes P. Ischemia-reperfusion in feline small intestine: a role for nitric oxide.  Am J Physiol. 1993;  264 G143-G149
• 26 Boje K M. Inhibition of nitric oxide synthase partially attenuates alterations in the blood-cerebrospinal fluid barrier during experimental meningitis in the rat.  Eur J Pharmacol. 1995;  272 297-300
• 27 Chi O Z, Chang Q, Wang G, Weiss H R. Effects of nitric oxide on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats.  Anesth Analg. 1997;  84 370-375
• 28 Weaver C E , Park-Chung M, Gibbs T T, Farb D H. 17b-Estradiol protects against NMDA-induced excitotoxicity by direct inhibition of NMDA receptors.  Brain Res. 1997;  761 338-341
• 29 Zaulyanov L L, Green P S, Simpkins J W. Glutamate receptor requirement for neuronal cell death from anoxia-reoxygenation: an in vitro model for assessment of the neuroprotective effects of estrogen.  Cell Mol Neurobiol. 1999;  19 705-718
• 30 Sawada H, Ibi M, Kihara T, Urushitani M, Akaike A, Shimohama S. Estradiol protects mesencephalic dopaminergic neurons from oxidative stress-induced neuronal death.  J Neurosci Res. 1998;  54 707-719
• 31 Hurn P D, Macrai I M. Estrogen as a neuroprotectant in stroke.  J Cereb Blood Flow Metab. 2000;  20 631-652
• 32 Fisher G, Swain M L. Effects of estradiol and progesterone on the increased synthesis of collagen in atherosclerotic rabbit aortas.  Atherosclerosis. 1985;  54 177-185
• 33 Morales D E, McGowan K A, Grant D S, Maheshwari S, Bhartiya D, Cid M C, Kleinman H K, Schnaper H W. Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model.  Circulation. 1995;  91 755-763
• 34 Mukherjee M, de Lorenzo F, Kadziola Z, Rutlin A, Ranlall N, Sembhi K, Dawson G, Kakkar V V. Correlation of circulating 17beta-oestradiol with haemostatic factors in healthy postmenopausal women.  Haemostasis. 1999;  29 336-342