title: Inhibition of SUR1 decreases the vascular permeability of cerebral metastases.
abstract: Inhibition of sulfonylurea receptor 1 (SUR1) by glyburide has been shown to decrease edema after subarachnoid hemorrhage. We investigated if inhibiting SUR1 reduces cerebral edema due to metastases, the most common brain tumor, and explored the putative association of SUR1 and the endothelial tight junction protein, zona occludens-1 (ZO-1). Nude rats were intracerebrally implanted with small cell lung carcinoma (SCLC) LX1 or A2058 melanoma cells (n = 36). Rats were administered vehicle, glyburide (4.8 µg twice, orally), or dexamethasone (0.35 mg, intravenous). Blood-tumor barrier (BTB) permeability (K (trans)) was evaluated before and after treatment using dynamic contrast-enhanced magnetic resonance imaging. SUR1 and ZO-1 expression was evaluated using immunofluorescence and Western blots. In both models, SUR1 expression was significantly increased (P < .05) in tumors. In animals with SCLC, control mean K (trans) (percent change ± standard error) was 101.8 ± 36.6%, and both glyburide (-21.4 ± 14.2%, P < .01) and dexamethasone (-14.2 ± 13.1%, P < .01) decreased BTB permeability. In animals with melanoma, compared to controls (117.1 ± 43.4%), glyburide lowered BTB permeability increase (3.2 ± 15.4%, P < .05), while dexamethasone modestly lowered BTB permeability increase (63.1 ± 22.1%, P > .05). Both glyburide (P < .001) and dexamethasone (P < .01) decreased ZO-1 gap formation. By decreasing ZO-1 gaps, glyburide was at least as effective as dexamethasone at halting increased BTB permeability caused by SCLC and melanoma. Glyburide is a safe, inexpensive, and efficacious alternative to dexamethasone for the treatment of cerebral metastasis-related vasogenic edema.
authors: Department of Neurological Surgery, Oregon Health & Science University, Portland, OR 97239, USA.
authors: Eric M
authors: EM
authors: Thompson
authors: Gregory L
authors: GL
authors: Pishko
authors: Leslie L
authors: LL
authors: Muldoon
authors: Edward A
authors: EA
authors: Neuwelt
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D002199:Capillary Permeability / Q000187:drug effects*; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000008:administration & dosage; D015870:Gene Expression; D005905:Glyburide / Q000008:administration & dosage*; D055104:Infusions, Subcutaneous; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D051381:Rats; D011923:Rats, Nude; D055752:Small Cell Lung Carcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D064233:Sulfonylurea Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: C577507:ABCC8 protein, human; D000964:Antimetabolites, Antineoplastic; D064233:Sulfonylurea Receptors; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D003907:Dexamethasone; D005905:Glyburide
references: Acta Neurochir (Wien). 1998;140(9):919-24
references: 9842429
references: Clin Lung Cancer. 2012 Jan;13(1):24-30
references: 21831719
references: Curr Opin Neurol. 2008 Dec;21(6):717-9
references: 18989118
references: Neuro Oncol. 2011 Jan;13(1):51-60
references: 21123368
references: AJNR Am J Neuroradiol. 2006 Oct;27(9):1975-82
references: 17032878
references: J Cereb Blood Flow Metab. 2009 Feb;29(2):317-30
references: 18854840
references: J Neurotrauma. 2009 Dec;26(12):2257-67
references: 19604096
references: Neurosurgery. 2010 Jul;67(1):87-93
references: 20559095
references: Neuro Oncol. 2012 Nov;14 Suppl 5:v1-49
references: 23095881
references: J Neurochem. 2005 May;93(4):1047-56
references: 15857408
references: J Magn Reson Imaging. 2008 Sep;28(3):588-97
references: 18777539
references: Acta Neuropathol. 2006 Dec;112(6):651-64
references: 16855833
references: J Magn Reson Imaging. 2004 Nov;20(5):748-57
references: 15503330
references: J Clin Oncol. 2007 Oct 20;25(30):4722-9
references: 17947719
references: J Clin Invest. 1996 Sep 15;98(6):1400-8
references: 8823305
references: J Neurosurg. 2010 Sep;113(3):622-9
references: 20035575
references: Am J Physiol Heart Circ Physiol. 2001 Jan;280(1):H434-40
references: 11123261
references: FEBS Lett. 1997 Jan 13;401(1):59-64
references: 9003806
references: Nat Med. 2006 Apr;12(4):433-40
references: 16550187
references: Cancer Imaging. 2012 Jan 23;12:1-6
references: 22275724
references: AJNR Am J Neuroradiol. 2010 Mar;31(3):549-53
references: 19850765
references: Stroke. 2011 Mar;42(3):710-5
references: 21330623
references: Expert Rev Anticancer Ther. 2007 Nov;7(11):1561-6
references: 18020924
references: J Neurosci. 2003 Sep 17;23(24):8568-77
references: 13679426
references: Neurology. 1994 Apr;44(4):675-80
references: 8164824
references: Nat Rev Clin Oncol. 2009 Apr;6(4):229-36
references: 19333229
references: J Magn Reson. 2010 Oct;206(2):190-9
references: 20674422
references: Nat Rev Clin Oncol. 2011 Jun;8(6):344-56
references: 21487419
references: Br J Radiol. 2008 Feb;81(962):120-8
references: 18070824
references: Anticancer Res. 2010 Jun;30(6):1977-98
references: 20651342
references: Radiol Med. 2012 Oct;117(7):1225-41
references: 22744350
references: J Cereb Blood Flow Metab. 2010 Apr;30(4):837-48
references: 19997118
references: Stroke. 2007 Sep;38(9):2526-30
references: 17673715
references: Med Klin (Munich). 2003 Apr 25;98(5):266-70
references: 12721671
references: AJNR Am J Neuroradiol. 2005 Nov-Dec;26(10):2455-65
references: 16286385
references: Neoplasia. 2007 Jul;9(7):546-55
references: 17710157
references: J Magn Reson Imaging. 2004 May;19(5):527-36
references: 15112301
references: Cancer Res. 2003 Dec 15;63(24):8899-911
references: 14695207
references: J Clin Invest. 2007 Aug;117(8):2105-13
references: 17657312
references: Cell Tissue Res. 2006 Jan;323(1):117-25
references: 16163490
references: J Magn Reson Imaging. 1999 Sep;10(3):223-32
references: 10508281
references: J Cereb Blood Flow Metab. 2009 Apr;29(4):853-60
references: 19142191