PMID- 27729477 OWN - NLM STAT- MEDLINE DCOM- 20170516 LR - 20181202 IS - 1521-0103 (Electronic) IS - 0022-3565 (Print) IS - 0022-3565 (Linking) VI - 359 IP - 3 DP - 2016 Dec TI - Blood-Brain Barrier Disruption and Neurovascular Unit Dysfunction in Diabetic Mice: Protection with the Mitochondrial Carbonic Anhydrase Inhibitor Topiramate. PG - 452-459 AB - All forms of diabetes mellitus are characterized by chronic hyperglycemia, resulting in the development of a number of microvascular and macrovascular pathologies. Diabetes is also associated with changes in brain microvasculature, leading to dysfunction and ultimately disruption of the blood-brain barrier (BBB). These changes are correlated with a decline in cognitive function. In diabetes, BBB damage is associated with increased oxidative stress and reactive oxygen species. This occurs because of the increased oxidative metabolism of glucose caused by hyperglycemia. Decreasing the production of bicarbonate with the use of a mitochondrial carbonic anhydrase inhibitor (mCAi) limits oxidative metabolism and the production of reactive oxygen species. In this study, we have demonstrated that 1) streptozotocin-induced diabetes resulted in BBB disruption, 2) ultrastructural studies showed a breakdown of the BBB and changes to the neurovascular unit (NVU), including a loss of brain pericytes and retraction of astrocytes, the two cell types that maintain the BBB, and 3) treatment with topiramate, a mCAi, attenuated the effects of diabetes on BBB disruption and ultrastructural changes in the neurovascular unit. CI - U.S. Government work not protected by U.S. copyright. FAU - Salameh, Therese S AU - Salameh TS AD - Geriatrics Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (T.S.S., W.A.B.); Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington (T.S.S., W.A.B.); Division of Endocrinology, Department of Internal Medicine, School of Medicine, Saint Louis University, St. Louis, Missouri (G.N.S., T.O.P.); Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Missouri, Columbia, Missouri (M.R.H.); Diabetes and Cardiovascular Research Laboratory, University of Missouri, Columbia, Missouri (M.H.R.). FAU - Shah, Gul N AU - Shah GN AD - Geriatrics Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (T.S.S., W.A.B.); Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington (T.S.S., W.A.B.); Division of Endocrinology, Department of Internal Medicine, School of Medicine, Saint Louis University, St. Louis, Missouri (G.N.S., T.O.P.); Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Missouri, Columbia, Missouri (M.R.H.); Diabetes and Cardiovascular Research Laboratory, University of Missouri, Columbia, Missouri (M.H.R.). FAU - Price, Tulin O AU - Price TO AD - Geriatrics Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (T.S.S., W.A.B.); Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington (T.S.S., W.A.B.); Division of Endocrinology, Department of Internal Medicine, School of Medicine, Saint Louis University, St. Louis, Missouri (G.N.S., T.O.P.); Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Missouri, Columbia, Missouri (M.R.H.); Diabetes and Cardiovascular Research Laboratory, University of Missouri, Columbia, Missouri (M.H.R.). FAU - Hayden, Melvin R AU - Hayden MR AD - Geriatrics Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (T.S.S., W.A.B.); Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington (T.S.S., W.A.B.); Division of Endocrinology, Department of Internal Medicine, School of Medicine, Saint Louis University, St. Louis, Missouri (G.N.S., T.O.P.); Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Missouri, Columbia, Missouri (M.R.H.); Diabetes and Cardiovascular Research Laboratory, University of Missouri, Columbia, Missouri (M.H.R.). FAU - Banks, William A AU - Banks WA AD - Geriatrics Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington (T.S.S., W.A.B.); Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington (T.S.S., W.A.B.); Division of Endocrinology, Department of Internal Medicine, School of Medicine, Saint Louis University, St. Louis, Missouri (G.N.S., T.O.P.); Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Missouri, Columbia, Missouri (M.R.H.); Diabetes and Cardiovascular Research Laboratory, University of Missouri, Columbia, Missouri (M.H.R.) wabanks1@uw.edu. LA - eng GR - R01 DK083485/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20161011 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 RN - 0 (Blood Glucose) RN - 0 (Carbonic Anhydrase Inhibitors) RN - 0H73WJJ391 (Topiramate) RN - 30237-26-4 (Fructose) SB - IM MH - Animals MH - Blood Glucose/metabolism MH - Blood Vessels/drug effects/*physiopathology MH - Blood-Brain Barrier/*drug effects/metabolism MH - Carbonic Anhydrase Inhibitors/*pharmacology MH - Diabetes Mellitus, Experimental/*metabolism/*pathology/physiopathology MH - Fructose/*analogs & derivatives/pharmacology MH - Male MH - Mice MH - Mitochondria/*enzymology MH - Permeability/drug effects MH - Topiramate PMC - PMC5118649 EDAT- 2016/10/13 06:00 MHDA- 2017/05/17 06:00 PMCR- 2017/12/01 CRDT- 2016/10/13 06:00 PHST- 2016/08/04 00:00 [received] PHST- 2016/09/23 00:00 [accepted] PHST- 2016/10/13 06:00 [pubmed] PHST- 2017/05/17 06:00 [medline] PHST- 2016/10/13 06:00 [entrez] PHST- 2017/12/01 00:00 [pmc-release] AID - jpet.116.237057 [pii] AID - JPET_237057 [pii] AID - 10.1124/jpet.116.237057 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2016 Dec;359(3):452-459. doi: 10.1124/jpet.116.237057. Epub 2016 Oct 11.