title: Blood-Brain Barrier Disruption and Neurovascular Unit Dysfunction in Diabetic Mice: Protection with the Mitochondrial Carbonic Anhydrase Inhibitor Topiramate.
abstract: 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.
authors.affiliation: 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.).
authors.forename: Therese S
authors.initials: TS
authors.lastname: Salameh
authors.affiliation: 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.).
authors.forename: Gul N
authors.initials: GN
authors.lastname: Shah
authors.affiliation: 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.).
authors.forename: Tulin O
authors.initials: TO
authors.lastname: Price
authors.affiliation: 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.).
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: 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.
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001808:Blood Vessels / Q000187:drug effects / Q000503:physiopathology*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D010539:Permeability / Q000187:drug effects; D000077236:Topiramate
chemical_list: D001786:Blood Glucose; D002257:Carbonic Anhydrase Inhibitors; D000077236:Topiramate; D005632:Fructose