title: Topiramate treatment protects blood-brain barrier pericytes from hyperglycemia-induced oxidative damage in diabetic mice.
abstract: Diabetes mellitus causes cerebral microvasculature deterioration and cognitive decline. The specialized endothelial cells of cerebral microvasculature comprise the blood-brain barrier, and the pericytes (PC) that are in immediate contact with these endothelial cells are vital for blood-brain barrier integrity. In diabetes, increased mitochondrial oxidative stress is implicated as a mechanism for hyperglycemia-induced PC loss as a prerequisite leading to blood-brain barrier disruption. Mitochondrial carbonic anhydrases (CA) regulate the oxidative metabolism of glucose and thus play an important role in the generation of reactive oxygen species and oxidative stress. We hypothesize that the inhibition of mitochondrial CA would reduce mitochondrial oxidative stress, rescue cerebral PC loss caused by diabetes-induced oxidative stress, and preserve blood-brain barrier integrity. We studied the effects of pharmacological inhibition of mitochondrial CA activity on streptozotocin-diabetes-induced oxidative stress and PC loss in the mouse brain. At 3 wk of diabetes, there was significant oxidative stress; the levels of reduced glutathione were lower and those of 3-nitrotyrosine, 4-hydroxy-2-trans-nonenal, and superoxide dismutase were higher. Treatment of diabetic mice with topiramate, a potent mitochondrial CA inhibitor, prevented the oxidative stress caused by 3 wk of diabetes. A significant decline in cerebral PC numbers, at 12 wk of diabetes, was also rescued by topiramate treatment. These results provide the first evidence that inhibition of mitochondrial CA activity reduces diabetes-induced oxidative stress in the mouse brain and rescues cerebral PC dropout. Thus, mitochondrial CA may provide a new therapeutic target for oxidative stress related illnesses of the central nervous system.
authors: Division of Endocrinology, Department of Internal Medicine, Saint Louis University, Edward A. Doisy Research Center, 1100 South Grand Boulevard, St. Louis, Missouri 63104, USA.
authors: Tulin O
authors: TO
authors: Price
authors: Vijay
authors: V
authors: Eranki
authors: William A
authors: WA
authors: Banks
authors: Nuran
authors: N
authors: Ercal
authors: Gul N
authors: GN
authors: Shah
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D024404:Carbonic Anhydrase V / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020286:Pericytes / Q000187:drug effects / Q000473:pathology; D000077236:Topiramate
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D000077236:Topiramate; D005632:Fructose; D024404:Carbonic Anhydrase V