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.

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

“…A possible mechanism responsible for the prevention of mitochondrial depolarization and H 2 O 2 production is that pharmacological inhibition of mitochondrial CAs slows down the production of ${\text{HCO}}_3^{-}$, limiting Krebs cycle and electron transport chain, and thus reducing the production of H 2 O 2 and subsequent oxidative stress. This mechanism is also proposed by Shah's group, who showed that inhibition of CAs rescued high‐glucose induced mitochondrial dysfunction, ROS production, and pericyte loss in diabetic mice (Price, Eranki, Banks, Ercal & Shah, 2012; Shah, Morofuji, Banks & Price, 2013). The known effects of CAIs on specific ion channels, aquaporins (Kamegawa, Hiroaki, Tani & Fujiyoshi, 2016), or other receptors which interact with Aβ on mitochondrial or cell membranes may also be mechanisms responsible for the amelioration of Aβ‐induced mitochondrial dysfunction (Aggarwal et al., 2013).…”

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

“…228 One factor contributing to BBB disruption is pericyte loss 229 that occurs from hyperglycemia-induced mitochondrial oxidative stress in a rodent model of diabetes. 149 Pericyte loss in this model is blocked by the carbonic anhydrase inhibitor topiramate that shifts glucose metabolism to aerobic glycolysis and prevents generation of superoxide. 149 Together, these results suggest that diabetes causes BBB dysfunction that could contribute to AD.…”

“…149 Pericyte loss in this model is blocked by the carbonic anhydrase inhibitor topiramate that shifts glucose metabolism to aerobic glycolysis and prevents generation of superoxide. 149 Together, these results suggest that diabetes causes BBB dysfunction that could contribute to AD. Traumatic Brain Injury Traumatic brain injury (TBI) increases the risk for developing AD by 2-to 4.5-fold, depending on severity of the injury.…”

Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke

“…DM rats suffer from vascular damage, which is aggravated after an ischemic insult; the effects of VEGF may be exacerbated in DM stroke rats compared with nondiabetic stroke rats 42, 43. In DM, mitochondrial oxidative stress leads to both endothelial cell damage as well as pericyte depletion and BBB leakage 44. In the minutes to hours following ischemia, endothelial swelling and pericytes mediate capillary constriction, which is followed by rapid pericyte death leading to irreversible constriction of capillaries and BBB damage 34, 45…”

“…Mitochondrial oxidative stress with an increased abundance of reactive oxygen species (ROS) after I/R is a key mediator of diabetic, stroke, and diabetic stroke pathologies 44. ROS generated from mitochondria mediate neurodegeneration and apoptotic signaling pathways after stroke.…”