Protective Effect of Topiramate on Hyperglycemia-Induced Cerebral Oxidative Stress, Pericyte Loss and Learning Behavior in Diabetic Mice.

Abstract

Diabetes mellitus-associated damage to the microvasculature of the brain is caused by hyperglycemia-induced oxidative stress, which results in pericyte loss, blood-brain barrier disruption, and impaired cognitive function. Oxidative stress, in diabetes, is caused by reactive oxygen species produced during accelerated respiration (mitochondrial oxidative metabolism of glucose). The rate of respiration is regulated by mitochondrial carbonic anhydrases (CAs). Inhibition of these enzymes protects the brain from diabetic damage. Previously, we reported that topiramate, a mitochondrial CA inhibitor, at a dose of 50 mg/kg/day protects the brain in diabetes by reducing oxidative stress and restoring pericyte numbers. Topiramate has high affinity for both mitochondrial CAs; therefore, it is conceivable that a much lower dose may inhibit these enzymes and thus protect the brain from hyperglycemia-induced oxidative damage. Therefore, in an effort to reduce the toxicity associated with higher doses of topiramate, the current study was designed to investigate the effect of 1.0 mg/kg topiramate on reducing oxidative stress, restoring pericyte numbers in the brain, and improving the impaired learning behavior in diabetic mouse. Diabetes was induced by a one-time injection of streptozotocin and topiramate was administered daily for 12 weeks. Levels of oxidative stress, reduced glutathione (GSH) and 4-hydroxy-2-trans-nonenal (HNE) were measured in the brain and pericyte/endothelial cell ratios in isolated brain microvessels. Learning behavior was assessed by T-maze foot shock avoidance test. A significant decrease in GSH (control, 12.2 ± 0.4 vs. diabetic, 10.8 ± 0.4 vs. diabetic + topiramate, 12.6 ± 0.6, p<0.05) and an increase in HNE (control, 100 ± 4.2, vs. diabetic, 127.3 ± 8.8 vs. diabetic + topiramate, 93.9 ± 8.4 p<0.05) in diabetic mice were corrected by topiramate treatment. Topiramate treatment also resulted in restoration of pericyte numbers in diabetic mice (control, 25.89 ± 0.85 vs. diabetic, 18.14 ± 0.66 vs. diabetic + topiramate, 24.35 ± 0.53, p<0.001) and improvement in learning behavior. In conclusion, these data clearly demonstrate that topiramate at 1.0 mg/kg protects the mouse brain from diabetic damage. A 1.0 mg/kg topiramate in the mouse translates to a 5.0 mg daily dose in a 60 kg human, which may help slow the onset and progression of diabetic complications in the human brain.