Disruption of the hippocampal and hypothalamic blood–brain barrier in a diet-induced obese model of type II diabetes: prevention and treatment by the mitochondrial carbonic anhydrase inhibitor, topiramate

Abstract

Background

Type II diabetes is a vascular risk factor for cognitive impairment and increased risk of dementia. Disruption of the blood–retinal barrier (BRB) and blood–brain barrier (BBB) are hallmarks of subsequent retinal edema and central nervous system dysfunction. However, the mechanisms by which diet or metabolic syndrome induces dysfunction are not understood. A proposed mechanism is an increase in reactive oxygen species (ROS) and oxidative stress. Inhibition of mitochondrial carbonic anhydrase (mCA) decreases ROS and oxidative stress. In this study, topiramate, a mCA inhibitor, was examined for its ability to protect the BRB and BBB in diet-induced obese type II diabetic mice.

Methods

BBB and BRB permeability were assessed using ¹⁴C-sucrose and ^99mTc-albumin in CD-1 mice fed a low-fat (control) or a high-fat diet. Topiramate administration was compared to saline controls in both preventative and efficacy arms examining BRB and BBB disruption. Body weight and blood glucose were measured weekly and body composition was assessed using EchoMRI. Metabolic activity was measured using a comprehensive laboratory animal monitoring system. Brain tissues collected from the mice were assessed for changes in oxidative stress and tight junction proteins.

Results

High-fat feeding caused increased entry of ¹⁴C-sucrose and ^99mTc-albumin into the brains of diet-induced obese type II diabetic mice. Increased permeability to ¹⁴C-sucrose was observed in the hypothalamus and hippocampus, and attenuated by topiramate treatment, while increased permeability to ^99mTc-albumin occurred in the whole brain and was also attenuated by topiramate. Treatment with topiramate decreased measures of oxidative stress and increased expression of the tight junction proteins ZO-1 and claudin-12. In the retina, we observed increased entry of ^99mTc-albumin simultaneously with increased entry into the whole brain during the preventative arm. This occurred prior to increased entry to the retina for ¹⁴C-sucrose which occurred during the efficacy arm. Treatment with topiramate had no effect on the retina.

Conclusions

Blood–brain barrier and blood–retinal barrier dysfunction were examined in a mouse model of diet-induced obese type II diabetes. These studies demonstrate that there are spatial and temporal differences in ¹⁴C-sucrose and ^99mTc-albumin permeability in the brain and retina of diet-induced obese type II diabetic mice. Topiramate, a mitochondrial carbonic anhydrase inhibitor, is efficacious at both preventing and treating BBB disruption in this diet-induced obese type II diabetic mouse model.