Resistin has been linked to diabetes, obesity, insulin resistance, atherosclerosis, and the development of cardiovascular disease. However, the effects and the molecular mechanisms of resistin on endothelial permeability, a key event in the development of atherosclerosis, inflammation, and vascular disease, have not been fully elucidated. Diabetes is associated with changes in the brain microvasculature leading to dysfunction and disruption of the blood-brain barrier (BBB), a specialized system of microvascular endothelial cells protecting the brain from toxic substances in circulation, while permitting CNS entry of nutrients and endocrine signals using active transport mechanisms and passive diffusion. As diabetes is associated with cognitive impairment, understanding the molecular mechanisms of endothelial permeability in the brain is important in developing appropriate therapeutic agents. Topiramate (TPM), a mitochondrial carbonic anhydrase inhibitor, prevents BBB disruption in mouse models of type I and II diabetes. Mice resistant to the development of diet-induced obesity, when treated with TPM, had increased serum levels of resistin and increased BBB permeability to all brain regions except the hippocampus and hypothalamus, brain regions paradoxically disrupted in models of type II diabetes. In vitro treatment of brain endothelial cells with resistin demonstrated a decrease in endothelial nitric oxide synthase (eNOS) along with increased permeability and decreased TEER, a measure of electrical resistance across a cell monolayer. This increase in permeability occurs because diet-resistant mice treated with TPM are unable to attenuate the effects of hyperglycemia-induced oxidative stress and inflammation. Topiramate, which is protective of the BBB in types I and II diabetes, seems paradoxically toxic to the BBB in mice resistant to diet-induced obesity and this toxicity is associated with increases in serum resistin.
T.S. Salameh: None. W. Mortell: None. W.A. Banks: None.