Pharmaceutical Sciences ETDs

Publication Date

Spring 5-10-2019

Abstract

The objective of this study was to investigate the biphasic effects of vanadyl sulfate in cerebral vascular endothelial cells with a focus on understanding the mechanisms underlying vanadyl sulfate benefits. To first address the effects of vanadyl sulfate on endothelial permeability, mouse cerebrovascular endothelial cells were grown to confluence in 96-well electrode ECIS plates and treated with three different vanadium containing compounds: vanadyl sulfate, vanadium pentoxide, and ammonium metavanadate. Resistance of the endothelial cell monolayer was measured at 4kHz for 24 hours for different concentrations of vanadium containing compounds. The mouse cerebrovascular endothelial cells were also treated with different concentrations of vanadyl sulfate plus a superoxide dismutase mimetic, tempol, or a rho kinase inhibitor, fasudil, for 48 hours to assess oxidative stress and rho kinase activation by vanadium. All three vanadium-containing compounds exhibited a dose dependent biphasic effect in resistance. The addition of tempol and fasudil did not increase resistance of vanadyl sulfate. Additionally, an in vivo mouse study was conducted with two concentrations of vanadyl sulfate 0.025 mg and 0.25 mg, dosed twice daily for 24 hours. Brain tissue was collected and mRNA transcription levels of intracellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), zona occludens-1 (ZO-1), occludin and claudin-5 were measured by qPCR. The transcription levels for the genes of TNF-α and ICAM-1 did not change with vanadyl sulfate treatment. Blood brain barrier endothelial tight junction protein occludin transcription levels significantly increased with 0.025 mg vanadyl sulfate treatment. Levels remained unchanged compared to control for blood brain barrier tight junction proteins ZO-1 and claudin-5. These studies suggest that vanadium-containing compounds at certain concentrations may improve the blood brain barrier. Further investigation of the mechanisms of this effect may reveal novel therapeutic pathways/targets.

First Committee Member (Chair)

Matthew Campen

Degree Name

Pharmaceutical Sciences

Second Committee Member

Barry Bleske

Third Committee Member

Alicia Bolt

Document Type

Thesis

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