Date of Award

2012

Degree Name

Biomedical Sciences

College

College of Science

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Richard Egleton

Second Advisor

Todd Green

Third Advisor

Lawrence Grover

Fourth Advisor

Kelley Kiningham

Fifth Advisor

William McCumbee

Abstract

Diabetes is a risk factor for stroke and vascular dementia. Clinical studies using gadolinium-magnetic resonance imaging techniques have shown diabetic patients exhibit a permeability increase at the blood-brain barrier (BBB) (Starr et al, 2003). The BBB, a vascular interface at the level of brain microvascular vessels, functions to provide nutrients and oxygen from the peripheral circulation, mediates waste efflux from the brain, and protects the brain from toxins. These functions are due to the presence of tight junction proteins. Animal studies have shown increased BBB permeability is due to a decrease in these proteins (Hawkins et al, 2007). Based on these studies and using the streptozotocin (STZ) model of diabetes, I hypothesized that the permeability and molecular changes can be attenuated by minocycline, a tetracycline known to cross the BBB. STZ animals treated with minocycline exhibited a decrease in permeability and an increase in the tight junction protein, claudin-5. Previous studies have shown that the pro-angiogenic and permeability cytokine, vascular endothelial growth factor (VEGF), is able to influence claudin-5 expression (Argaw et al, 2009). Therefore, VEGF may be involved in a minocycline-induced increase in claudin-5 expression. VEGF significantly increased in STZ animals with minocycline treatment. Additionally, there was a significant increase in expression of the VEGF receptor, Flt-1, of control animals treated with minocycline, and a similar trend in minocycline-treated STZ animals. However, there were no changes in the other VEGF receptors. Based on these results, I hypothesized that VEGF might exert its effects on the BBB in diabetes. Although there were no changes in VEGF, there was a glucose-dependent change in PLCγ, a downstream signaling molecule involved in proliferation, which might help explain the permeability change observed in diabetes.

Subject(s)

Blood-brain barrier disorders.

Diabetes - Research.

Vascular endothelial growth factors.

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