All ETDs from UAB

Advisory Committee Chair

Brian Sims

Advisory Committee Members

Stephen Watts

Thane Wibbels

Document Type

Thesis

Date of Award

2012

Degree Name by School

Master of Science (MS) College of Arts and Sciences

Abstract

Neonatal brain injury is a significant health concern of premature low birth weight babies that often leads to devastating developmental complications. Many of these babies do not survive and those that survive could end up with social and mental disorders. Premature babies are susceptible to brain injury due to their unique and underdeveloped anatomy. The insufficiency of the neonatal defense and antioxidant system prevents the body from buffering against ROS, causing oxidative stress. Adenosine, known as a modulator of cerebral blood flow, has been shown to be neuroprotective; it prevents excessive neuronal firing. However, depending on the cell type and condition, it can be neurotoxic. In these cases, neuroprotection is conferred when adenosine receptors are blocked with methylxanthines. Methylxanthines are phosphodiester inhibitors, which increase levels of cyclic AMP and cyclic GMP. Theophylline, a candidate methylxanthine, may be neuroprotective. However, theophylline's mechanism of action in neural stem cells is not well known. We believe that a potential pathway of neuroprotection involves theophylline utilizing the actions of System Xc. System Xc, a cystine-glutamate antiporter exchanger, is important in the biosynthesis of glutathione, an antioxidant used to detoxify ROS and prevent oxidative stress. Data from our lab shows that upregulation of System Xc increases cell viability. From our lab's preliminary data, I hypothesize that theophylline increases neural stem cell viability. To test this hypothesize, experiments were conducted to elucidate theophylline's time and dose-dependent effect on neural stem cell survival. Other experiments were conducted to determine theophylline's effect on the cystine glutamate exchanger. Experiments were done to determine if theophylline effects could be reversed by adenosine. Finally, experiments were conducted to determine if theophylline induces its neuroprotective effect through the Mitogen Activated Protein (MAP) Kinase pathway.

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