Date of Award

1-1-2016

Embargo Period

1-1-2022

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Inderjit Singh

Second Advisor

Dorothea Jenkins

Third Advisor

Carl Atkinson

Fourth Advisor

Bruce Hollis

Fifth Advisor

Carol Wagner

Sixth Advisor

Rita Young

Abstract

Many neonates with hypoxic ischemic encephalopathy (HIE) still have devastating, life-long neurological deficits such as cerebral palsy, cognitive delays, and psychiatric, visuospatial and behavioral problems even with standard of care hypothermia. Animal and human data indicate that hypothermia is not neuroprotective when preexisting neuroinflammation or infection is superimposed on HI injury, necessitating adjunctive therapies to improve outcomes after HIE. The objectives for this work were to determine whether vitamin D deficiency is exacerbated by neuroinflammation caused by intrauterine infection or hypoxia ischemia injury, to characterize the role of iNOS and nNOS on vitamin D metabolism after intrauterine inflammation using knockout mouse models, and if the combination of N-acetylcysteine (NAC) and 1,25(OH)2 vitamin D (1,25(OH)2D) would improve outcomes after hypoxia ischemia injury with or without preexisting endotoxin induced inflammation. Endotoxin exposure or hypoxia ischemia injury induced vitamin D catabolism and decreased vitamin D activation. Both iNOS and nNOS knockouts had reduced vitamin D activation and degradation enzyme levels in the brain and lack of increased degradation with LPS stimulation indicating normal vitamin D metabolism may be partially under NO control. 1,25(OH)2D therapy induced negative feedback regulation in female animal brains resulting in increased degradation, but males did not have similar increases. The combination of NAC and 1,25(OH)2D significantly restored brain glutathione as measured by magnetic resonance spectroscopy in both rats and humans and improved long term behavioral outcomes in the pure hypoxia ischemia rat model with males achieving the greatest benefits from the addition of 1,25(OH)2 vitamin D over NAC therapy. However, in the endotoxin sensitized hypoxia ischemia animal model, NAC and 1,25(OH)2D dosed every 12hours recovered more slowly from the combined insult. HIE infants exhibited increased ionized calcium levels in the blood after rewarming with the combined therapy, suggesting 1,25(OH)2D dosing needs to be reevaluated for safety and efficacy.

Rights

All rights reserved. Copyright is held by the author.

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