Neonatal hypoxic ischemic encephalopathy (HIE) is a devastating disease that primarily causes neuronal and white matter injury and is among the leading cause of death among infants. Currently there are no well-established treatments; thus, it is important to understand the pathophysiology of the disease and elucidate complications that are creating a gap between basic science and clinical translation. In the development of neuroprotective strategies and translation of experimental results in HIE, there are many limitations and challenges to master based on an appropriate study design, drug delivery properties, dosage, and use in neonates. Since there are no established therapies for HIE and it is critical to develop treatments that provide protection after HIE. In three separate studies we evaluated the efficacy of interferon beta (IFNβ), granulocyte-colony stimulating factor (G-CSF), and osteopontin (OPN) in reducing apoptosis and inflammation following neonatal hypoxic ischemic encephalopathy and have outlined the cellular pathways involved in their abilities to provide neuroprotection. Our work showed that intranasal administration of IFNβ was able to be detected in the central nervous system, reduce brain infarction volumes, and improve neurological behavior tests 24 hours after HIE. Administration of G-CSF was able to play a pivotal role in attenuating neuroinflammation and BBB disruption 48 hours following HIE. Similarly, OPN was able to decrease blood-brain barrier permeability and brain edema after HIE. In addition, we have also reviewed and discussed the current literature on the pathophysiology, potential intervention sites, novel neuroprotecitve molecules, clinical trials, and future directions concerning HIE.

LLU Discipline



Basic Sciences


School of Medicine

First Advisor

Tang, Jiping

Second Advisor

Ashwal, Stephen

Third Advisor

Gridley, Daila S.

Fourth Advisor

Pearce, William J.

Fifth Advisor

Zhang, John H.

Degree Name

Doctor of Philosophy (Medical Science)

Degree Level


Year Degree Awarded


Date (Title Page)




Library of Congress/MESH Subject Headings

Fetal Hypoxia -- Pathology; Hypoxia-Ischemia; Brain -- etiology; Brain Infraction -- pathology

Subject - Local

Neonatal hypoxic ischemic encephalopathy; Interferon Beta; Apoptosis; Brain Infarction; Encephalopathy



Page Count


Digital Format


Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.


Loma Linda University Electronic Theses and Dissertations

Collection Website



Loma Linda University. Del E. Webb Memorial Library. University Archives