Abstract

With an incidence approaching 1/4000 live births and as high as 60% in low birth weight infants, cerebral hypoxia-ischemia during the perinatal period is the single most important cause of acute mortality and chronic disability in newborns. Herein, we tested the hypothesis that following a hypoxic-ischemic insult hyperbaric oxygen (HBO) treatment can restore high energy metabolite levels in the affected regions of the brain and through this increase in energy levels ameliorate the spread of cell death following the insult. We also investigated if an additional mechanism by which HBO affords its neuroprotection is by altering the expression of the transcription factor hypoxia-inducible factor (HIF)-1α.

Seven-day-old rat pups were subjected to unilateral carotid artery ligation, followed by 2-2.5 hours of hypoxia (8% O2 at 37°C). HBO treatment was administered by placing pups in a chamber (100% O2 at 3 ATA or 2.5 ATA for 1-2 hrs) one hour after hypoxia exposure. Following the insult, severe atrophy, along with extensive cell death was observed in the ipsilateral hemisphere, which led to noticeable neurological deficits. The levels of ATP and phosphocreatine remained at levels below normal, whereas the level of glucose and other glycolytic intermediates were elevated. At this same time, an elevated expression of HIF-1α and several of its target genes, including Glut-1 and p53. was also noted. An elevated expression of several components of the apoptotic machinery was also observed, followed closely by a time-dependent increase in the number of apoptotic cells. HBO treatment reduced brain injury, in terms of weight and volume, and preserved sensorimotor function. Treatment with HBO restored the energy state of the brain, decreased the expression of HIF-1α and its target genes, and attenuated the hypoxic-ischemic-induced apoptotic cell death. Importantly, no signs of retinopathy of prematurity were observed after HBO treatment.

These results suggest that a single treatment of HBO affords neuroprotection when administered during the initial recovery period from a hypoxic-ischemic insult. Thus, we propose that a short duration of HBO may offer an acceptable, safe, convenient, and effective therapy for brain protection for premature or hypoxic infants.

LLU Discipline

Physiology

Department

Physiology

School

Graduate School

First Advisor

John H. Zhang

Second Advisor

Stephen Ashwal

Third Advisor

Jonathan W. Neidigh

Fourth Advisor

Lawrence C. Sowers

Fifth Advisor

Steven M. Yellon

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2005

Date (Title Page)

12-2005

Language

English

Library of Congress/MESH Subject Headings

Hypoxia-Ischemia, Brain -- physiopathology; Infant Mortality; Perinatal Care; Hyperbaric Oxygenation; Brain -- physiopathology.

Type

Dissertation

Page Count

xvi; 263

Digital Format

PDF

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.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

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

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