Abstract

Hypoxic and hypoxic/ischemic episodes contribute to various neurological aberrations, learning disabilities, et cetera in surviving infants. Despite major advances in understanding the pathophysiology of hypoxia, the cellular basis for hypoxic-mediated injury remains poorly understood. In addition, the role of developmentally essential enzymes vis á vis their contributions, or lack thereof, to hypoxic-mediated injury has not been adequately investigated. In the series of studies comprising this dissertation, we tested the hypothesis that acute and/or chronic hypoxia affect the activity of omithine decarboxylase (ODC; E.C. 4.1.1.17), the developmentally essential enzyme in polyamine biosynthesis, in the fetal and newborn rat brain. Fetal and newborn rat brain ODC activity patterns showed a normal developmental profile; high activity near term that gradually declined to adult levels by postnatal day 10. Acute maternal hypoxia (≤ 4 h, 9% O2) elevated fetal hippocampal ODC activity 4- to 5-fold that of control. Coupled to this, were significant increases in brain polyamine concentrations. Similar, but less robust ODC activities were recorded in the newborn and adult rat as well. Chronic maternal hypoxia (≥ 48 h), however, was associated with only marginal changes in fetal brain ODC activity. Although some moderate changes in polyamines were evident in this instance, these were not as distinct nor large as those in acute hypoxia. Because these data were affected by maternal handling of the pups and other confounders, we developed an in vitro neonatal rat brain slice preparation to examine ODC activity responses to hypoxia. Thin brain slices from 3-d old rat pups showed a 2- to 3-fold increase in ODC activity, after 2 h exposure to oxygen concentrations ranging from 15% to 30%, when compared to slices incubated in 95% oxygen. Oxygen concentrations below 15% or above 30% did not induce any changes in ODC activity. Moreover, the initial rate of efflux of polyamines from similar slices treated with hydrogen peroxide (100-400 μM), appeared to be significantly enhanced. From these data, we concluded that: 1) ODC activity and polyamine concentration changes may be appropriate markers for acute, but not chronic hypoxia in the rat. 2) The increase in polyamines associated with acute hypoxia in vivo may be beneficial to the cell vis á vis the scavenging of reactive oxygen free radicals. 3) The identification of a distinct range of oxygen concentrations in vitro, in which the slices respond to hypoxia with ODC activity increases, suggests that a "window" for metabolic responses to hypoxic insults may exist. 4) The hydrogen peroxide effects on polyamine efflux may reflect a pathway via which hypoxia exerts its deleterious effects on neurons. Alternatively, because polyamines mediate several membrane functions, the hydrogen peroxide-mediated apparent increase in the rate of polyamine efflux from brain slices may be relevant to the stabilization of the neuronal membrane, as well as its receptor complexes, in response to hypoxic-associated free radical damage. 5) A deeper understanding of the regulation of the hypoxic-associated ODC activity and polyamine concentration changes in hypoxia may provide insight into the mechanism(s) by which neurons sense and respond to hypoxia per se.

LLU Discipline

Physiology

Department

Physiology

School

Graduate School

First Advisor

Lawrence D. Longo

Second Advisor

Craig V. Byus

Third Advisor

Christopher D. Cain

Fourth Advisor

Robert B. Stagg

Fifth Advisor

Barry L. Taylor

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

1995

Date (Title Page)

6-1995

Language

English

Library of Congress/MESH Subject Headings

Fetal Anoxia; Ornithine Decarboxylase; Polyamines

Type

Dissertation

Page Count

2 xv; 255

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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