Nancy Fathali

Abstract

Hypoxia-ischemia (HI) occurs in 1-6/1000 live full-term births (Shankaran, 2009). Of those affected, 15-20% will die in the postnatal period, and 25% of survivors will be left with long-term neurological disabilities (Gunn, 2000; Vannucci, 1997; Fatemi, 2009). It has become increasingly clear that peripheral immune cells infiltrate the brain parenchyma as part of the physiological response to tissue damage after HI injury. The interplay between infiltrating immune cells and brain resident cells during the inflammatory response is however dynamic and complex; in that neuro-immune crosstalk, by way of specific molecular mediators, is responsible for both neurodestructive as well as neuroprotective outcomes. Herein, we tested the hypothesis that COX-2 mediates mechanisms of brain injury and that G-CSF exerts structural and functional protection after neonatal HI.

To mimic the clinical features of HI brain injury, neonatal rat pups were subjected to unilateral carotid artery ligation followed by 2 hours of hypoxia (8% O2 at 37°C). We used a gain and loss of function approach (pharmacological activation or inhibition, respectively) for COX-2, a neutralizing antibody for lL-15, and a gene silencer for natural killer cells in both splenectomized and non-splenectomized rats to verify the role of COX-2 in splenic immune cell responses following HI. We found that elevations in COX-2 expression by immune cells promoted IL-15 expression in astrocytes and infiltration of inflammatory cells; additionally, down-regulated the pro-survival protein, PI3K, resulting in caspase-3 mediated neuronal death. Additionally, we investigated the efficacy of G-CSF on long-term Hl-induced morphological and functional outcomes using two different dosing regimens; and found the neurotrophic factor to significantly improve behavioral and neuropathological recovery.

These results provide insight into the mechanistic basis of mflammation and indentify key components of the neuroinflammatory response after HI. Thus, we propose that COX-2 inhibition or G-CSF administration during the acute phase of injury are novel therapeutic modalities that target detrimental and beneficial mechanisms of neuroinflammation, respectively, and may offer a safe and effective option with longterm benefits for the Hl-injured infant.

LLU Discipline

Anatomy

Department

Anatomy

School

Graduate Studies

First Advisor

John H. Zhang

Second Advisor

Stephen Ashwal

Third Advisor

Michael A. Kirby

Fourth Advisor

Pedro B. Nava

Fifth Advisor

Jiping Tang

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2010

Date (Title Page)

6-2010

Language

English

Library of Congress/MESH Subject Headings

Hypoxia-Ischemia, Brain -- physiopathology; Brain Injuries -- etiology; Brain Infarction -- drug therapy; Inflammation -- pathology; Inflammation Mediators -- therapeutic use; Neuroprotective Agents -- pharmacology; Neurologic Examination -- methods; Blotting; Western; Animals; Newborn Rats; Sprague-Dawley

Type

Dissertation

Page Count

xiv; 178

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

Download

Included in

Anatomy Commons

Share

COinS