Abstract

The inherently fragile vasculature of the germinal matrix is susceptible to rupture, possibly as a result of hemodynamic and cardiorespiratory instability associated with prematurity. Germinal matrix hemorrhage is a leading cause of morbidity and mortality in preterm and/or very low birthweight infants, and post-hemorrhagic hydrocephalus is major consequence of severe grade hemorrhages. Chronic post-hemorrhagic hydrocephalus treatment involves surgical insertion of shunts, which are costly and prone to complications. Thus, a safe non-invasive therapeutic approach towards post-hemorrhagic hydrocephalus clinical management would significantly improve the quality of life for this patient population. Thrombin, cerebroventricular blood clots, and iron have been identified as causative factors of hydrocephalus formation. Thrombin stimulates proteinase-activated receptors, leading to subsequent mTOR activation and extracellular matrix protein proliferation, which possibly obstruct the cerebroventricular system. Blood clots may directly impair cerebrospinal fluid circulation and absorption. PPARγ stimulation enhances micgroglial/macrophage phagocytosis of erythrocytes via CD36 scavenger receptor, augmenting clot resolution and improving outcomes after adult cerebral hemorrhage. Additionally, lysed erythrocytes and metabolized hemoglobin release iron, which is associated with brain injury after adult cerebral hemorrhage and contribute to post-hemorrhagic hydrocephalus development. The central aim of this proposal is to determine the role of activated thrombin/PAR-1/mTOR pathway as well as the role of hematoma resolution by PPARγ/CD36 and iron chelation by Deferoxamine in hydrocephalus development after germinal matrix hemorrhage. Direct thrombin inhibition reduced short-term mTOR activation and ameliorated long-term post-hemorrhagic hydrocephalus development, neurocogntive deficits, and extracellular matrix protein proliferation, although PAR-1 inhibition alone did not achieve the same therapeutic benefits. PPARγ stimulation improved short-term hematoma resolution, which was reversed by PPARγ antagonism and CD36 knockdown. PPARγ stimulation attenuated long-term neurocognitive deficits and post-hemorrhagic hydrocephalus, which was reversed by PPARγ antagonism. Acute and delayed iron chelation also reduced long-term post-hemorrhagic hydrocephalus development, neurocognitive deficits, and extracellular matrix protein proliferation. Thus, thrombin/PAR/mTOR pathway inhibition, enhanced PPARγ/CD36 mediated hematoma resolution, and iron chelation significantly ameliorated short and long-term brain sequelae after germinal matrix hemorrhage and are clinically viable therapeutic targets warranting further investigation.

LLU Discipline

Physiology

Department

Basic Sciences

School

School of Medicine

First Advisor

Zhang, John H.

Second Advisor

Gridley, Daila

Third Advisor

Hartman, Richard E.

Fourth Advisor

Obenaus, Andre

Fifth Advisor

Tang, Jiping

Degree Name

Doctor of Philosophy (Medical Science)

Degree Level

Ph.D.

Year Degree Awarded

2016

Date (Title Page)

6-2016

Language

English

Library of Congress/MESH Subject Headings

Hydrocephalus; infant - Premature;

Subject - Local

Germinal Matrix Hemorrhage; Post-hemorrhagic Hydrocephalus; Brain Sequelae; Thrombin; Iron chelation;

Type

Dissertation

Page Count

209

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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