Abstract

Traumatic brain injury (TBI) is a major health concern in the United States. With over two million occurrences and approximately 50,000 deaths annually, TBI is a leading cause of death in young adults and is associated with cognitive deficits influenced by acute and persistent neuroinflammation. Melanocortins, such as adrenocorticotropic hormone (ACTH), are agonists for melanocortin receptors located in the adrenal glands and peripheral immune cells as well as throughout the central nervous system. Melanocortins ameliorate inflammation and provide a novel therapeutic approach for TBI. The focus of this dissertation was to describe and quantify effects of cosyntropin, a synthetic ACTH analog and melanocortin receptor agonist, on the early inflammatory response and functional outcome in a murine TBI model. We used the controlled-cortical impact model of TBI to induce injury followed by subcutaneous saline or cosyntropin administration. We investigated the effect of cosyntropin on the early inflammatory response through quantification of cytokine expression in contused cortical and hippocampal tissue following injury. Immune cell response was evaluated through immunohistochemical staining and quantification of microglia/macrophage and neutrophil density as well as microglia/macrophage response through morphological feature quantification. Additionally, we assessed and compared the behavioral outcomes through open field, novel object recognition, and Morris water maze (MWM) testing. Cosyntropin reduced the inflammatory response by attenuation of injury-induced increases in IL-1ß, IL-6, and MIP-1 and increased MCP-1 and IL-12 expression in injured cortical tissue. Furthermore, cosyntropin administration reduced accumulation of microglia/macrophages and neutrophils in perilesional cortex and hippocampal regions. Additionally, cosyntropin administration attenuated injury-induced microglia/macrophage morphological changes, suggesting that cosyntropin reduced the activation state of microglia/macrophages. Cosyntropin administration also decreased latency to find the hidden platform during the training period of the MWM compared to saline-treated mice, suggesting improved spatial memory. Reduced immune cell response in conjunction with improved spatial learning in our cosyntropin-treated TBI mice suggests a beneficial anti-inflammatory effect of cosyntropin following TBI. A better understanding of the mechanisms driving the anti-inflammatory and immune modulatory effect of melanocortins in the central nervous system could lead to novel therapeutics providing treatment options for millions suffering from the consequences of TBI and other CNS disorders.

LLU Discipline

Physiology

Department

Physiology

School

School of Behavioral Health

First Advisor

Christopher G. Wilson

Second Advisor

Stephen Ashwal

Third Advisor

Barbara Holshouser

Fourth Advisor

Brenda Bartnik-Olson

Fifth Advisor

Johnny D. Figueroa

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2020

Date (Title Page)

6-2020

Language

English

Library of Congress/MESH Subject Headings

Brain Injuries, Traumatic; Cosyntropin; Melanocortins

Type

Dissertation

Page Count

xix; 174 p.

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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