Abstract

Traumatic injury to the central nervous system (CNS) presents a devastating problem to our society. Although current interventions are promising, no effective treatments are available. The neural membrane fatty acid composition is markedly altered during the first few days after spinal cord injury (SCI). SCI results in autonomic dysfunction, paralysis, spasticity, and significant chronic neuropathic pain. The trauma leads to significantly increased levels of free radical and oxidative stress that contribute to obstructing tissue healing and recovery. A growing body of evidence shows that administration of hydrophobic molecules such as Vitamin E and long-chain omega-3 polyunsaturated fatty acids (ω3PUFAs) are capable of attenuating secondary damage, while promoting functional recovery after SCI. The precise molecular mechanisms coupling ω3PUFAs and Vitamin E to pro-restorative targets, is not well understood. Increasing attention is now being paid to understand the cellular targets of these hydrophobic molecules and how they are being transported after CNS trauma. The present study investigates the impact pre-treatment with ω3PUFAs and Vitamin E (alpha-tocopherol) in key functional outcomes observed during the acute phase of SCI. Additionally, we explored potential mechanisms through which these hydrophobic molecules were exerting its beneficial effects such as the survival of motor neurons and oligodendrocytes and the transport of ω3PUFAs and Vitamin E. Due to the hydrophobicity of ω3PUFAs and Vitamin E, membrane transport may be required to facilitate their mobilization and meet the increased metabolic demand at the injury site. The fatty acid translocase/membrane cluster of differentiation 36 (FAT/CD36) is a B class scavenger receptor, which has been implicated in the uptake and signaling of hydrophobic molecules, including ω3PUFAs and Vitamin E. Female adult Sprague-Dawley rats were received tail injections with ω3PUFAs (i.e. DHA) or were fed either with a normal diet or a regiment supplemented with ω3PUFAs and Vitamin E for eight weeks. Following the treatment animals were exposed to a contusion SCI or Sham. All animals were examined using standard functional behavior analysis. We report that pre-treatment with DHA injections improved locomotion, bladder recovery, and survival of both neurons and oligodendrocytes. Dietary ω3PUFAs pre-treatment yielded the same results as DHA injections and in addition it decreased neuropathic pain as measured through thermal hyperalgesia and allodynia. Dietary Vitamin E improved locomotion, improved H-reflex depression (indirect measure for spasticity), accelerated bladder recovery, and significantly increased the numbers of oligodendrocytes, but did not seem to preserve neurons in the ventral horn of injured rats. Further, dietary Vitamin E also increased the levels of supraspinal serotonin immunoreactivity. FAT/CD36 mRNA levels were increased at 7 days post-injury and its protein levels remained constant despite neuronal and oligodendrocyte loss. We observed the highest IR in motor neurons of the ventral gray matter and mature oligodendrocytes expressing the adenomatous polyposis coli protein (APC). Quantitative analysis of FAT/CD36 expression showed only Vitamin E upregulated this protein in neurons after SCI. Our findings support the complementary use of ω3PUFAs and Vitamin E to ameliorate motor, sensory, and autonomic dysfunctions observed following SCI. Lastly, given the beneficial roles of ω3PUFAs and Vitamin E in ameliorating functional recovery, FAT/CD36 may be a contributor to basic protection mechanisms in the injured spinal cord. Future pharmacological studies will confirm the role of FAT/CD36 in cell survival after SCI.

LLU Discipline

Physiology

Department

Basic Sciences

School

School of Medicine

First Advisor

De Leon, Marino

Second Advisor

Figueroa, Johnny D.

Third Advisor

Kirby, Michael

Fourth Advisor

Payne, Kimberly J.

Fifth Advisor

Zhang, Lubo

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2018

Date (Title Page)

6-2018

Language

English

Library of Congress/MESH Subject Headings

Spinal Cord Injuries; Fatty Acids, Omega-3 - Physiological effect; Fatty Acids, Omega-3 - Therapeutic use; Vitamin E - Physiological effect; Vitamin E - Therapeutic use

Subject - Local

Lipid Transport

Type

Dissertation

Page Count

252

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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