All ETDs from UAB

Advisory Committee Chair

Tara M Desilva

Advisory Committee Members

Etty Benveniste

John J Hablitz

Linda Overstreet-Wadiche

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Multiple sclerosis is the most common neurological disorder in young adults. Current treatments modulate the immune system, but no treatments prevent central nervous system damage. Inflammation occurs even during disease remission, contributing to ongoing damage and resulting in disease progression. The lack of neuroprotective treatments despite continued inflammatory onslaught in the central nervous system indicates the need for therapeutic discovery in this area. One potential therapeutic target is glutamate, whose dysregulation in multiple sclerosis has been implicated in excitotoxic cellular death. Herein we describe the roles of glutamate in multiple sclerosis and explore the blockade of a source of excitotoxic glutamate, the system xc- transporter, as a therapeutic target. Surprisingly, we found that system xc- is both immunomodulatory and neuroprotective, making it a good candidate target. Because drugs may have multiple effects on the immune and nervous systems, we describe a protocol for determining immunomodulatory versus neuroprotective effects in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. This protocol will aid in the discovery of neuroprotective therapies through the use of fluorescence-activated cell sorting analysis of immune cell proliferation and infiltration, in combination with quantification of immunohistochemical markers for demyelination and reactive gliosis in the central nervous system. Finally, we use this protocol and mice with selective deletion of AMPA receptors in oligodendrocytes to show for the first time that oligodendrocytes are a target of excitotoxic glutamate in EAE, resulting in demyelination. Together our findings suggest that glutamate contributes to the pathogenesis of multiple sclerosis by mediating immune cell infiltration and excitotoxic oligodendrocyte death, and that inhibition of system xc- may be an important therapeutic strategy in preventing these effects.

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