Novel Strategy to Protect and Induce Repair in Experimental Autoimmune Encephalomyelitis (EAE)
Date
2020-10-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Thesis
Degree Level
Masters
Abstract
Multiple Sclerosis (MS) is an inflammatory disease of the central nervous system (CNS)
that is characterized by immune-mediated segmental demyelination and variable degrees of
axonal and neuronal degeneration. Efficient repair of demyelinated lesions is one of the major
challenges of MS. Conventional therapeutic approaches tend to focus on modulation of the
immune response responsible for the generation of these lesions. While this may help to alleviate
some symptoms and mitigate damage, immune system modulation alone does not tackle the
fundamental problem of remyelinating the damaged areas of the nervous system. In MS,
demyelination can be followed early on by efficient remyelination, supporting that endogenous
repair mechanisms exist. Our lab focuses on therapies that enhance intrinsic repair mechanisms
of the injured nervous system. We find that acute intermittent hypoxia (AIH; intermittent periods
of reduced oxygen), a non-invasive therapy, improves outcomes in spinal cord and peripheral
nerve injured animals, the latter in a manner akin to electrical stimulation, likely due to AIH’s
ability to increase neural activity. But its potential for repair in MS is unknown.
We hypothesized that AIH treatment would enhance repair of the demyelinated CNS and
mitigate experimental autoimmune encephalomyelitis (EAE) disease progression in the MOG35-
55 EAE mouse model of MS. AIH or Normoxia control treatments were administered either at
onset of EAE disease (score = 1) or at near peak EAE disease (score = 2.5) once daily for 7 days,
with EAE mice followed for an additional 7 days post-treatment. Animals were examined daily
for changes in clinical scores and spinal cord tissue at the end of clinical score analysis was
processed for immunofluorescence to assess the impact that AIH treatment has on the degree of
myelination, axonal integrity, oligodendrocyte precursor cell (OPC) recruitment, and immune
response modulation. Analysis of clinical scores showed that 7 days of daily AIH treatment
significantly improved clinical scores when treatment was started at near peak EAE disease but
showed no significant changes when started at onset of disease. AIH treatment at near peak of
disease, as compared to the Normoxia treatment group, resulted in significantly elevated levels of
myelin basic protein (MBP), axon protective phosphorylated neurofilaments, reorganization of
node of Ranvier Caspr+ve paranodes and OPC recruitment. I also observed a quicker resolution
of the inflammatory response and the polarization of macrophages/microglia toward a pro-repair
M2 phenotype. Collectively, these findings support a role for AIH treatment as a non-invasive
therapeutic strategy to enhance CNS repair following demyelination.
Description
Keywords
Multiple Sclerosis, Experimental Autoimmune Encephalomyelitis, EAE, Acute Intermittent Hypoxia, AIH, Myelin, Repair, Remyelination
Citation
Degree
Master of Science (M.Sc.)
Department
Anatomy and Cell Biology
Program
Anatomy and Cell Biology