Exploring Novel Therapies for Motor and Non-Motor Symptoms in a Mouse Model of Multiple Sclerosis

• Author / Creator

  Benson, Curtis A

• Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by neurodegeneration, inflammation and demyelination. Symptoms of multiple sclerosis not only include motor deficits, but also secondary symptoms of pain, depression and anxiety. The purpose of this thesis was firstly to understand the underlying mechanism of these symptoms and secondly to investigate possible treatments. The first half of this thesis investigates the role of several key neurotransmitter systems in the progression and symptomatology of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. The second half of this thesis examines whether exercise can modify the non-motor symptoms associated with EAE. Experiments in chapter 2 examined the effect of phenelzine (PLZ) in EAE. Daily PLZ treatment, starting seven days after disease induction, delayed EAE onset, reduced disease severity in the chronic phase and was associated with improvements in exploratory behaviour and a novel measure of sickness behaviour. EAE mice treated with daily PLZ showed a recovery in the levels of serotonin (5-HT) and norepinephrine (NE). In particular, EAE mice treated with PLZ showed a normalization of 5-HT levels in the ventral horn of the spinal cord. However, no differences were observed in the amount of T cell infiltration, microglia/macrophage reactivity, demyelination or axonal injury in PLZ-treated spinal cords. In chapter 3, we conducted experiments in which PLZ treatment only began when mice with EAE exhibited the first clinical signs of the disease, to determine whether PLZ could have beneficial effects in an already established disease state. Using this more clinically relevant treatment approach, we found that PLZ treatment reduced the severity of clinical signs and improved exploratory behaviours for the duration of the experiment in mice with EAE. These improvements were associated with higher levels of γ-aminobutyric acid (GABA), 5-HT, dopamine (DA) and NE in the brain and spinal cord. In chapter 4, work was undertaken to assess whether exercise could improve both the motor deficits and secondary symptoms of EAE. Allowing EAE mice 1 hour every day of voluntary running led to a significant delay in the onset of disease symptoms. The development of mechanical allodynia was assessed using Von Frey hairs and indicated that wheel running had a modest positive effect on the pain hypersensitivity associated with EAE. These behavioural changes were associated with decreased CNS inflammation, reduced oxidative stress and less mitochondrial protein expression. Unlike the case in chapters 2 and 3, voluntary wheel running led to only minor changes in neurotransmitter levels. The work done in chapter 5 further investigates the mitochondrial changes that occur during early EAE by examining the proteins involved in mitochondrial fission, fusion and biogenesis. EAE animals had increased levels of both the outer mitochondrial membrane protein Tom20 and the complex IV protein (COX IV) within the dorsal horn of the spinal cord compared to control mice. This increase was associated with an increase in the mitochondrial fission mediator, Drp1, a decrease in phosphorylated Drp1 at ser616, a decrease the fusion protein mitofusin 2 (MFN2), and a decrease in the expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1α). The work in this thesis demonstrated the therapeutic potential of the monoamine oxidase (MAO) inhibitor PLZ and of daily exercise in MS. This study led to the identification of the role of several key neurotransmitters and also highlights mitochondrial dysfunction in the secondary symptoms of the disease. Further research into these mechanisms may lead to the development of novel therapies for MS.

• Subjects / Keywords

  • Inflammation
  • Oxidative Stress
  • Exercise
  • Multiple sclerosis
  • Pain

• Graduation date

  Spring 2016

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R34M91S6B

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.