Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that causes a range of neurological deficits expressed in a series of relapses separated by remissions. Surprisingly, our understanding of the mechanisms responsible for both relapses and remissions remains incomplete, even for the expression of major deficits. To explore the mechanisms, a model of MS (experimental autoimmune encephalomyelitis, EAE) has been studied neurologically, electrophysiologically and histologically at five time points along the course of the disease, i.e., 'preinduction', 'predisease, 'peak disease', 'remission', and 'relapse'. The animals were assessed daily to determine the magnitude of any neurological deficit, and electrophysiological techniques were developed to permit serial measures of axonal conduction, synaptic transmission, and the excitability of motor neurons. Also, to investigate whether inflammatory factors can modulate the expression of neurological deficits, a proinflammatory agent, lipopolysaccharide (LPS) was injected systemically in animals at the ‘remission’ phase to explore whether systemic inflammation exacerbates the disease. A selective inhibitor of inducible nitric oxide synthase (iNOS), 1400W, was also administered into animals with EAE at the onset of disease expression to examine whether inhibition of nitric oxide (NO) production ameliorates the disease. The findings have revealed that no electrophysiological deficits were detected before the onset of neurological deficits, but axonal conduction and synaptic transmission were significantly impaired at the ‘peak disease’. These measures remained reduced during the ‘remission’ and ‘relapse’, at which time motor neuronal excitability was also significantly decreased. It is intriguing that none of the electrophysiological measures have so far revealed changes that correlate closely with the expression of, and recovery from, neurological deficit. Present data also show that systemic inflammation induced by an injection of LPS in animals with EAE caused an acute relapse that peaked 3.5 hours post injection. However, no electrophysiological changes occurring at this peak were detected that could be responsible for the transient neurological deficits, and so the exact mechanisms underlying the deficits remain unknown. Also, based on the histological analysis revealing an exclusive expression of iNOS at ‘peak disease’ in animals with EAE, the consequences of selective inhibition of iNOS using 1400W were explored. This treatment significantly reduced the severity of the neurological deficits, implicating NO in their production. Importantly, electrophysiological and histological examination of 1400W-treated animals revealed that the inhibition of iNOS also provided significant protection from the loss of function, and degeneration, of axons, again implicating NO in a pathogenic role. In conclusion, these findings add further weight to the evidence that inflammation plays a key role in the pathogenesis of EAE, although the exact mechanisms underlying the production of the neurological deficits remain unknown. Potential explanations are discussed, including the possibility that the deficits may arise from spinal hypoxia. In addition, the inhibition of NO production may provide an effective protection from both the functional and pathological consequences of neuroinflammatory diseases such as MS.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:565502 |
| Date | January 2011 |
| Creators | Lee, W. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1333232/ |
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