Multiple sclerosis (MS) is a common neurological disorder that generally starts in young adults, and it has a median duration lasting greater than 30 years. Although the etiology of MS is unknown, recent evidence from biochemical, histochemical and pharmacological studies indicate that reactive oxygen species (ROS) may play a significant pathogenic role. Hydroxyl radical is a ROS that is highly toxic. The substrates for hydroxyl radical formation are hydrogen peroxide and ferrous iron, while superoxide anion radical converts ferric iron into the ferrous state. Hydrogen peroxide and superoxide anion radical are produced by inflammatory cells, which are present at an active demyelination site, and iron has been recently demonstrated to be highly enriched at the myelin sheath. Thus, all the compounds necessary for hydroxyl radical production are together at the myelin sheath during inflammation. Since myelin is a lipid rich structure, hydroxyl radial can readily target the lipids of myelin and initiate the chain reaction of lipid peroxidation, which will result in myelin damage. We put forth several hypotheses about the role of ROS in MS and its animal model, experimental allergic encephalomyelitis (EAE). These hypotheses are as follows: 1) Iron in myelin has pathogenic role in demyelination; 2) desferrioxamine, which has therapeutic effect in EAE and possible indications of effect in MS, acts by chelating iron within the extracellular space of an active MS brain lesion; 3) iron levels are elevated in the cerebral spinal fluid (CSF) from EAE animals and MS patients with active disease and 4) an oligosaccharide derivative of desferrioxiamine will be more efficacious than desferrioxamine for the treatment of EAE. These hypotheses will be tested by the following specific aims: 1) Determine the light and electron microscopic localization of desferrioxamine in animals with EAE; 2) repeat a study by Willenborg et al. (1988) that failed to obtain a therapeutic effect from desferrioxamine treatment for mylelin basic protein-induced EAE, but instead of treating before the onset of disease only, as was done in their study, several treatment regimens will be examined including treatment administered during the clinical and pathological signs; 3) compare the therapeutic effectiveness of desferrioxmine to that of oligosaccharide-desferrioxamine; 4) measure the concentration of iron in the CSF of rats with EAE, and correlate iron levels to the disease activity; and 5) measure the iron concentration in the CSF of multiple sclerosis patients, and correlate iron levels to the disease activity. The methodologies to be employed are immunocytochemistry at the light and electron microscope levels, atomic absorption spectroscopy, spinal taps on MS and control patients, spinal taps on EAE rats, and pharmacological treatments of EAE. The long-range objectives of this grant are to gain insight about the role that iron plays in demyelination and to understand how iron chelation limits disease in EAE and possibility MS. This information may lead to the planning and implementation of new strategies for the treatment of MS.
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