NEUTRON ACTIVATION ANALYSIS OF MANGANESE, IRON AND ZINC IN A RODENT MODEL OF DYSMYELINATION

Abstract

<p>Transition metals such as manganese (Mn), iron (Fe) and zinc (Zn) are some of the essential metals for normal CNS development and function. Each must be present at specific levels to avoid deficiencies or toxic excess. The research in this thesis investigates the role of transition metals in diseases in which myelin is lost in the central nervous system (CNS). A loss of myelin is termed demyelination, and an example of a disease with prominent demyelination is multiple sclerosis. An incomplete formation of myelin sheaths is termed dysmyelination. This thesis focused on the measurements of manganese, iron and zinc concentrations in a rodent model of dysmyelination; the Long Evans Shaker (<em>les</em>) rat.<strong></strong></p> <p>The Long Evans Shaker (<em>les</em>) rat is a fragile, severely dysmyelinated rodent model with body tremors at a young age and severe ataxia in older rats. The mutation causing the severe dysmyelination in these rats is transmitted as an autosomal recessive trait. With a lifespan of 4 to 5 months, the <em>les</em> rat is markedly deficient in myelin in the CNS, where most axons are entirely naked and the remaining ones are surrounded by a loosely woven, thin myelin sheath.</p> <p>In this thesis we studied alterations in manganese, iron and zinc transition metal levels in 3 and 16-week-old <em>les</em> rats and their age-matched control counterparts. Using neutron activation analysis (NAA), manganese measurements were made in the brain, spinal cord and visceral organs using an existing protocol, while a new assay was developed for iron and zinc measurements that were made in the spinal cord tissues. The higher trend in manganese concentration observed within the 3 and 16 week old <em>les</em> rats in comparison to the controls, where there was a significant increase (ples cerebellum, supports evidence suggesting that manganese levels are associated with astrogliosis. Whereas for iron and zinc, which were measured in the spinal cord tissues, there was also an overall increase in the levels of these metals in the <em>les</em> mutant strain when compared to the controls; however, only significant increases in zinc concentration within the 16 week old <em>les </em>spinal cords were observed.</p> <p>The characterization of the <em>les</em> rodent model mutation and its biochemical abnormality will advance our understanding of not only the process of myelination, but also diseases related to aberrant myelination or the maintenance of myelin sheaths.</p>