UBC Theses and Dissertations

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UBC Theses and Dissertations

Neurochemical studies of the pathogenesis of four central nervous system disorders : Parkinson's disease, Huntington's chorea, dialysis encephalopathy, and Hallervorden-Spatz syndrome Yong, Voon Wee


My thesis is divided into.4 chapters, each dealing with a particular central nervous system disorder. The first chapter is devoted to the understanding of the pathogenesis of Parkinson's disease (PD). Several studies with living or dead patients with PD were performed. Animal experiments relied heavily on the use of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to create an animal model of PD. Two major conclusions of this chapter are firstly, that patients with PD may be exposed up to the time of death to one or more neurotoxins that may act via reactive free radicals,, and secondly, that antioxidant compounds such as α-tocopherol may be useful in slowing the progression of neuronal loss in PD. The second chapter in this thesis tested the hypothesis that the premature neuronal death that occurs in Huntington's chorea (HC) may be the result of a genetically-determined enzymatic failure in the degradation of a circulating neurotoxin of either endogenous or exogenous origin. Two main types of studies were performed: an in vivo experiment in which rats were injected repeatedly with serum or serum ultrafiltrate from HC patients or control subjects, and, an in vitro study in which rat striatal explants were exposed in tissue culture to serum or CSF from patients or controls. The results from both types of experiments are suggestive for the presence of a neurotoxin in the serum of patients with HC. This putative neurotoxin may either be a small molecule irreversibly bound to serum proteins, or, a molecule larger than 10000 daltons. The identity of the putative neurotoxin is presently unclear. In the third chapter of this thesis, we examined for neurochemical abnormalities that might be present in the autopsied brains of patients who died with dialysis encephalopathy (DE). A major finding was a deficiency of GABA contents in several regions of autopsied brains of DE patients. Aluminum levels were abnormally high in the frontal cortical gray matter of DE patients. Animal experiments were unsuccessful in clarifying whether or not aluminum is the causative factor in DE, principally because we failed to produce elevation of aluminum content in the brains of rats injected with aluminum hydroxide. The latter was the case even though we employed hemi-nephrectomy, 5/6 nephrectomy, and/or chronic lithium administration in attempts to decrease the renal excretion of aluminum. Finally, in the fourth chapter, we searched for neurochemical abnormalities in the autopsied brain of 2 patients who died with a rare disease, Hallervorden-Spatz syndrome (HSS). In one patient, contents of cystine and of glutathione-cysteine mixed disulfide in the globus pallidus were elevated 2 SD above those of controls. On the other hand, activity of cysteine dioxygenase, the enzyme that converts cysteine to cysteine sulfinate, was reduced in the globus pallidus of both patients. We propose the hypothesis that cysteine accumulates locally in the globus pallidus in HSS as a result of decreased activity of cysteine dioxygenase. Accumulated cysteine may serve to chelate iron, accounting for the local increase in iron content in the1globus pallidus of HSS. The combination of iron and cysteine may generate free radicals that damage neuronal membranes to cause the typical morphological changes observed in HSS.

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