Thiamine deficiency-induced pathologic damage in humans is associated with Wernicke's encephalopathy (WE), Korsakoffs syndrome, and mixed sensory motor neuropathy. The prevalence of WE ranges from 1.7-2.8 percent among all autopsies to as high as 12-18 percent among chronic alcoholics. WE has also been diagnosed clinically and at postmortem in a number of non-alcoholic populations including those with Alzheimer's disease, acquired immunodeficiency syndrome (AIDS), leukemia, and gastrointestinal disorders. An important feature of these thiamine deficiency (TD) disorders is the selective vulnerability of specific brain regions to pathologic damage. Regions of thalamus, mammillary, body, and certain brainstem nuclei are particularly vulnerable to TD-induced lesions. Despite its accepted etiological role in WE, the biochemical, molecular, and physiological mechanisms responsible for TD-induced brain lesions remain unknown. Consequently, there is currently no therapeutic intervention which will provide an abrupt cessation or interruption of the ongoing pathologic events during thiamine deficiency. The long-term objective of this ongoing project is to develop effective treatments for the prevention or reduction of brain lesions, particularly within the thalamus, and associated cognitive and memory deficits produced by thiamine deficiency. The immediate goal is to test specific hypotheses regarding the role of histamine, cytokines and nitric oxide in TD-induced lesions to the thalamus. The specific goals are to examine the effects of pharmacological and genetic manipulations on quantitative measures of early vascular changes, i.e., swelling of endfoot processes, perivascular edema, and mast cell degranulation and the late changes, i.e., number of apoptotic and necrotic of neurons within the thalamus of TD rats. Separate groups of rats will be subjected to pyrithiamine-induced thiamine deficiency (PTD) or pairfeeding (PFC) and receive the following manipulations; i) inhibition of histamine synthesis using alphaFMH (i.c.v.), bilateral lesions of the histaminergic tuberomammillary nucleus, administration of mepyramine (H1 receptor antagonist) or cimetidine (H2 receptor antagonist); ii) inhibition of both neuronal nitric oxide synthase (nNOS), using 7-nitroindazole (i.p.), and inducible NOS using aminoguanidine (i.p.); iii) administration of a recombinant human interleukin-1 receptor antagonist (i.c.v.); and iv) mutant, mast cell deficient (Ws/Ws) rats. Quantitative measures of early vascular changes will be performed after 10 days and measures of late neurodegenerative changes performed after 15 days of treatment.
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