Thiamine deficiency induced pathologic damage in humans is associated with Wernicke-Korsakoff's disease, mixed sensory motor neuropathy, and infantile subacute necrotizing encephalopathy. The prevalence of Wernicke-Korsakoff pathologic changes ranges from 1.7-2.8% among all autopsies to as high as 12.5% among chronic alcoholics. Individuals with Wernicke-Korsakoff disease suffer from anterograde and retrograde amnesia, cognitive dysfunctions, multimodal sensory discrimination deficits, and emotional flattening and thus require constant care and institutionalization. An important feature of these thiamine deficiency disorders is the selective vulnerability of specific brain regions to pathologic damage. Regions of thalamus, mammillary bodies, and certain brainstem nuclei are consistently damaged in Wernicke-Korsakoff s disease and are probably responsible for the behavioral deficits. Despite this knowledge, the biochemical and physiological mechanisms responsible for the lesions and their topographic distribution in the brain following acute thiamine deficiency remain unknown. Consequently, there is currently no therapeutic treatment for the abrupt cessation of ongoing pathologic events during acute thiamine deficiency. The long-term objective of this project is to develop effective treatments for the prevention of brain lesions and associated cognitive and memory deficits produced by thiamine deficiency. The immediate goal of this project is to test a recent hypothesis that suggests glutamate receptor-mediated neurotoxicity is involved in the brain lesions produced by acute thiamine deficiency. The specific goals are to conduct the following studies in the pyrithiamine induced thiamine deficiency (PTD) rat model of Wernicke-Korsakoff's disease: i) measure by in vivo microdialysis the extracellular fluid levels of excitatory amino acids in affected and unaffected brain regions during acute thiamine deficiency; ii) quantitatively measure the effects of the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, in reducing thiamine deficiency induced brain lesions; and iii) conduct an ultrastructural analysis of dendritic and somal degenerative changes induced by acute thiamine deficiency for evidence of 'excitotoxic' type of damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029481-02
Application #
3416325
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1991-04-01
Project End
1995-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
San Diego State University
Department
Type
Schools of Arts and Sciences
DUNS #
073371346
City
San Diego
State
CA
Country
United States
Zip Code
92182
Siman, Robert; Zhang, Chen; Roberts, Victoria L et al. (2005) Novel surrogate markers for acute brain damage: cerebrospinal fluid levels corrrelate with severity of ischemic neurodegeneration in the rat. J Cereb Blood Flow Metab 25:1433-44
Siman, R; Flood, D G; Thinakaran, G et al. (2001) Endoplasmic reticulum stress-induced cysteine protease activation in cortical neurons: effect of an Alzheimer's disease-linked presenilin-1 knock-in mutation. J Biol Chem 276:44736-43
Savage, L M; Castillo, R; Langlais, P J (1998) Effects of lesions of thalamic intralaminar and midline nuclei and internal medullary lamina on spatial memory and object discrimination. Behav Neurosci 112:1339-52
Langlais, P J; Hall, T (1998) Thiamine deficiency-induced disruptions in the diurnal rhythm and regulation of body temperature in the rat. Metab Brain Dis 13:225-39
Langlais, P J; Zhang, S X (1997) Cortical and subcortical white matter damage without Wernicke's encephalopathy after recovery from thiamine deficiency in the rat. Alcohol Clin Exp Res 21:434-43
Savage, L M; Sweet, A J; Castillo, R et al. (1997) The effects of lesions to thalamic lateral internal medullary lamina and posterior nuclei on learning, memory and habituation in the rat. Behav Brain Res 82:133-47
Langlais, P J; Zhang, S X; Savage, L M (1996) Neuropathology of thiamine deficiency: an update on the comparative analysis of human disorders and experimental models. Metab Brain Dis 11:19-37
Langlais, P J; Savage, L M (1995) Thiamine deficiency in rats produces cognitive and memory deficits on spatial tasks that correlate with tissue loss in diencephalon, cortex and white matter. Behav Brain Res 68:75-89
Zhang, S X; Weilersbacher, G S; Henderson, S W et al. (1995) Excitotoxic cytopathology, progression, and reversibility of thiamine deficiency-induced diencephalic lesions. J Neuropathol Exp Neurol 54:255-67
Langlais, P J (1995) Pathogenesis of diencephalic lesions in an experimental model of Wernicke's encephalopathy. Metab Brain Dis 10:31-44

Showing the most recent 10 out of 12 publications