Role of thiamine in Huntington’s disease pathogenesis: In vitro studies (original) (raw)
Related papers
PLoS ONE, 2010
Background: Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine monophosphate (ThMP), thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), present in many organisms, may have still unidentified physiological functions. Diseases linked to thiamine deficiency (polyneuritis, Wernicke-Korsakoff syndrome) remain frequent among alcohol abusers and other risk populations. This is the first comprehensive study on the distribution of thiamine derivatives in human biopsies, body fluids and cell lines.
Metabolic and Histological Reversibility of Thiamine Deficiency
Journal of Cerebral Blood Flow & Metabolism, 1983
The rapid improvement in the clinical manifestations of thiamine deficiency with thiamine supplementation is well known. To study this process in more detail, we rendered rats thiamine deficient either by dietary deprivation alone (DD) or, in addition, by daily pyrithiamine administration (DD + PT). We observed the cerebral metabolic and histological responses of these rats after 1 or 7 days of thiamine supplementation both prior to and at the onset of clinical sequelae. The cerebral metabolic response to thiamine deficiency and replenishment was determined with the [14C]deoxyglucose technique for measurement of local cerebral glucose utilization (LCGU). Our results indicate that thiamine replenishment reverses the LCGU changes resulting from thiamine deprivation of short duration. However, prolonged thiamine deprivation may result in LCGU changes that are not completely reversible by thiamine replenishment, before the appearance of the clinical or histological consequences of thiam...
Frontiers in Biology, 2017
BACKGROUND: Thiamine is an essential cofactor associated with several enzymes in energy metabolism and its deficiency may lead to neurological deficits. Current research evaluated the biochemical and molecular changes in TCA cycle enzymes using the mitochondrial fraction of the brain following thiamine deficiency (TD) in mice. METHODS: The investigation was carried out on Swiss mice (6-8 week old) allocated into three groups. First group was control; second and third group were made thiamine deficient for 8 and 10 days. RESULTS: Current study showed that alpha-ketoglutarate dehydrogenase (KGDHC) (thiamine-dependent enzyme) level found to be significantly reduced in experimental groups as compared to control group. In comparison to control group, a significant decrease in the succinate dehydrogenase (SDH) activity was calculated in group II and group III (p < 0.0001) mice. Diminished enzymatic activity of fumarase and MDH enzyme in thiamine deficient groups exposed for 8 and 10 days was calculated as compared to control group. The expression analysis of different genes governing TCA cycle enzymes in different experimental groups showed that there was a negotiable change in the expression of fumarase and DLD (dihydrolipoyl dehydrogenase-E3 subunit of KGDHC) whereas a declined in the expression of SDH and two subunits of KGDHC i.e. OGDH (2-oxoglutarate dehydrogenase-E1 subunit of KGDHC) and DLST (dihydrolipoyllysine-residue succinyltransferase-E2 subunit of KGDHC) was observed as compared to control group. CONCLUSIONS: Hence, current findings strongly entail that TD promotes alteration in energy metabolism in brain mitochondria which will decline the neuronal progression which may lead to neurodegenerative diseases such as Alzheimer's diseases.
Detection of Mitochondrial Diseases, 1997
Culture of neuroblastoma cells in the presence of low thiamine concentration (6 nM) and of the transport inhibitor amprolium leads to the appearance of signs of necrosis: the chromatin condenses, the oxygen consumption decreases and is uncoupled, the mitochondrial cristae are disorganized, the thiamine diphosphate-dependent dehydrogenase activities are impaired. When 10 µM thiamine are added to these cells, the basal respiration increases, the coupled respiration is restored and mitochondrial morphology is recovered within 1 h. Addition of succinate, which is oxidized via a thiamine diphosphate-independent dehydrogenase, to digitonin-permeabilized cells immediately restores a coupled respiration. Our results suggest that the slowing of the citric acid cycle is the cause of the biochemical lesion induced by severe thiamine deficiency and that part of the mitochondria remain functional. (Mol Cell Biochem 174: [121][122][123][124] 1997)
Alteration in MDA, GSH level and hematological changes due to thiamine deficiency in Mus musculus
Interdisciplinary Toxicology, 2018
It is known that thiamine deficiency may lead to Alzheimer’s diseases in humans. The present study has thus been conducted to understand the role of thiamine deficiency with respect to alteration in the peripheral blood of Swiss albino mice. For this purpose, adult Swiss albino mice (6–8 week old) were divided into three groups. The first group was control; the second (group II) and the third group (group III) were made thiamine deficient for 08 and 10 days respectively. Thiamine deficiency was induced in mice by injecting pyrithiamine (5 µg/10 g bwt) and feeding a thiamine deficient diet. The erythrocytes, leukocytes count, hemoglobin, hematocrit value, mass cell volume, mean corpuscular hemoglobin in blood of mice were determined by hematoanalyzer. Malondialdehyde (MDA) and reduced glutathione (GSH) level was also determined in serum of treated and non-treated groups. A significant reduction in leukocyte and erythrocyte count was observed in both the thiamine deficient groups as c...
Nutrition Research, 2007
A moderate thiamine deficiency that does not affect weight gain or produce the classical signs of thiamine deficiency may have adverse health effects. We assessed the effect of marginally thiamine-deficient diets by measuring the effects of the diets on an enzyme marker for thiamine adequacy and markers for plasma and tissue exposure to potential endogenous carbonyl toxins. Five groups of male F344 rats were fed an AIN76-based diet containing thiamine at 2, 2.9, 5.2, 11, or 18 mg/kg diet. The animals were killed at 70 days by carbon dioxide inhalation, and cardiac blood, liver, colon, and brain samples were obtained. Erythrocytes were analyzed for transketolase activity; plasma for glyoxal, methylglyoxal, hydroimidazolone, nitrotyrosine, and protein carbonyl adducts; and tissue extracts for the 3 protein adducts. Thiamine pyrophosphate-dependent transketolase activity was inversely correlated with dietary thiamine of less than 5.2 mg/kg diet. Plasma methylglyoxal and protein adduct concentrations also increased significantly at dietary thiamine levels or at thiamine level of less than 2.6 mg/kg diet. The brain, liver, and colon showed similar trends, with evident tissue specificity. Diets marginally deficient in thiamine increase the endogenous formation of carbonyl products at thiamine levels only slightly below the requirement levels, 4 mg/kg diet (0.25 mg/kJ diet).
The Journal of nutrition, 1999
This study was prompted by our incomplete understanding of the mechanism responsible for the clinical benefits of pharmacological doses of thiamin in some patients with maple syrup urine disease (MSUD) and the question of whether thiamin diphosphate (TDP), a potent inhibitor of the activity of the protein kinase that phosphorylates and inactivates the isolated branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, affects the activity state of the complex. Rats were fed a chemically-defined diet containing graded levels of thiamin (0, 0.275, 0.55, 5.5, and 55 mg thiamin/kg diet). Maximal weight gain was attained over a 3-wk period only in rats fed diets with 5.5 and 55 mg thiamin/kg. Feeding rats the thiamin-free diet for just 2 d caused loss of nearly half of the TDP from liver mitochondria. Three more days caused over 70% loss, an additional 3 wk, over 90%. Starvation for 2 d had no effect, suggesting a mechanism for conservation of TDP in this nutritional state. Mitochondri...
Journal of Inherited Metabolic Disease, 2019
Thiamine is a crucial cofactor involved in the maintenance of carbohydrate metabolism and participates in multiple cellular metabolic processes within the cytosol, mitochondria and peroxisomes. Currently, four genetic defects have been described causing impairment of thiamine transport and metabolism: SLC19A2 dysfunction leads to diabetes mellitus, megaloblastic anaemia and sensory-neural hearing loss, whereas SLC19A3, SLC25A19 and TPK1-related disorders result in recurrent encephalopathy, basal ganglia necrosis, generalized dystonia, severe disability and early death. In order to achieve early diagnosis and treatment, biomarkers play an important role. SLC19A3 patients present a profound decrease of free-thiamine in CSF and fibroblasts. TPK1 patients show decreased concentrations of thiamine pyrophosphate in blood and muscle.
Neurochemistry International, 2011
Emerging evidence suggests that thiamine deficiency (TD), the cause of Wernicke's encephalopathy, produces alterations in brain function and structural damage that closely model a number of maladies in which neurodegeneration is a characteristic feature, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, along with alcoholic brain disease, stroke, and traumatic brain injury. Impaired oxidative metabolism in TD due to decreased activity of thiaminedependent enzymes leads to a multifactorial cascade of events in the brain that include focal decreases in energy status, oxidative stress, lactic acidosis, blood-brain barrier disruption, astrocyte dysfunction, glutamate-mediated excitotoxicity, amyloid deposition, decreased glucose utilization, immediate-early gene induction, and inflammation. This review describes our current understanding of the basis of these abnormal processes in TD, their interrelationships, and why this disorder can be useful for our understanding of how decreased cerebral energy metabolism can give rise to cell death in different neurodegenerative disease states. ß
Biochemistry (Moscow), 2020
Thiamine (vitamin B1) is a major vitamin of B group that is widely used in medical practice due to its neu rotrophic action and stimulating effect on the central glu cose metabolism [1 3]. Mostly, these actions are ascribed to the vitamin diphosphorylated derivative, thiamine diphosphate (ThDP), which is an essential coenzyme of such enzymes of central metabolism as transketolase and 2 oxo acid dehydrogenases. However, also other, so called non coenzyme, actions of thiamine and its natural derivatives have acquired increasing attention recently,