Brain thiamin

Mastrogiacoma, F., Bettendorff, L., Grisar, T., and Kish, S.J., 1996. Brain thiamine, its phosphate esters, and its metabolizing enzymes in Alzheimer s disease. Annals of Neurology. 39 585-591. 

Parkhomenko, Y.M., Kudryavtsev, P.A., Pylypchuk, Yu, S., Chekhivska, L.I., Stepanenko, S.P., Sergiichuk, A.A., and Bunik, V.I., 2011. Chronic alcoholism in rats induces a compensatory response, preserving brain thiamine diphosphate, but the 2-oxo- acid dehydrogenases are inactivated despite unchanged coenzyme. Journal of Neurochemistry. 117 1055 1065. 

Vitamin Bi, also called thiamine, is required for all tissues and high concentrations are found in skeletal muscle, heart, liver, kidneys and brain. Thiamine diphosphate (TDP) is the active form and it serves as a cofactor for several enzymes involved in carbohydrate catabolism. These enzymes are also important in the biosynthesis of many cellular constituents, including neurotransmitters, and for the production of reducing equivalents used in oxidant stress defenses (Ba 2008). Thiamine is considered an anti-stress vitamin because it strengthens the immune system and improves the body s ability to withstand stress conditions (Haas 1988). 

Alcoholism. Alcoholism or impaired nutrition severely affects the level of thiamine in brain. Thiamine deficiency strongly affects the activity of transketolase (TK) and often leads to the severe neurological disorder, Wemicke-Korsakoff syndrome (WKS). Although thiamine administration results in normalization of neurological symptoms, the TK activity does not completely recover in all regions of the brain [39],... 

In the tissues of animals, most thiamine is found as its phosphorylated esteis (4—6) and is piedominandy bound to enzymes as the pyrophosphate (5), the active coen2yme form. As expected for a factor involved in carbohydrate metaboHsm, the highest concentrations ate generally found in organs with high activity, such as the heart, kidney, Hver, and brain. In humans this typically amounts to 1—8 p.g/g of wet tissue, with lesser amounts in the skeletal muscles (35). A typical healthy human body may contain about 30 mg of thiamine in all forms, about 40—50% of this being in the muscles owing to their bulk. Almost no excess is stored. Normal human blood contains about 90 ng/mL, mostly in the ted cells and leukocytes. A value below 40 ng/mL is considered indicative of a possible deficiency. Amounts and proportions in the tissues of other animal species vary widely (31,35). 

Numerous reports of prodrugs in the literature show improved drug effects. Prodrugs that have shown some measure of success for site-specific delivery include L-3,4-dihydroxyphenylalanine (L-dopa) to the brain [56], dipivaloyl derivative of epinephrine to the eye [57], /-glutamyl-L-dopa to the kidney [58], fi-n-glucoside dexamethasone and prednisolone derivatives to the colon [59], thiamine-tetrahydrofuryldisulfide to red blood cells, and various amino acid derivatives of antitumor agents such as daunorubicin [61,62], acivicin [63], doxorubicin [63], and phenylenediamine [63] to tumor cells. 

The BBB also has sodium- and pH-independent transporters of organic cations. They are important for the homeostasis of choline and thiamine in the brain and for the permeation of cationic drugs like propranolol, lidocaine, fentanyl, Hl-an-... 

Langlais, P. J., McRee, R. C., Nalwalk, J. A. and Hough, L. B. Depletion of brain histamine produces regionally selective protection against thiamine deficiency-induced lesions in the rat. Metab. Brain Dis. 17 199-210, 2002. 

Navaro, D., Zwingmann, C., Hazell, A. S. and Butterworth, R. F. Brain lactate synthesis in thiamine deficiency a re-evaluation using H-13C nuclear magnetic resonance spectroscopy. /. Neurosci. Res. 79 33—41, 2005. 

Thiamine deficiency results in early decreases in activity of the mitochondrial enzyme a-ketoglutarate dehydrogenase in brain. Wernicke s encephalopathy, also known as the Wernicke-Korsakoff syndrome is a neuropsychiatric disorder characterized by ophthalmoplegia, ataxia and memory loss. Wernicke s encephalopathy is encountered in chronic alcoholism, in patients with HIV-AIDS and in other disorders associated with grossly impaired nutritional status. The condition results from thiamine deficiency. 

In the 1930s, Peters and co-workers showed that thiamine deficiency in pigeons resulted in the accumulation of lactate in the brainstem [ 15]. Furthermore, they showed that the addition of small quantities of crystalline thiamine to the isolated brainstem tissue from thiamine-deficient birds in vitro resulted in normalization of lactate levels. These findings led to the formulation of the concept of the biochemical lesion in thiamine deficiency. Subsequent studies showed that the enzyme defect responsible for the biochemical lesion was a-KGDH rather than pyruvate dehydrogenase (PHDC), as had previously been presumed. a-KGDH and PHDC are major thiamine diphosphate (TDP)-dependent enzymes involved in brain glucose oxidation (Fig. 34-4). 

In brain, as in most mammalian cells, thiamine occurs predominantly in the form of TDP, the remainder being made up of thiamine monophosphate (10%), thiamine triphosphate (5-10%) and trace amounts of free thiamine. Thiamine is transported into brain and phosphory-lated by the action of thiamine pyrophosphokinase, and inhibition of this enzyme by thiamine antagonists such as pyrithiamine results in decrease synthesis of TDP. Treatment of experimental animals with pyrithiamine results in a generalized reduction of TDP concentrations and an early selective loss in activity of a-KGDH in regions... 

A recent study showed significant increases of expression of eNOS in the brains of rats treated with pyrithia-mine [20]. Increased eNOS expression was apparent prior to the onset of neurological symptoms and was restricted to vulnerable medial thalamus and inferior colliculus. Expression of inducible (iNOS) and neuronal (nNOS) isoforms were minimally altered in brain in thiamine deficiency and it has also been shown that targeted disruption of the eNOS (but not the iNOS or nNOS) gene results in reduced extent of neuropathological damage in thalamus of thiamine deficient animals [21] (Fig. 34-5). 

Kruse, M., Desjardins, P. and Butterworth, R. F. Increased brain endothelial nitric synthase expression in thiamine deficiency relationship to selective vulnerability. Neurochem. Int. 43 49-56, 2004. 

Straightforward thiamine deficiency in man, beri-beri, is characterized by accumulation of pyruvic and lactic acids in the blood and brain, and impairment of cardiovascular, nervous, and gastrointestinal function (DIO, G17, P4, Yl). Neurological lesions characterize thiamine deficiency in growing rats (B40), guinea pigs (M6), mice (M13), chicks, and pigeons (B30). The effects of thiamine deficiency on the central nervous system of animals have been reviewed (DIO). 

The clinical significance of thiamine and its necessity for pyruvic acid oxidation has been discussed. Recent reports concerning the coenzyme function of thiamine in pentose (H13), tryptophan (D2), and lipoic acid metabolism (R6) have increased our knowledge of thiamine in metabolism and lend added interest to the role of thiamine in clinical problems. This method has also been used to assay thiamine in liver and brain. 

Insufficient thiamine significantly impairs glucose oxidation, causing highly aerobic tissues, such as brain and cardiac muscle, to fail first. In addition, branched-chain amino acids are sources of energy in brain and muscle. 

Which of the following enzymes is thiamine-dependent and essential for glucose oxidation in the brain ... 

Substance-Induced Dementias. Substances of abuse can also cause dementia. The most common is alcohol-related dementia. Chronic alcoholism leads to dementia in several ways. The poor diet of the alcoholic causes a deficiency of certain essential nutrients such as thiamine. The alcoholic often suffers recurrent head injuries from falls or altercations. Alcohol-induced liver failure can expose the brain to toxic injury. Finally, the direct toxic effects of alcohol itself on the brain can lead to dementia. In addition to alcohol, the abuse of inhalants such as paint thinner and... 

The transport of amino acids at the BBB differs depending on their chemical class and the dual function of some amino acids as nutrients and neurotransmitters. Essential large neutral amino acids are shuttled into the brain by facilitated transport via the large neutral amino acid transporter (LAT) system [29] and display rapid equilibration between plasma and brain concentrations on a minute time scale. The LAT-system at the BBB shows a much lower Km for its substrates compared to the analogous L-system of peripheral tissues and its mRNA is highly expressed in brain endothelial cells (100-fold abundance compared to other tissues). Cationic amino acids are taken up into the brain by a different facilitative transporter, designated as the y system, which is present on the luminal and abluminal endothelial membrane. In contrast, active Na -dependent transporters for small neutral amino acids (A-system ASC-system) and cationic amino acids (B° system), appear to be confined to the abluminal surface and may be involved in removal of amino acids from brain extracellular fluid [30]. Carrier-mediated BBB transport includes monocarboxylic acids (pyruvate), amines (choline), nucleosides (adenosine), purine bases (adenine), panthotenate, thiamine, and thyroid hormones (T3), with a representative substrate given in parentheses [31]. 

TAs one might predict, mutations in the genes for the subunits of the PDH complex, or a dietaiy thiamine deficiency, can have severe consequences. Thiamine-deficient animals are unable to oxidize pyruvate normally. This is of particular importance to the brain, which usually obtains all its energy from the aerobic oxidation of glucose in a pathway that necessarily includes the oxidation of pyruvate. Beriberi, a disease that results from thiamine deficiency, is characterized by loss of neural function. This disease occurs primarily in populations that rely on a diet consisting mainly of white (polished) rice, which lacks the hulls in which most of the thiamine of rice is found. People who habitually consume large amounts of alcohol can also develop thiamine deficiency, because much of their dietaiy intake consists of the vitamin-free empty calories of distilled spirits. An elevated level of pyruvate in the blood is often an indicator of defects in pyruvate oxidation due to one of these causes. ... 

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