Brain thiamin deficiency

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],... 

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). 

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). 

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. ... 

Thiamine Deficiency and Brain Function Individuals with thiamine deficiency show some characteristic neurological signs and symptoms, including loss of reflexes, anxiety, and mental confusion. Why might thiamine deficiency be manifested by changes in brain function ... 

Early studies showed that the development of neurological abnormalities in thiamin deficiency did not follow the same time course as the impairment of pyruvate and 2-oxoglutarate dehydrogenase or transketolase activities. The brain regions in which metabolic disturbances are most marked were not those that are vulnerable to anatomical lesions. These studies suggested a function for thiamin in the nervous system other than its coenzyme role. 

As noted in Section 6.3.1.3, brain GABA falls in thiamin deficiency, but there is increased flux through the GABA shunt. The changes in the cerebellum occur early, and asymptomatic animals are more sensitive than normal to the GABA antagonist picrotoxin. Brain concentrations of glutamate and aspartate are also reduced in thiamin deficiency, as are several other neurotransmitters. 

Studies in thiamin-deficient animals revealed the presence of Alzheimer-like amyloid plaques in the brain. Although there is no evidence of similar plaque formation in the brains of patients with the Wernicke-Korsakoff syndrome, this has led to trials of thiamin for treatment of Alzheimer s disease... 

Calingasan NY and Gibson GE (2000) Vascular endothelium is a site of free radical production and inflammation in areas of neuronal loss in thiamine-deficient brain. Annals of the New York Academy of Sciences 903,353-6. 

Calingasan NY, Gandy SE, Baker H, Sheu KF, Smith JD, Lamb BT, Gearhart JD, Buxbaum JD, Harper C, Selkoe DJ, Price DL, Sisodia SS, and Gibson GE (1996) Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursorlike protein 2 immunoreactivity in brain regions damaged by thiamine deficiency. American Journal of Pathology 149,1063-71. 

Crespi F and Jouvet M (1982) Sleep and indolamine alterations induced by thiamine deficiency. Brain Research 248,275-83. 

Page MG, Ankoma-Sey V, Coulson WF, and Bender DA (1989) Brain glutamate and gamma-amlnohutyrate (GABA) metaholism in thiamin-deficient rats. British Journal of Nutrition 62, 245-53. 

Direct measurement of high-energy phosphates in the brains of thiamine-deficient animals reveals early losses of ATP in brainstem (Aikawa et al., 1984). The... 

Haemorrhagic lesions are characteristic of experimental thiamine deficiency and WE in humans indicative of a breakdown of the blood-brain barrier (BBB). A study using immunoglobulin G (IgG) as an indicator of BBB integrity in thiamine-deficient rats revealed increased IgG immunoreactivity in the inferior colliculus and inferior olive prior to the onset of cell death in these regions (Calingasan et al.,... 

Beauchesne E, Desjardins P, HazeU AS, Butterworth RE (2009) eNOS gene deletion restores blood-brain barrier integrity and attenuates neurodegeneration in the thiamine-deficient mouse brain. J Neurochem 111 452-459... 

Butterworth RF (2006) Metabolic Encephalopathies. In Siegel GJ, Albers RW, Brady ST, Price DL (eds) Basic neurochemistry, 7th edn. Elsevier, London, pp 593-602 Butterworth RF, Besnard AM (1990) Thiamine-dependent enzyme changes in temporal cortex of patients with Alzheimer s disease. Metab Brain Dis 5(4) 179-184 Butterworth RF, GaudreauC, Vincelette J, Bouigault AM, LamotheF, Nutini AM (1991) Thiamine deficiency and Wernicke s encephalopathy in AIDS. Metab Brain Dis 6(4) 207-212 Butterworth RF, Heroux M (1989) Effect of pyrithiamine treatment and subsequent thiamine rehabilitation on regional cerebral amino acids and thiamine-dependent enzymes. J Neurochem 52(4) 1079-1084... 

Harata N, Iwasaki Y (1995) Evidence for early blood-brain btirrier breakdown in experimental thiamine deficiency in the mouse. Metab Brain Dis 10(2) 159-174 Harper CG (1983) The incidence of Wernicke s encephalopathy in Australia A neuropathological study of 131 cases. J Neurol Neurosurg Psychiatry 46 593-598 Harper CG, Butterworth RF (1997) Nutritional and metabolic disorders. In Graham DI, Lantos PL (eds) Greenfield s neuropathology. Arnold, London, pp 601-655 Hayton SM, Kriss T, Wase A, Muller DP (2006) Effects on neural function of repleting vitamin E-deflcient rats with alpha-tocopherol. J Neurophysiol 95(4) 2553-2559 Hayton SM, MuUer DP (2004) Vitamin E in neural and visual function. Ann N Y Acad Sd 1031 263-270... 

Jolitha AB, Subramanyam MV, Asha Devi S (2006) Modification by vitamin E and exercise of oxidative stress in regions of aging rat brain studies on superoxide dismutase isoenzymes and protein oxidation status. Exp Gerontol 41(8) 753-763 Kruse M, Navarro D, Desjardins P, Butterworth RF (2004) Increased brain endothelial nitric oxide synthase expression in thiamine deficiency relationship to selective vulnerability. Neurochem Int45(l) 49-56... 

Langlais PJ, Anderson G, Guo SX, Bondy SC (1997) Increased cerebral free radical production during thiamine deficiency. Metab Brain Dis 12(2) 137-143 Langlais PJ, Mair RG (1990) Protective effects of the glutamate antagonist MK-801 on pyrithiamine-induced lesions and amino acid changes in rat brain. J Neurosd 10(5) 1664-1674... 

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