Thiamine (vitamin B1) deficiency, the underlying cause of Wernicke-Korsakoff syndrome, is associated with the development of focal neuronal loss in vulnerable areas of the brain. Although the actual mechanism(s) that lead to the selective histological lesions characteristic of this disorder remain unresolved, oxidative stress has been shown to play a major role in its pathophysiology. In this review, the multifactorial influence of oxidative stress on a variety of processes known to take part in the development of structural lesions in TD including excitotoxicity, neuroinflammation, blood-brain barrier integrity, mitochondrial integrity, apoptosis, nucleic acid function, and neural stem cells will be discussed, and therapeutic strategies undertaken for treating neurodegeneration examined which may have an impact on the future treatment of this important vitamin deficiency. © 2012 Elsevier Ltd. All rights reserved.625796802Aikawa, H., Watanabe, I.S., Furuse, T., Iwasaki, Y., Satoyoshi, E., Sumi, T., Moroji, T., Low energy levels in thiamine-deficient encephalopathy (1984) J. Neuropathol. Exp. Neurol., 43, pp. 276-287Alberdi, E., Sanchez-Gomez, M.V., Marino, A., Matute, C., Ca2+ influx through AMPA or kainate receptors alone is sufficient to initiate excitotoxicity in cultured oligodendrocytes (2002) Neurobiol. Dis., 9, pp. 234-243Armstrong-James, M., Ross, D.T., Chen, F., Ebner, F.F., The effect of thiamine deficiency on the structure and physiology of the rat forebrain (1988) Metab. Brain Dis., 3, pp. 91-124Au, A.M., Chan, P.H., Fishman, R.A., Stimulation of phospholipase A2 activity by oxygen-derived free radicals in isolated brain capillaries (1985) J. Cell. Biochem., 27, pp. 449-453Bart, J., Groen, H.J.N., Hendrikse, N.H., Van Der Graaf, W.T.A., Vaalburg, W., Vries, E.G.E., The blood brain barrier and oncology: New insight into function and modulation (2000) Cancer Treat. Rev., 26, pp. 449-462Beauchesne, E., Desjardins, P., Hazell, A.S., Butterworth, R.F., Endothelial NOS mediates blood-brain barrier alterations in the thiamine-deficient mouse brain (2009) J. Neurochem., 111, pp. 452-459Benavides, J., Fage, D., Carter, C., Scatton, B., Peripheral type benzodiazepine binding sites are a sensitive indirect index of neuronal damage (1987) Brain Res., 421, pp. 167-172Berra, M.B., Menck, C.F.M., Oxidative stress, genome lesions and signaling processes in cell cycle control (2006) Chem. News, 29 (6), pp. 1340-1346Bjorklund, L., Spenger, C., Stromberg, I., Tirilazad mesylate increases dopaminergic neuronal survival in the in Oculo grafting model (1997) Exp. Neurol., 148, pp. 324-333Butterworth, R.F., Cerebral thiamine-dependent enzyme changes in experimental Wernicke's encephalopathy (1986) Metab. Brain Dis., 1, pp. 165-175Butterworth, R.F., Heroux, M., Effect of pyrithiamine treatment and subsequent thiamine rehabilitation on regional cerebral amino acids and thiamine-dependent enzymes (1989) J. Neurochem., 52, pp. 1079-1084Butterworth, R.F., Kril, J.J., Harper, C.G., Thiamine-dependent enzyme changes in the brains of alcoholics: Relationship to the Wernicke-Korsakoff syndrome (1993) Alcohol. Clin. Exp. Res., 17, pp. 1084-1088Cagnin, A., Myers, R., Gunn, R.N., Lawrence, A.D., Stevens, T., Kreutzberg, G.W., Jones, T., Banati, R.B., In vivo visualization of activated glia by [11C] (R)-PK11195-PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion (2001) Brain, 124, pp. 2014-2027Calingasan, N.Y., Gibson, G.E., Vascular endothelium is a site of free radical production and inflammation in areas of neuronal loss in thiamine-deficient brain (2000) Ann. N.Y. Acad. Sci., 903, pp. 353-356Calingasan, N.Y., Baker, H., Sheu, K.F., Gibson, G.E., Blood-brain barrier abnormalities in vulnerable brain regions during thiamine deficiency (1995) Exp. Neurol., 134, pp. 64-72Calingasan, N.Y., Gandy, S.E., Baker, H., Sheu, K.-F.R., Kim, K.-S., Wisniewski, H.M., Gibson, G.E., Accumulation of amyloid precursor protein-like immunoreactivity in rat brain in response to thiamine deficiency (1995) Brain Res., 677, pp. 50-60Calingasan, N.Y., Park, L.C., Calo, L.L., Trifiletti, R.R., Grandy, S.E., Gibson, G.E., Induction of nitric oxide synthase and microglial responses precede selective cell death induced by chronic impairment of oxidative metabolism (1998) Am. J. Pathol., 153, pp. 599-610Carmichael, E.A., Stern, R.O., Korsakoff's syndrome: Its histopathology (1931) Brain, 54, pp. 189-213Castellani, R.J., Rolston, R.K., Smith, M.A., Alzheimer disease (2010) Dis. Mon., 56, pp. 484-546Ceccatelli, S., Tamm, C., Sleeper, E., Orrenius, S., Neural stem cells and cell death (2004) Toxicol. Lett., 149, pp. 59-66Chan, P.H., Schmidley, J.W., Fishman, R.A., Longar, S.M., Brain injury, edema, and vascular permeability changes induced by oxygen-derived free radicals (1984) Neurology, 34, pp. 315-320Cheng, A., Chan, S.L., Milhavet, O., Wang, S., Mattson, M.P., P38 MAP kinase mediates nitric oxide-induced apoptosis of neural progenitor cells (2001) J. Biol. Chem., 276, pp. 43320-43327Collins, G.H., Glial cell changes in the brain stem of thiamine-deficient rats (1967) Am. J. Pathol., 50, pp. 791-814Coskun, P.E., Busciglio, J., Oxidative stress and mitochondrial dysfunction in Down's syndrome: Relevance to aging and dementia (2012) Curr. Gerontol. Geriatr. Res., 2012, p. 383170Danbolt, N.C., Glutamate uptake (2001) Prog. Neurobiol., 65, pp. 1-105Del Maestro, R.F., Björk, J., Arfors, K.E., Increase in microvascular permeability induced by enzymatically generated free radicals. II. Role of superoxide anion radical, hydrogen peroxide, and hydroxyl radical (1981) Microvasc. Res., 22, pp. 255-270Devilin, T.M., (2007) Manual de Bioquesmistry with Cliniques Correlaçtions, , Sixth Edition Publisher Blucher São PauloDiorio, D., Welner, S.A., Butterworth, R.F., Meaney, M.J., Suranyi-Cadotte, B.E., Peripheral benzodiazepine binding sites in Alzheimer's disease frontal and temporal cortex (1991) Neurobiol. Aging, 12, pp. 255-258Evans, M.D., Dizdaroglu, M., Cooke, M.S., Oxidative DNA damage and disease: Induction, repair and significance (2004) Mutat. Res., 567, pp. 1-61Esdar, C., Milasta, S., Maelicke, A., Herget, T., Differentiation-associated apoptosis of neural stem cells is effected by Bcl-2 overexpression: Impact on cell lineage determination (2001) Eur. J. Cell Biol., 80, pp. 539-553Federico, A., Cardaioli, E., Da Pozzo, P., Formichi, P., Gallus, G.N., Radi, E., Mitochondria, oxidative stress and neurodegeneration (2012) J. Neurol. Sci., 322, pp. 254-262Gaitonde, M.D., Fayein, N.A., Johnson, A.L., Decreased metabolism in vivo of glucose into amino acids of the brain of thiamine-deficient rats after treatment with pyrithiamine (1975) J. Neurochem., 24, pp. 1215-1223Gerhard, A., Banati, R.B., Goerres, G.B., Cagnin, A., Myers, R., Gunn, R.N., Turkheimer, F., Brooks, D.J., [11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy (2003) Neurology, 61, pp. 686-689Gibson, G.E., Ksiezak-Reding, H., Sheu, K.F., Mykytyn, V., Blass, J.P., Correlation of enzymatic, metabolic, and behavioral deficits in thiamin deficiency and its reversal (1984) Neurochem. Res., 9, pp. 803-814Gibson, G.E., Zhang, H., Interactions of oxidative stress with thiamine homeostasis promote neurodegeneration (2002) Neurochem. Int., 40, pp. 493-504Gonsette, R.E., Neurodegeneration in multiple sclerosis: The role of oxidative stress and excitotoxicity (2008) J. Neurol. Sci., 274, pp. 48-53Hakim, A.M., The induction and reversibility of cerebral acidosis in thiamine deficiency (1984) Ann. Neurol., 16, pp. 673-679Hakim, A.M., Effect of thiamine deficiency and its reversal on cerebral blood flow in the rat. Observations on the phenomena of hyperperfusion, no reflow, and delayed hypoperfusion (1986) J. Cereb. Blood Flow Metab., 6, pp. 79-85Hansson, O., Castilho, R.F., Kaminski Schierle, G.S., Karlsson, J., Nicotera, P., Leist, M., Brundin, P., Additive effects of caspase inhibitor and lazaroid on the survival of transplanted rat and human embryonic dopamine neurons (2000) Exp. Neurol., 164, pp. 102-111Harata, N., Iwasaki, Y., Evidence for early blood-brain barrier breakdown in experimental thiamine deficiency in the mouse (1995) Metab. Brain Dis., 10, pp. 159-174Hazell, A.S., Butterworth, R.F., Update of cell damage mechanisms in thiamine deficiency: Focus on oxidative stress, excitotoxicity and inflammation (2009) Alcohol Alcohol, 44, pp. 141-147Hazell, A.S., Butterworth, R.F., Hakim, A.M., Cerebral vulnerability is associated with selective increase in extracellular glutamate concentration in experimental thiamine deficiency (1993) J. Neurochem., 61, pp. 1155-1158Hazell, A.S., Rao, K.V., Danbolt, N.C., Pow, D.V., Butterworth, R.F., Selective down-regulation of the astrocyte glutamate transporters GLT-1 and GLAST within the medial thalamus in experimental Wernicke's encephalopathy (2001) J. Neurochem., 78, pp. 560-568Hazell, A.S., Pannunzio, P., Rama Rao, K.V., Pow, D.V., Rambaldi, A., Thiamine deficiency results in downregulation of the GLAST glutamate transporter in cultured astrocytes (2003) Glia, 43, pp. 175-184Hazell, A.S., Sheedy, D., Oanea, R., Aghourian, M., Sun, S., Yong, J.J., Wang, D., Wang, C., Loss of astrocytic glutamate transporters in Wernicke's encephalopathy (2010) Glia, 58, pp. 148-156Héroux, M., Butterworth, R.F., Regional alterations of thiamine phosphate esters and of thiamine diphosphate-dependent enzymes in relation to function in experimental Wernicke's encephalopathy (1995) Neurochem. Res., 20, pp. 87-93Huang, H.M., Ou, H.C., Xu, H., Chen, H.L., Fowler, C., Gibson, G.E., Inhibition of alpha-ketoglutarate dehydrogenase complex promotes cytochrome c release from mitochondria, caspase-3 activation, and necrotic cell death (2003) J. Neurosci. Res., 74, pp. 309-317Izzotti, A., Bagnasco, M., Cartiglia, C., Longobardi, M., Camoirano, A., Tampa, E., Lubet, R.A., De Flora, S., Modulation of multigene expression and proteome profiles by chemopreventive agents (2005) Mutation Res., 591, pp. 212-223Jakovcevic, D., Harder, D.R., Role of astrocytes in matching blood flow to neuronal activity (2007) Curr. Top. Dev. Biol., 79, pp. 75-97Jena, N.R., DNA damage by reactive species: Mechanisms, mutation and repair (2012) J. Biosci., 37, pp. 503-517Jhala, S.S., Hazell, A.S., Modeling neurodegenerative disease pathophysiology in thiamine deficiency: Consequences of impaired oxidative metabolism (2011) Neurochem. Int., 58, pp. 248-260Jomova, K., Vondrakova, D., Lawson, M., Valko, M., Metals, oxidative stress and neurodegenerative disorders (2010) Mol. Cell. Biochem., 345, pp. 91-104Kamat, C.D., Gadal, S., Mhatre, M., Williamson, K.S., Pye, Q.N., Hensley, K., Antioxidants in central nervous system diseases: Preclinical promise and translational challenges (2008) J. Alzheimers Dis., 15, pp. 473-493Karuppagounder, S.S., Shi, Q., Xu, H., Gibson, G.E., Changes in inflammatory processes associated with selective vulnerability following mild impairment of oxidative metabolism (2007) Neurobiol. Dis., 26, pp. 353-362Ke, Z.J., Bowen, W.M., Gibson, G.E., Peripheral inflammatory mechanisms modulate microglial activation in response to mild impairment of oxidative metabolism (2006) Neurochem. Int., 49, pp. 548-556Kokoszka, J.E., Coskun, P., Esposito, L.A., Wallace, D.C., Increased mitochondrial oxidative stress in the Sod2 (+/-) mouse results in the age-related decline of mitochondrial function culminating in increased apoptosis (2001) Proc. Natl. Acad. Sci. USA, 98, pp. 2278-2283Langlais, P.J., Mair, R.G., Protective effects of the glutamate antagonist MK-801 on pyrithiamine-induced lesions and amino acid changes in rat brain (1990) J. Neurosci., 10, pp. 1664-1674Langlais, P.J., Zhang, S.X., Extracellular glutamate is increased in thalamus during thiamine deficiency-induced lesions and is blocked by MK-801 (1993) J. Neurochem., 61, pp. 2175-2182Langlais, P.J., Zhang, S.X., Cortical and subcortical white matter damage without Wernicke's encephalopathy after recovery from thiamine deficiency in the rat (1997) Alcohol. Clin. Exp. Res., 21, pp. 434-443Layton, M.E., Pazdernik, T.L., Samson, F.E., Cerebral penetration injury leads to H2O2 generation in microdialysis samples (1997) Neurosci. Lett., 236, pp. 63-66Lebel, M., Picard, F., Ferland, G., Gaudreau, P., Drugs, nutrients, and phytoactive principles improving the health span of rodent models of human age-related diseases (2012) J. Gerontol. A Biol. Sci. Med. Sci., 67, pp. 140-151Leong, D.K., Lê, O., Oliva, L., Butterworth, R.F., Increased densities of binding sites for the peripheral-type benzodiazepine receptor ligand [3H]PK11195 in vulnerable regions of the rat brain in thiamine deficiency encephalopathy (1994) J. Cereb. Blood Flow Metab., 14, pp. 100-105Li, S., Mealing, G.A., Morley, P., Stys, P.K., Novel injury mechanism in anoxia and trauma of spinal cord white matter: Glutamate release via reverse Na+-dependent glutamate transport (1999) J. Neurosci., 19, p. 16Li, L., Liu, F., Salmonsen, R.A., Turner, T.K., Litofsky, N.S., Di Cristofano, A., Pandolfi, P.P., Ross, A.H., PTEN in neural precursor cells: Regulation of migration, apoptosis, and proliferation (2002) Mol. Cell. Neurosci., 20, pp. 21-29Li, L., Liu, F., Ross, A.H., PTEN regulation of neural development and CNS stem cells (2003) J. Cell. Biochem., 88, pp. 24-28Limón-Pacheco, J., Gonsebatt, M.E., The role of antioxidants and antioxidant-related enzymes in protective responses to environmentally induced oxidative stress (2009) Mutat. Res., 674, pp. 137-147Mandel, S., Grunblatt, E., Riederer, P., Gerlach, M., Levites, Y., Youdim, M.B., Neuroprotective strategies in Parkinson's disease: An update on progress (2003) CNS Drugs, 17, pp. 729-762Manz, H.J., Robertson, D.M., Vascular permeability to horseradish peroxidase in brainstem lesions of thiamine-deficient rats (1972) Am. J. Pathol., 66, pp. 565-576Mastroeni, D., Grover, A., Delvaux, E., Whiteside, C., Coleman, P.D., Rogers, J., Epigenetic mechanisms in Alzheimer's disease (2011) Neurobiol. Aging, 32, pp. 1161-1180Matsushima, K., Macmanus, J.P., Hakim, A.M., Apoptosis is restricted to the thalamus in thiamine-deficient rats (1997) NeuroReport, 8, pp. 867-870McCandless, D.W., Energy metabolism in the lateral vestibular nucleus in pyrithiamin-induced thiamin deficiency (1982) Ann. NY Acad. Sci., 378, pp. 355-364Melo, A., Monteiro, L., Lima, R.M., Oliveira, D.M., Cerqueira, M.D., El-Bacha, R.S., Oxidative stress in neurodegenerative diseases: Mechanisms and therapeutic perspectives (2011) Oxid. Med. Cell. Longev., 2011, p. 467180Mohapel, P., Brundin, P., Harnessing endogenous stem cells to treat neurodegenerative disorders of the basal ganglia (2004) Parkinsonism Relat. Disord., 10, pp. 259-264Moncada, S., Palmer, R.M., Higgs, E.A., Nitric oxide: Physiology, pathophysiology, and pharmacology (1991) Pharmacol. Rev., 43, pp. 109-142Muller, W.E., Eckert, A., Kurz, C., Eckert, G.P., Leuner, K., Mitochondrial dysfunction: Common final pathway in brain aging and Alzheimer's disease-therapeutic aspects (2010) Mol. Neurobiol., 41, pp. 159-171Munujos, P., Vendrell, M., Ferrer, I., Proto-oncogene c-fos induction in thiamine-deficient encephalopathy. Protective effects of nicardipine on pyrithiamine-induced lesions (1993) J. Neurol. Sci., 118, pp. 175-180Murphy, S., Minor, Jr.R.L., Welk, G., Harrison, D.G., Evidence for an astrocyte-derived vasorelaxing factor with properties similar to nitric oxide (1990) J. Neurochem., 55, pp. 349-351Myers, R., Manjil, L.G., Cullen, B.M., Price, G.W., Frackowiak, R.S., Cremer, J.E., Macrophage and astrocyte populations in relation to [3H]PK 11195 binding in rat cerebral cortex following a local ischaemic lesion (1991) J. Cereb. Blood Flow Metab., 11, pp. 314-322Navarro, D., Zwingmann, C., Hazell, A.S., Butterworth, R.F., Brain lactate synthesis in thiamine deficiency: A re-evaluation using 1H-13C nuclear magnetic resonance spectroscopy (2005) J. Neurosci. Res., 79, pp. 33-41O'Brien, J.T., Burns, A., Clinical practice with anti-dementia drugs: A revised (second) consensus statement from the British Association for psychopharmacology (2011) J. Psychopharmacol., 25, pp. 997-1019Olney, J.W., Neurotoxicity of excitatory amino acids (1978) Kainic Acid As A Tool in Neurobiology, pp. 95-121. , E.G. McGeer, J.W. Olney, P.L. McGeer, Raven Press New YorkOthberg, A., Keep, M., Brundin, P., Lindvall, O., Tirilazad mesylate improves survival of rat and human embryonic mesencephalic neurons in vitro (1997) Exp. Neurol., 147, pp. 498-502Ouchi, Y., Yagi, S., Yokokura, M., Sakamoto, M., Neuroinflammation in the living brain of Parkinson's disease (2009) Parkinsonism Relat Disord., 15 (SUPPL. 3), pp. 200-204Owen, F., Poulter, M., Waddington, J.L., Mashal, R.D., Crow, T.J., [3H]R05-4864 and [3H]flunitrazepam binding in kainate-lesioned rat striatum and in temporal cortex of brains from patients with senile dementia of the Alzheimer type (1983) Brain Res., 278, pp. 373-375Papadopoulos, V., Peripheral-type benzodiazepine/diazepam binding inhibitor receptor: Biological role in steroidogenic cell function (1993) Endocr. Rev., 14, pp. 222-240Percy, M.E., Kruck, T.P., Pogue, A.I., Lukiw, W.J., Towards the prevention of potential aluminum toxic effects and an effective treatment for Alzheimer's disease (2011) J. Inorg. Biochem., 105, pp. 1505-1512Petzold, G.C., Murthy, V.N., Role of astrocytes in neurovascular coupling (2011) Neuron, 71, pp. 782-797Plaschke, K., Bergmann, M., Kopitz, J., Ginkgo extract EGb 761((R)) shields from slowly accumulating neurodegenerative-like changes in a newly developed cell culture model induced by the combined action of low doses of antimycin A1 and 2-deoxy-d-glucose (2011) J. Neural. Transm., 118, pp. 1247-1254Provenzale, J.M., Mukundan, S., Dewhirst, M., The role of blood brain barrier permeability in brain tumor imaging and therapeutics (2005) AJR Am. J. Roentgenol., 185, pp. 763-767Robertson, D.M., Wasan, S.M., Skinner, D.B., Ultrastructural features of early brain stem lesions of thiamine-deficient rats (1968) Am. J. Pathol., 52, pp. 1081-1097Rosenberg, L.J., Teng, Y.D., Wrathall, J.R., 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline reduces glial loss and acute white matter pathology after experimental spinal cord contusion (1999) J. Neurosci., 19, pp. 464-475Sacks, T., Moldow, C.F., Craddock, P.R., Bowers, T.K., Jacob, H.S., Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes. An in vitro model of immune vascular damage (1978) J. Clin. Invest., 61, pp. 1161-1167Schoemaker, H., Morelli, M., Deshmukh, P., Yamamura, H.I., [3H]Ro5-4864 benzodiazepine binding in the kainate lesioned striatum and Huntington's diseased basal ganglia (1982) Brain Res., 248, pp. 396-401Sorolla, M.A., Rodríguez-Colman, M.J., Vall-Llaura, N., Tamarit, J., Ros, J., Cabiscol, E., Protein oxidation in Huntington disease (2012) BioFactors, 38, pp. 173-185Terlecky, S.R., Terlecky, L.J., Giordano, C.R., Peroxisomes, oxidative stress and inflammation (2012) World J. Biol. Chem., 3, pp. 93-97Todd, K.G., Butterworth, R.F., Early microglial response in experimental thiamine deficiency: An immunohistochemical analysis (1999) Glia, 25, pp. 190-198Vemuganti, R., Kalluri, H., Yi, J.-H., Bowen, K.K., Hazell, A.S., Gene expression changes in thalamus and inferior colliculus associated with inflammation, cellular stress, metabolism, and structural damage in thiamine deficiency (2006) Eur. J. Neurosci., 23, pp. 1172-1188Victor, M., Adams, R.D., Collins, G.H., (1989) The Wernicke-Korsakoff Syndrome and Related Neurologic Disorders Due to Alcoholism and Malnutrition, , F.A. Davies PhiladelphiaVon Arnim, C.A., Gola, U., Biesalski, H.K., More than the sum of its parts? Nutrition in Alzheimer's disease (2010) Nutrition, 26, pp. 694-700Warnock, L.G., Burkhalter, V.J., Evidence of malfunctioning blood-brain barrier in experimental thiamine deficiency in rats (1968) J. Nutr., 94, pp. 256-260Watanabe, I., Pyrithiamine induced acute thiamine deficient encephalopathy in the mouse (1978) Exp. Mol. Pathol., 28, pp. 381-394Wei, Y., Lu, C., Lee, H., Pang, C., Ma, Y., Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function (1998) Ann. N.Y. Acad. Sci., 854, pp. 155-170Wendel, U., Lombeck, I., Bremer, H.J., Maple-syrup-urine disease (1983) N. Engl. J. Med., 308, pp. 1100-1101Yamashita, M., Yamamoto, T., Wernicke encephalopathy with symmetric pericentral involvement: MR findings (1995) J. Comput. Assist. Tomogr., 19, pp. 306-308Zhang, Q., Yang, G., Li, W., Fan, Z., Sun, A., Luo, J., Ke, Z.J., Thiamine deficiency increases beta-secretase activity and accumulation of beta-amyloid peptides (2011) Neurobiol. Aging, 32, pp. 42-53Zhao, J., Sun, X., Yu, Z., Pan, X., Gu, F., Chen, J., Dong, W., Zhong, C., Exposure to pyrithiamine increases beta-amyloid accumulation, tau hyperphosphorylation, and glycogen synthase kinase-3 activity in the brain (2011) Neurotox. Res., 19, pp. 575-583