Neurochemical Mechanisms in Disease P14 pdf

Vitamin Deficiencies 115 (Gibson and Blass, 1985). Also, antiniacin compounds can induce deficiency states within days in rodents on a normal diet. Neurological symptoms are more obvious in rats with antimetabolite-induced niacin deficiencies than in the corn-fed dogs. Niacin deficiency causes pellagra which includes mental symptoms and was once common in areas where American corn was a dietary staple. Addition of purified niacin to t he diet has largely abolished the disorder. Pellagra is associated with the “four Ds”: dermatitis, diarrhea, dementia, and death. Dietary niacin deficiency reduces the levels of NAD and NADP coenzymes in the brain. Niacin requirements can be modified by genetic and environmental factors. Hartnup syndrome is a hereditary disorder in which tryptophan transport is impaired and niacin requirements increase. A chronic toxic delirium may be the only clinical abnormal- ity, at least early in the course of the disorder. The delirium may resemble some forms of schizophrenia (Gibson and Blass, 1985). Neuropathological changes seen in pellagra are restricted to neurons and the characteristic finding is chromatolysis. Affected neurons are ballooned, there is loss of Nissl substance, and the nuclei are located eccentrically. Although the issue of chromatolysis has been debated (Harper and Butterworth, 1997) the consensus now is that the brain regions and lesion characteristics are a function of the nature of the underlying cause (dietary, alcohol-related, or isoniazid toxicity). At present, pellagra is encountered most often in patients with chronic alco- holism, often referred to as alcoholic pellagra encephalopathy (APE). APE patients often show only disturbances of consciousness, but may also manifest myoclonus and ataxia. Administration of niacin is recommended in APE patients showing myoclonus and ataxia even without the classical symptoms found in endemic pellagra patients (Sakai et al., 2006). Epidemiological studies suggest that niacin may be implicated in the pathogen- esis of Parkinson’s disease via the following process. NAD produced from niacin releases nicotinamide via poly(ADP-ribosyl)ation which is activated in Parkinson’s disease. Released excess nicotinamide is methylated to 1-methylnicotinamide (MNA) in the cytoplasm by nicotinamide N-methyltransferase. MNA destroys several subunits of complex I via superoxide formation. This can destroy complex I subunits either directly or indirectly via mitochondrial DNA damage, and stimulates poly(ADP-ribosyl)ation. It has been proposed that this implicates nicotinamide as a potential causal agent in the development of Parkinson’s disease (Fukushima et al., 2004). 6 Folic Acid (Vitamin B 9 ) Folate (pteroylglutamic acid) is essential for the synthesis and methylation of DNA during fetal and early postnatal development (Nunn et al., 1986). Folate deficiency may result from poor diet, malabsorption, from treatment with anticonvulsant drugs such as phenytoin or primidone, as well as from antifolate drugs such as methotrexate. Folate deficiency during pregnancy leads to an increased prevalence of fetal malformations such as spina bifida and related neural tube defects. Findings 116 C. Bémeur et al. from two multicentre trials confirmed that folate supplements starting periconcep- tionally and continuing through pregnancy reduce the risk of neural tube defects (Werler et al., 1993; MRC Vitamin Study, 1991). Studies in experimental animals suggest that folate deficiency during gestation and lactation results in alterations of myelin lipids (Hirono and Wada, 1978). Studies in the developing rat central nervous system suggest that folate uptake and storage depend upon a folate-binding protein (10-formyltetrahydrofolate dehydrogenase) which is preferentially localized in glial cells (Martinasevic et al., 1999). 7 Antioxidant Vitamins Oxidative stress has been clearly implicated in a wide range of human diseases by an impressive body of scientific evidence. Oxidative stress is an imbalance in the equi- librium status of pro-oxidant/antioxidant systems in cells (Sies, 1985) and comes from external sources such as ionizing radiation, toxins, drugs, chemicals and environmental pollutants, or endogenous sources resulting from (patho)physiological metabolism of the cell. Antioxidant compounds can be classified into several gen- eral categories: (1) antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, catalase, and heme-oxygenase, (2) antioxidants s uch as vitamin E (α- tocopherol), vitamin C (ascorbic acid), and carotenoids, (3) secondary antioxidants including selenium, zinc, riboflavin, and manganese and, finally, (4) antioxidants such as flavonoids, coenzyme Q, lipoic acid, albumin, and bilirubin. Deficiency of any antioxidant vitamin or nutrient has the potential to lead to an imbalance which may to cause oxidative stress. 7.1 α-Tocopherol (Vitamin E) α-Tocopherol is a lipid-soluble vitamin which is an effective antioxidant. Vitamin E consists of two groups of lipid-soluble compounds: tocopherol and tocotrienol. In humans, α-tocopherol predominates and is considered the more active form of the vitamin. Vitamin E was first isolated as a factor that prevented infertility in rats (Evans and Bishop, 1922). It can inhibit the peroxidation of polyunsaturated fatty acids and it stimulates prostacyclin synthesis which promotes vasodilation and platelet aggregation. Vitamin E also protects membrane structure. Vitamin E deficiency is quite rare. Nevertheless, pure vitamin E deficiency secondary to deficiencies in absorption have been described (Traber, 2006). Vitamin E deficiency can occur with abetalipoproteinemia, cholestatic liver disease, fat malabsorption, celiac disease, cystic fibrosis, and small bowel resection. The typical neurological syndrome in humans is a spinocerebellar degeneration, with loss of reflexes, ataxia, and impaired vibration and position sense. A severe and chronic deficiency of vitamin E is associated with a characteristic neurological syndrome with typical clinical, neuropathological, and electrophysiological abnormalities in both humans and experimental animals. Chronic vitamin E Vitamin Deficiencies 117 deficiency (38 weeks) in mice decreases superoxide radical production in multiple regions of male brain (Cuddihy et al., 2004). These results suggest that α-tocopherol can act as a nonclassic uncoupler. Significant impairment in neural and visual function are observed in vitamin E-deficient rats after approximately 8 months (Hayton and Muller, 2004). Low serum vitamin E is associated with demyelinating motor– sensory neuropathy related to spinocerebellar ataxia (Puri et al., 2005). Vitamin E supplementation leads to clinical and electrophysiological recovery of sensory conduction and evoked potentials; motor nerve conduction, however, shows only partial recovery. Vitamin E deficiency has also been associated with an increase in lipid peroxidation and protein oxidation in the rat brain (Jolitha et al., 2006). The concentration of free malondialdehyde (an indicator of lipid peroxidation) is significantly increased in tissues from vitamin E-deficient compared to control animals. This is consistent with a deficiency of α-tocopherol causing increased lipid peroxidation leading to abnormal neural electrophysiology (Hayton and Muller, 2004). A longitudinal study recently showed significant improvements in growth and a number of electrophysiological parameters of both neural and visual function after repletion with vitamin E (Hayton et al., 2006). It was suggested that vitamin E could play a role in hypothalamo–pituitary system regulation. Early vitamin E supplementation may provide considerable improvement of neurological signs and other associated abnormalities (Marzouki et al., 2005). A wide range of cell culture, animal, and human epidemiological studies are suggestive of a role of vitamin E in brain function and in the prevention of neurodegeneration. It was recently suggested that vitamin E deficiency results in transcriptional alterations in the cerebral cortex of the rat which are consistent with the observed neurological and electrophysiological alterations (Hyland et al., 2006). Vitamin E deficiency was shown to have a strong impact on gene expression in the hippocampus. An important number of genes found to be regulated by vitamin E are associated with hormones and hormone metabolism, and clearance of amyloid-beta and advanced glycated end-products. A protective effect of vitamin E in AD pro- gression has been reported (Rota et al., 2005). A recent study strongly supports the hypothesis of an impairment of lipophilic antioxidant delivery to neuronal cells in AD which could facilitate oxidative stress (Mas et al., 2006). Low-plasma vitamin E concentrations may represent a higher risk of developing dementia in subsequent years (Helmer et al., 2003). The retention and secretion of vitamin E are regulated by α-tocopherol trans- fer protein (αTP) in the brain. Dysfunction of αTP results in deficiency of vitamin E in humans and mice, and increased oxidative stress i n mouse brain. Ataxia with isolated vitamin E deficiency (AVED) is an autosomal recessive neurode- generative disorder due to mutations in the αTP protein gene on chromosome 8q13. This genetic disorder is characterized by neurological symptoms often with a striking resemblance to those of Friedrich’s ataxia. AVED patients have progressive spinocerebellar symptoms and markedly reduced plasma levels of vitamin E (Mariotti et al., 2004). Vitamin E supplementation therapy allows 118 C. Bémeur et al. stabilization of the neurological conditions in most of the patients. However, development of spasticity and retinitis pigmentosa can appear during therapy (Mariotti et al., 2004). 7.2 Ascorbic Acid (Vitamin C) Vitamin C is used as the generic descriptor for all compounds exhibiting quali- tatively the biological activity of ascorbic acid. Ascorbic acid is an unsaturated sugar derivative that is a potent reducing agent. The oxidation of ascorbic acid to dehydroascorbic acid is reversible (Fig. 7). Both forms are biologically active. Because dehydroascorbic acid is readily reduced in vivo, it possesses vitamin C (anti-scurvy) activity, whereas diketogulonic acid, a metabolite, has no activity. Vitamin C has many functions in the organism, not least of which is the absorption and metabolism of iron. It is an effective antioxidant. Ascorbic acid participates in neurotransmitter synthesis as well as the synthesis of collagen. Vitamin C is neces- sary for the synthesis of carnitine and facilitates immune functions. Finally, ascorbic acid participates in the hydroxylation of catecholamines. The uptake of ascorbic acid into synaptosomes requires glucose and oxygen; uptake into the brain appears to be via the cerebrospinal fluid rather than the blood. Fatigue and emotional changes are common in the full-blown deficiency disease scurvy, but diffuse disease of the small blood vessels with small haemorrhages is much more striking. Ascorbic acid has been implicated in many neurological diseases. There is a strong inverse relation between serum vitamin C concentration and stroke incidence CH 2 OH H 2 O HO CH 2 OH CHHOCH OO OO OO O O diketogulon acid oxalic and threonic acids and other products dehydroascorbic acidascorbic acid C C OH OH 2H + 2e – 1H + 1e – OH 4 3 2 1 4 3 2 1 1 2 O C HC OH HO CH CH 2 OH 3 4 Fig. 7 Structure of a scorbic acid (vitamin C). Oxidation of ascorbic acid to dehydrogenase acid is reversible; both forms are biologically active Vitamin Deficiencies 119 (Sanchez-Moreno et al., 2004). Epidemiological evidence links adequate vitamin C ingestion with decreased risk of suffering from a stroke. Inversely, decreased plasma antioxidant status is associated with increased neurological damage following a stroke. It was recently shown that dehydroascorbic acid, the oxidized form of vitamin C which is a superoxide scavenger, normalizes several markers of oxidative stress and inflammation in acute hyperglycemic focal cerebral ischemia in the rat (Bémeur et al., 2005). It was also demonstrated that intraventricular ascorbic acid injection is neuroprotective after hypoxic-ischemic brain injury in rats (Miura et al., 2006). Vitamin C is also able to protect the hypothalamus from oxidative stress induced in rats by an environmental toxicant (Muthuvel et al., 2006). Ascorbic acid confers protection from increased free-radical activity in the brain of spontaneously hypertensive rats by improving total antioxidant and superoxide dismutase status, thus preventing high blood pressure and its complications (Newaz et al., 2005). Also, intravenous cerebroprotective doses of citrate/sorbitol-stabilized DHA are correlated with increased brain ascorbate levels and a suppression of excessive lipid peroxidation (Mack et al., 2006). A case-control study showed that plasma vitamin C levels were lower in subjects with dementia compared to controls, which was not explained by their dietary vitamin C intakes (Charlton et al., 2004). Low brain ascorbic acid and glutathione levels associated with a perturbation of the dopaminergic system actively participate in the development of some cognitive deficits affecting schizophrenic patients (Castagné et al., 2004). It has been proposed that low ascorbate in striatal extracellular fluid may contribute to Huntington’s disease symptoms (Rebec et al., 2006) and evidence suggests that the level of extracellular ascorbate plays a critical role in regulating corticostriatal glutamate transmission (Rebec et al., 2005). A recent study suggested that ascorbate could participate in normalizing neuronal function in Huntington’s disease (Rebec et al., 2006). Antioxidant vitamins, particularly vitamins E and C may act synergistically. A short period of combined deficiency of vitamins E and C causes profound central nervous system dysfunction in guinea pigs (Burk et al., 2006). The damage consists mainly of nerve cell death, axonal degeneration, vascular injury, and associated glial cell responses. These findings suggest that the paralysis and death caused by combined deficiency of vitamins E and C in these animals is caused by severe damage to brainstem and spinal cord. Also, a recent study demonstrated that vitamin E and vitamin C prevented oxidative stress due to maternal hyperphenylalaninemia, (an inborn error of intermediary metabolism) in the brains of rat pups (Martínez- Cruz et al., 2006). Pretreatment with α-tocopherol and ascorbic acid prevents the impairment of energy metabolism caused by hyperargininemia in the cerebellum and hippocampus of rats (Delwing et al., 2006). Vitamin C and E administration, alone or in combination, increases striatal catalase activity in rats subjected to oral dyskinesias, which are implicated in a series of neuropathologies and associated with increased oxidative stress. A beneficial effect of these vitamins on reserpine- induced oral dyskinesia in rats has also been reported (Faria et al., 2005) and a recent study suggested that vitamins C and E hold promise in helping prevent AD (Frank 120 C. Bémeur et al. and Gupta, 2005). Finally, low brain glutathione and ascorbic acid l evels associated with a perturbation of the dopaminergic system may actively participate in the development of some cognitive deficits affecting schizophrenic patients (Castagné et al., 2004). 7.3 Carotenoids Carotenoids are plant pigments which constitute more than 600 compounds, most of them being lipid-soluble and which contribute significantly to the nutritional bene- fits of fruit and vegetable consumption. β-carotene is the most common form of the vitamin and is the precursor of vitamin A. β-cryptoxanthine is another precursor of vitamin A. The latter is a powerful lipid-soluble antioxidant which protects cellular membranes from oxidative stress. Vitamin A is carried into the plasma by retinal binding protein which is synthesized in the liver. Decreased carotenoid concentrations are associated with increased risk of stroke (Leppälä et al., 1999) and vitamin A levels are decreased in stroke patients (Cherubini et al., 2000). Plasma concentrations of alpha- and beta-carotene are lower in patients with acute ischemic stroke than in healthy controls and are nega- tively correlated with neurological deficits in stroke patients (Chang et al., 2005). References Agamanolis DP, Victor M, Harris JW, Hines JD, Chester EM, Kark JA (1978) An ultrastructural study of subacute combined degeneration of the spinal cord in vitamin B12-deficient rhesus monkeys. J Neuropathol Exp Neurol 37(3):273–299 Aikawa H, Watanabe IS, Furuse T, Iwasaki Y, Satoyoshi E, Sumi T, Moroji T (1984) Low energy levels in thiamine-deficient encephalopathy. J Neuropathol Exp Neurol 43(3):276–287 Albers DS, Augood SJ, Park LC, Browne SE, Martin DM, Adamson J, Hutton M, Standaert DG, Vonsattel JP, Gibson GE, Beal MF (2000) Frontal lobe dysfunction in progressive supranuclear palsy: evidence for oxidative stress and mitochondrial impairment. J Neurochem 74(2):878–881 Bates CJ, Mansoor MA, van der Pols J, Prentice A, Cole TJ, Finch S (1997) Plasma total homocysteine in a representative sample of 972 British men and women aged 65 and over. Eur J Clin Nutr 51(10):691–697 Beauchesne E, Desjardins P, Hazell AS, Butterworth RF (2009) eNOS gene deletion restores blood-brain barrier integrity and attenuates neurodegeneration in the thiamine-deficient mouse brain. J Neurochem 111:452–459 Bémeur C, Ste-Marie L, Desjardins P, Vachon L, Butterworth RF, Hazell AS, Montgomery J (2005) Dehydroascorbic acid normalizes several markers of oxidative stress and inflammation in acute hyperglycemic focal cerebral ischemia in the rat. Neurochem Int 46(5): 399–407 Bernstein AL (1990) Vitamin B 6 in clinical neurology. Ann N Y Acad Sci 585:250–260 Bettendorff L (1994) Thiamine in excitable tissues: reflections on a non-cofactor role. Metab Brain Dis 9(3):183–210 Briddon A (2003) Homocysteine in the context of cobalamin metabolism and deficiency states. Amino Acids 24(1–2):1–12 Burk RF, Christensen JM, Maguire MJ, Austin LM, Whetsell WO Jr, May JM, Hill KE, Ebner FF (2006) A Combined deficiency of vitamins E and C causes severe central nervous system damage in guinea pigs. J Nutr 136(6):1576–1581 Vitamin Deficiencies 121 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, Gaudreau C, Vincelette J, Bourgault AM, Lamothe F, Nutini AM (1991) Thiamine deficiency and Wernicke’s encephalopathy in AIDS. Metab Brain Dis 6(4):207–212 Butterworth RF, Héroux M (1989) Effect of pyrithiamine treatment and subsequent thiamine reha- bilitation on regional cerebral amino acids and thiamine-dependent enzymes. J Neurochem 52(4):1079–1084 Butterworth RF, Kril JJ, Harper CG (1993) Thiamine-dependent enzyme changes in the brains of alcoholics: relationship to the Wernicke-Korsakoff syndrome. Alcohol Clin and Exp Res 17(5):1084–1088 Calingasan NY, Baker H, Sheu KF, Gibson GE (1995) Blood-brain barrier abnormalities in vulnerable brain regions during thiamine deficiency. Exp Neurol 134(1):64–72 Calingasan NY, Park LC, Calo LL, Trifiletti RR, Gandy SE, Gibson GE (1998) Induction of nitric oxide synthase and microglial responses precede selective cell death induced by chronic impairment of oxidative metabolism. Am J Pathol 153(2):599–610 Carmel R (2005) Cobalamin (Vitamin B 12 ). In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ (eds) Modern nutrition in health and disease, 10th edn. Lippincott William & Wilkins, New York, NY, pp 482–497 Casley CS, Canevari L, Land JM, Clark JB, Sharpe MA (2002) β-Amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J Neurochem 80(1):91–100 Castagné V, Rougemont M, Cuenod M, Do KQ (2004) Low brain glutathione and ascorbic acid associated with dopamine uptake inhibition during rat’s development induce long-term cognitive deficit: relevance to schizophrenia. Neurobiol Dis 15(1):93–105 Chang SJ, Kirksey A, Morré DM (1981) Effects of vitamin B 6 deficiency on morphologi- cal changes in dendritic trees of Purkinje cells in developing cerebellum of rats. J Nutr 111(5):848–857 Chang CY, Chen JY, Ke D, Hu ML (2005) Plasma levels of lipophilic antioxidant vitamins in acute ischemic stroke patients: correlation to inflammation markers and neurological deficits. Nutrition 21(10):987–993 Charlton KE, Rabinowitz TL, Geffen LN, Dhansay MA (2004) Lowered plasma vitamin C, but not vitamin E, concentrations in dementia patients. J Nutr Health Aging 8(2): 99–107 Charness ME, DeLaPaz RL (1987) Mamillary body atrophy in Wernicke’s encephalopathy: antemortem identification using magnetic resonance imaging. Ann Neurol 22(5):595–600 Cherubini A, Polidori MC, Bregnocchi M, Pezzuto S, Cecchetti R, Ingegni T, Di Iorio A, Senin U, Mecocci P (2000) Antioxidant profile and early outcome in stroke patients. Stroke 31(10): 2295–2300 Cooper JR, Pincus JH (1979) The role of thiamine in nervous tissue. Neurochem Res 4(2):223–239 Cuddihy SL, Musiek ES, Morrow JD, Dugan LL (2004) Long-term vitamin E deficiency in mice decreases superoxide radical production in brain. Ann N Y Acad Sci 1031: 428–431 Dakshinamurti K, Paulose CS, Viswanathan M, Siow YL, Sharma SK, Bolster B (1990) Neurobiology of pyridoxine. Ann N Y Acad Sci 585:128–144 Delwing D, Tagliari B, Chiarani F, Wannmacher CMD, Wajner M, Wyse AT (2006) Alpha- tocopherol and ascorbic acid administration prevents the impairment of brain energy metabolism of hyperargininemic rats. Cell Mol Neurobiol 26(2):177–189 Evans HM, Bishop KS (1922) On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science 56(1458):650–651 Faria RR, Abílio VC, Grassl C, Chinen CC, Negrão LT, de Castro JP, Fukushiro DF, Rodrigues MS, Gomes PH, Registro S, de Carvalho RdeC, D’Almeida V, Silva RH, Ribeiro RdeA, Frussa-Filho R (2005) Beneficial effects of vitamin C and vitamin E on reserpine-induced oral dyskinesia i n rats: critical role of striatal catalase activity. Neuropharmacology 48(7):993–1001 122 C. Bémeur et al. Frank B, Gupta S (2005) A review of antioxidants and Alzheimer’s disease. Ann Clin Psychiatry 17(4):269–286 Fukushima T, Ohta M, Tanaka K, Kaneko S-Y, Maeda T, Sasaki A (2004) Niacin metabolism and Parkinson’s disease. Asia Pac J Clin Nutr 13(Suppl):S176 Gautam M, Noakes PG, Mudd J, Nichol M, Chu GC, Sanes JR, Merlie JP (1995) Failure of post- synaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice. Nature 377(6546):232–236 Gerster H (1996) The importance of vitamin B6 for development of the infant. Human medical and animal Experimental studies. Z Ernahrungswiss 35(4):309–317 Gibson GE, Blass JP (1985) Oxidative metabolism and acetylcholine synthesis during acetylpyri- dine treatment. Neurochem Res 10(4):453–467 Gibson GE, Sheu KF, Blass JP, Baker A, Carlson KC, Harding B, Perrino P (1988) Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer’s disease. Arch Neurol 45(8):836–840 Gibson GE, Zhang H (2002) Interactions of oxidative stress with thiamine homeostasis promote neurodegeneration. Neurochem Int 40(6):493–504 Gospe SM Jr, Hecht ST (1998) Longitudinal MRI findings in pyridoxine-dependent seizures. Neurology 51(1):74–78 Hakim AM (1984) The induction and reversibility of cerebral acidosis in thiamine deficiency. Ann Neurol 16(6):673–679 Harata N, Iwasaki Y (1995) Evidence for early blood-brain barrier 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-deficient rats with alpha-tocopherol. J Neurophysiol 95(4):2553–2559 Hayton SM, Muller DP (2004) Vitamin E in neural and visual function. Ann N Y Acad Sci 1031:263–270 Hazell AS, Butterworth RF, Hakim AM (1993) Cerebral vulnerability is associated with selective increase in extracellular glutamate concentration in experimental thiamine deficiency. J Neurochem 61(3):1155–1158 Hazell AS, Rao KV, Danbolt NC, Pow DV, Butterworth RF (2001) Selective down-regulation of the astrocyte glutamate transporters GLT-1 and GLAST within the medial thalamus in experimental Wernicke’s encephalopathy. J Neurochem 78(3):560–568 Helmer C, Peuchant E, Letenneur L, Bourdel-Marchasson I, Larrieu S, Dartigues JF, Dubourg L, Thomas MJ, Barberger-Gateau P (2003) Association between antioxidant nutritional indicators and the incidence of dementia: results form the PAQUID prospective cohort study. Eur J Clin Nutr 57(12):1555–1561 Hirono H, Wada Y (1978) Effects of dietary folate deficiency on developmental increase of myelin lipids in rat brain. J Nutr 108(5):766–772 Hyland S, Muller D, Hayton S, Stoecklin E, Barella L (2006) Cortical gene expression in the vitamin E-deficient rat: possible mechanisms for the electrophysiological abnormalities of visual and neural function. Ann Nutr Metab 50(5):433–441 Héroux M, Raghavendra Rao VL, Lavoie J, Richardson JS, Butterworth RF (1996) Alterations of thiamine phosphorylation and of thiamine-dependent enzymes in Alzheimer’s disease. Metab Brain Dis 11(1):81–88 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 Int 45(1):49–56 Vitamin Deficiencies 123 Laforenza U, Patrini C, Rindi G (1988) Distribution of thiamine, thiamine phosphates, and thiamine metabolizing enzymes in neuronal and glial cell enriched fractions of rat brain. J Neurochem 51(3):730–735 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 Neurosci 10(5): 1664–1674 Leppälä JM, Virtamo J, Fogelholm R, Albanes D, Heinonen OP (1999) Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants. Stroke 30(12):2535–2540 Mack WJ, Mocco J, Ducruet AF, Laufer I, King RG, Zhang Y, Guo W, Pinsky DJ, Connolly ES Jr (2006) A cerebroprotective dose of intravenous citrate/sorbitol-stabilized dehydroascorbic acid is correlated with increased cerebral ascorbic acid and inhibited lipid peroxidation after murine reperfused stroke. Neurosurgery 59(2):383–388 Mariotti C, Gellera C, Rimoldi M, Mineri R, Uziel G, Zorzi G, Pareyson D, Piccolo G, Gambi D, Piacentini S, Squitieri R, Capra R, Castellotti B, Di Donato S (2004) Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families. Neurol Sci 25(3):130–137 Martinasevic MK, Rios GR, Miller MW, Tephly TR (1999) Folate and folate-dependent enzymes associated with rat CNS development. Dev Neurosci 21(1):29–35 Martínez-Cruz F, Osuna C, Guerrero JM (2006) Mitochondrial damage induced by fetal hyperphenylalaninemia in the rat brain and liver: its prevention by melatonin, Vitamin E, and Vitamin C. Neurosci Lett 392(1–2):1–4 Marzouki N, Benomar A, Yahyaoui M, Birouk N, Elouazzani M, Chkili T, Benlemlih M (2005) Vitamin E deficieny ataxia with (744 del A) mutation on alpha-TTP gene: genetic and clinical peculiarities in Moroccan patients. Eur J Med Genet 48(1):21–28 Mas E, Dupuy AM, Artero S, Portet F, C ristol JP, Ritchie K, Touchon J (2006) Functional vitamin E deficiency in ApoE4 patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 21(3):198–204 Miller JW (2002) Vitamin B 12 deficiency, tumor necrosis factor-alpha, and epidermal growth factor: a novel function for vitamin B 12 ? Nutr Rev 60(5):142–144 Miura S, Ishida A, Nakajima W, Ohmura A, Kawamura M, Takada G (2006) Intraventricular ascorbic acid a dministrations decreases hypoxic-ischemic brain injury in newborn rats. Brain Res 1095(1):159–166 Mizuno Y, Matuda S, Yoshino H, Mori H, Hattori N, Ikebe S (1994) An immunohistochemical study on alpha-ketoglutarate dehydrogenase complex in Parkinson’s disease. Ann Neurol 35(2):204–210 MRC Vitamin Study Research Group (1991) Prevention of neural tube defects: result of the Medical Research Council Vitamin Study. Lancet 338(8760):131–137 Muthuvel R, Venkataraman P, Krishnamoorthy G, Gunadharini DN, Kanagaraj P, Jone Stanley A, Srinivasan N, Balasubramanian K, Aruldhas MM, Arunakaran J (2006) Antioxidant effect of ascorbic acid on PCB (Aroclor 1254) induced oxidative stress in hypothalamus of rats. Clin Chim Acta 365(1–2):297–303 Navarro D, Zwingmann C, Hazell AS, Butterworth RF (2005) Brain lactate synthesis in thiamine deficiency: a re-evaluation using 1 H/ 13 C nuclear magnetic resonance spectroscopy. J Neurosci Res 79(1–2):33–41 Newaz MA, Yousefipour Z, Nawa NN (2005) Modulation of nitric oxide synthase activity in brain, liver, and blood vessels of spontaneously hypertensive rats by ascorbic acid: protection from free radical injury. Clin Exp Hypertens 27(6):497–508 Nunn JF, Chanarin I, Tanner AG, Owen ER (1986) Megaloblastic bone marrow changes after repeated nitrous oxide anaesthesia. Reversal with folinic acid. Br J Anaesth 58(12):1469–1470 Parker WD Jr, Hass R, Stumpf DA, Parks J, Eguren LA, Jackson C (1984) Brain mitochondrial metabolism in experimental thiamine deficiency. Neurology 34(11):1477–1481 124 C. Bémeur et al. Peters RA (1936) The biochemical lesion in vitamin B 1 deficiency. application of modern biochemical analysis in its diagnosis. Lancet 1:1161–1164 Puri V, Chaudhry N, Tatke M, Prakash V (2005) Isolated vitamin E deficiency with demyelinating neuropathy. Muscle Nerve 32(2):230–235 Rao VL, Richardson JS, Butterworth RF (1993) Decreased activities of thiamine diphosphatase in frontal and temporal cortex in Alzheimer’s disease. Brain Res 631(2):334–336 Rebec GV, Conroy SK, Barton SJ (2006) Hyperactive striatal neurons in symptomatic Huntington R6/2 mice: variations with behavioral state and repeated ascorbate treatment. Neuroscience 137(1):327–336 Rebec GV, Witowski SR, Sandstrom MI, Rostand RD, Kennedy RT (2005) Extracellular ascorbate modulates cortically evoked glutamate dynamics in rat striatum. Neurosci Lett 378(3): 166–170 Rota C, Rimbach G, Minihane AM, Stoecklin E, Barella L (2005) Dietary vitamin E modulates dif- ferential gene expression in the rat hippocampus: potential implications for its neuroprotective properties. Nutr Neurosci 8(1):21–29 Sakai K, Nakajima T, Fukuhara N (2006) A suspected of alcoholic pellagra encephalopathy with marked response to niacin showing myoclonus and ataxia as chief complaints. No To Shinkei 58(2):141–144 Sanchez-Moreno C, Dashe JF, Scott T, Thaler D, Folstein MF, Martin A (2004) Decreased levels of plasma vitamin C and increased concentrations of inflammatory and oxidative stress markers after stroke. Stroke 35:163–168 Scalabrino G (2005) Cobalamin (vitamin B 12 ) in subacute combined degeneration and beyond tradional interpretations and novel theories. Exp Neurol 192(2):463–479 Scalabrino G, Buccellato FR, Veber D, Mutti E (2003) New basis of the neurotrophic action of vitamin B 12 . Clin Chem Lab Med 41(11):1435–1437 Shih JJ, Kornblum H, Shewmon DA (1996) Global brain dysfunction in an infant with pyridoxine dependency: evaluation with EEG, evoked potentials, MRI, and PET. Neurology 47(3): 824–826 Sies H (1985) Oxidative stress: introductory remarks.In: Sies H (eds) Oxidative stress. Academic Press, Orlando, pp 1–8 TanPhaichitr V (1985) Epidemiology and clinical assessment of vitamin deficiencies in Thai chil- dren. In: Eeckels RE, Ransome-Kuti O, Kroonenberg CC (eds) Child health in the tropics. Martinus Nijhoff Publishers, Dordrecht, pp 157–166 TanPhaichitr V (1999) Thiamin. In: Shils ME, Olsen JA, Shike M et al (eds) Modern nutrition in health and disease, 9th edn. Lippincott Williams & Wilkins, Baltimore, MD Todd KG, Butterworth RF (1999) Early microglial response in experimental thiamine deficiency: an immunohistochemical analysis. Glia 25(2):190–198 Torvik A (1985) Two types of brain lesions in Wernicke’s encephalopathy. Neuropathol Appl Neurobiol 11(3):179–190 Traber MG (2006) How much vitamin E Just enough! Am J Clin Nutr 84(5):959–960 Victor M, Adams RD, Collins GH (1971) The Wernicke-Korsakoff syndrome. A clinical and pathological study of 245 patients, 82 with post-mortem examinations. Contemp Neurol Ser 7:1–206 Werler MM, Shapiro S, Mitchell AA (1993) Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA 269(10):1257–1261 Xu Y, Sladky JT, Brown MJ (1989) Dose-dependent expression of neuronopathy after experimental pyridoxine intoxication. Neurology 39(8):1077–1083 . by hyperargininemia in the cerebellum and hippocampus of rats (Delwing et al., 2006). Vitamin C and E administration, alone or in combination, increases striatal catalase activity in rats subjected. trans- fer protein (αTP) in the brain. Dysfunction of αTP results in deficiency of vitamin E in humans and mice, and increased oxidative stress i n mouse brain. Ataxia with isolated vitamin E deficiency. participate in normalizing neuronal function in Huntington’s disease (Rebec et al., 2006). Antioxidant vitamins, particularly vitamins E and C may act synergistically. A short period of combined deficiency