Water Soluble Vitamins

Folic acid is transported into brain as methylenete-trahydrofolic acid, the major form of folic acid in the circulation. It is then transported rapidly into neurons and glia from the CSF/extracellular fluid. Once inside cells, folates are polyglutamated. Methylenetetrahydrofolate is used by neurons and glia in reactions involving single carbon groups, such as in the conversion of serine to glycine or homocysteine to methionine. Once methylenetetra-hydrofolate is consumed in these reactions, folic acid is transported out of the brain into the circulation. Folate has become an issue of neurologic concern because of a link between folate deficiency and abnormal CNS development. The incidence of spina bifida, a serious spinal cord abnormality, rises above the population mean in the children of women who are folate-deficient during pregnancy. Moreover, the incidence of spina bifida can be reduced by folic acid supplementation during pregnancy, beginning prior to conception. Initiating supplementation before conception is essential, since the basic design of the CNS is laid down during the first trimester. At present, the mechanism(s) by which folic acid deficiency leads to the improper formation of the spinal cord is unknown. Folate deficiency may also be linked to depression in adults, and occasional studies suggest that folate supplementation can improve mood in depressed patients. The mechanism(s) by which folate modifies mood is presently unknown.

Ascorbic acid (vitamin C) is actively transported into the brain extracellular fluid through the blood-CSF barrier, from which it is actively transported into cells. Brain ascorbate pools show minimal fluctuations over a wide range of plasma ascorbate concentrations, which presumably explains the absence of CNS signs in ascorbate deficiency. To date, the only defined biochemical function of ascorbic acid in brain is as a cofactor for the enzyme that converts dopamine to noradrenaline (norepinephrine) (though ascorbate is thought by some to function as an antioxidant).

Thiamine (vitamin Bj) is taken up into brain by a BBB transporter; small amounts also gain entry via transport from blood into CSF. It is then transported into neurons and glia; conversion to thiamine pyrophosphate effectively traps the molecule within the cell. In nervous tissue, thiamine functions as a cofac-tor in important enzymes of energy metabolism. Severe thiamine deficiency in animals reduces thia-mine pyrophosphate levels, and the activities of thia-mine-dependent reactions. It causes loss of the coordinated control of muscle movement; the exact biochemical mechanism is not clear. The functional deficits are rapidly corrected with thiamine treatment, suggesting that neurons have not been damaged or destroyed. Thiamine deficiency in humans (beriberi; Wernicke's disease) produces similar deficits in the control of muscle movements, and also mental confusion. Korsakoff's syndrome, which occurs in almost all patients with Wernicke's disease, involves a loss of short-term memory and mental confusion. Severe thiamine deficiency in humans appears to produce neuronal degeneration in certain brain regions. The motor abnormalities can be corrected with thiamine treatment, but the memory dysfunction is not improved.

Riboflavin enters brain via a saturable BBB transport carrier. It is then transported into neurons and glia, and trapped intracellularly by phosphorylation and conversion to flavin adenine dinucleotide. Flavin adenine dinucleotide functions as a cofactor in carboxylation reactions. The brain contents of ribo-flavin and its derivatives are not notably altered in states of riboflavin deficiency or excess.

Pantothenic acid is transported into brain by a BBB transport carrier. Neurons and glial cells take up pantothenic acid slowly by a mechanism of facilitated diffusion. Inside the cell, the vitamin becomes a component of coenzyme A, the coenzyme of acyl group transfer reactions. Relative to other tissues, the brain contains a high concentration of pantothe-nate, mostly in the form of coenzyme A. Brain coenzyme A concentrations are not depleted in pan-tothenate deficiency states.

Niacin (vitamin B3) is transported into brain as niacinamide, primarily via the BBB. Most niacin in brain is derived from the circulation, though brain may be able to synthesize small amounts. Niacin is taken up into neurons and glia and rapidly converted to nicotinamide adenine dinucleotide. The half-life of nicotinamide adenine dinucleotide in brain is considerably longer than in other tissues. Nicotinamide adenine dinucleotide and nicotin-amide adenine dinucleotide phosphate are involved in numerous oxidation-reduction reactions. Dietary niacin deficiency in the presence of a low intake of TRP causes pellagra in humans, a deficiency disease that includes mental depression and dementia, loss of motor coordination, and tremor. The mecha-nism(s) for these effects have not been identified.

Pyridoxine (vitamin B6) is taken up into brain via a transport carrier that has not been well described. The vitamin can be transported in any of its non-phosphorylated forms (pyridoxine, pyridoxal, pyr-idoxamine). Once within the brain extracellular fluid, the vitamin is readily transported into neurons and glia and phosphorylated (primarily to pyridoxal phosphate or pyridoxine phosphate). Pyridoxal phosphate is a cofactor in a variety of neurotransmitter reactions, such as aromatic-l-amino acid decarboxylase (an enzyme of mono-amine biosynthesis), glutamic acid decarboxylase (the enzyme of 7-amino butyric acid [GABA] synthesis), and GABA transaminase (the enzyme that catabolizes GABA). In humans, pyridoxine deficiency is rare, because of its widespread occurrence in foodstuffs. However, when identified, it has been associated with increased seizure activity, an effect dissipated by pyridoxine treatment. This effect may be linked to the production of GABA, an inhibitory neurotransmitter.

Biotin is transported into brain by a BBB carrier. It is a coenzyme for a variety of key carboxylation reactions in gluconeogenesis, fatty acid synthesis, and amino acid metabolism. Normally, biotin is recycled in cells during protein (enzyme) turnover, but not in brain; brain cells are thus more immediately dependent than other cells on circulating biotin availability. Biotin deficiency is rare; when it occurs, it can involve CNS symptoms (depression, sleepiness). The underlying basis for these effects is presently unknown.

Cobalamin (vitamin B12) is thought to be transported into brain by a carrier-mediated mechanism. Little is known about this process, or about the function of vitamin B12 in the nervous system. Vitamin B12 deficiency is associated with neurologic abnormalities, which are presumed to derive from the demyelinization of CNS axons seen in advanced deficiency cases. These effects are reversed if vitamin B12 treatment is provided early enough; left untreated, axonal degeneration occurs. Vitamin B12 may be important in neuronal repair mechanisms, which may become compromised in deficiency states. Nervous system damage associated with vitamin B12 deficiency can occur at any age.

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