B Vitamins and the Brain: Mechanisms, Dose and Efficacy--A Review

Abstract

The B-vitamins comprise a group of eight water soluble vitamins that perform essential, closely inter-related roles in cellular functioning, acting as co-enzymes in a vast array of catabolic and anabolic enzymatic reactions. Their collective effects are particularly prevalent to numerous aspects of brain function, including energy production, DNA/RNA synthesis/repair, genomic and non-genomic methylation, and the synthesis of numerous neurochemicals and signaling molecules. However, human epidemiological and controlled trial investigations, and the resultant scientific commentary, have focused almost exclusively on the small sub-set of vitamins (B9/B12/B6) that are the most prominent (but not the exclusive) B-vitamins involved in homocysteine metabolism. Scant regard has been paid to the other B vitamins. This review describes the closely inter-related functions of the eight B-vitamins and marshals evidence suggesting that adequate levels of all members of this group of micronutrients are essential for optimal physiological and neurological functioning. Furthermore, evidence from human research clearly shows both that a significant proportion of the populations of developed countries suffer from deficiencies or insufficiencies in one or more of this group of vitamins, and that, in the absence of an optimal diet, administration of the entire B-vitamin group, rather than a small sub-set, at doses greatly in excess of the current governmental recommendations, would be a rational approach for preserving brain health.

Keywords: biotin; brain; coenzyme; folate; homocysteine; niacin; pantothenic acid; riboflavin; thiamin; vitamin.

Figure 1

The role of B-vitamins in mitochondrial energy production. The citric acid cycle (tricarboxylic/Krebs cycle) is a series of chemical reactions that generate energy, in the form of ATP, in the mitochondria of eukaryotes. Carbohydrates, fats and proteins are first converted to acetyl-CoA, most often via pyruvate, and then undergo eight enzymatic reactions that result in the production of NADH and FADH₂, which transfer the energy generated by the citric acid cycle to the electron transport chain. This in turn leads to the synthesis of ATP, the energy currency of cells. B vitamins contribute (as shown) to this process as co-factors/enzymes such as FAD (B₂), NAD (B₃) and as a component of CoA (B₅), or Co-enzyme Q10 (B₅). The intermediate compounds of the cycle are also sequestered as substrates for the synthesis of other compounds, including amino acids and fatty acids, and several subsequently have to be replenished by anaplerotic synthesis, taking place outside of the cycle. The most prevalent examples are the augmentation of succinyl-CoA from α-ketobutyrate generated from methionine within the methionine cycle (see Figure 2), and synthesis of oxaloacetate direct from pyruvate. Abbreviations: BCKDC, branched-chain α-ketoacid dehydrogenase complex; CS, citrate synthase; CoA, coenzyme A; FAD/FADH2, flavin adenine dinucleotide (oxidised/reduced); IDH, isocitrate dehydrogenase; NAD, nicotinamide adenine dinucleotide (+/H = oxidised/reduced); MDH, malate dehydrogenase; MCM, methylmalonyl-CoA mutase; OGDH, α-ketoglutarate dehydrogenase; PCC, propionyl-CoA Carboxylase; PC, pyruvate carboxylase; PD, pyruvate dehydrogenase; SCS, succinyl-CoA synthetase; SQR, succinate-coenzyme Q reductase.

Figure 2

The interlinked folate and methionine cycles. Dietary folate enters the folate cycle and rotates through several enzymatic modifications which generate the one-carbon units required for the synthesis of DNA/RNA and the methyl groups required to regenerate methionine from homocysteine. The “methionine cycle” provides the methyl groups required for all genomic and non-genomic methylation reactions in the form of S-adenosyl methionine (SAM). These two enzymatic cycles are essential to cellular function, including via interactions with other pathways. As an example of the latter, the re-salvaging from dihydrobiopterin of tetrahydrobiopterin, an essential cofactor in trace amine and catecholamine neurotransmitter synthesis and nitric oxide production, is rate limited by provision of the enzyme dihydrofolate reductase produced by the folate cycle. * FAD (vitamin B₂) is a cofactor for methionine synthase reductase in the recycling of the vitamin B₁₂ cofactor for methionine synthase. Abbreviations: AADC, aromatic L-amino acid decarboxylase; AAAH, aromatic amino acid hydroxylases; ATP, adenosine triphosphate; BH2, dihydrobiopterin; BH4, tetrahydrobiopterin; CBS, cystathionine beta synthase; CGL, cystathionine gamma-lyase; DHFR, dihydrofolate reductase; dTMP, thymidine monophosphate; dUMP, deoxyuridine monophosphate; GR, glutathione reductase; GSSG, glutathione disulphide; MAT, methionine adenosyltransferase; MS, methionine synthase; MTHFR, methyltetrahydrofolate reductase; NOS, nitric oxide synthase; SAH, S-adenosylhomocysteine; SAHH, S-adenosylhomocysteine hydrolase; SAM, S-adenosyl methionine; SH, serine hydroxymethyltransferase; THF, tetrahydrofolate; TS, thymidylate synthase.