B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin.

BACKGROUND: Neurotropic B vitamins play crucial roles as coenzymes and beyond in the nervous system. Particularly vitamin B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) contribute essentially to the maintenance of a healthy nervous system. Their importance is highlighted by many neurological diseases related to deficiencies in one or more of these vitamins, but they can improve certain neurological conditions even without a (proven) deficiency. AIM: This review focuses on the most important biochemical mechanisms, how they are linked with neurological functions and what deficits arise from malfunctioning of these pathways. DISCUSSION: We discussed the main role of B Vitamins on several functions in the peripheral and central nervous system (PNS and CNS) including cellular energetic processes, antioxidative and neuroprotective effects, and both myelin and neurotransmitter synthesis. We also provide an overview of possible biochemical synergies between thiamine, pyridoxine, and cobalamin and discuss by which major roles each of them may contribute to the synergy and how these functions are inter-related and complement each other. CONCLUSION: Taking into account the current knowledge on the neurotropic vitamins B1, B6, and B12, we conclude that a biochemical synergy becomes apparent in many different pathways in the nervous system, particularly in the PNS as exemplified by their combined use in the treatment of peripheral neuropathy.

Thiamin and protein folding.

A huge number of proteins that occur in the body have to be folded into a specific shape in order to become functional. Proteins are made up of chains of amino acids and the folding process is exquisitely complex. When this folding process is inhibited, the respective protein is referred to as being misfolded and nonfunctional. So the hypothesis that follows is in regard to the diseases that are caused by the misfolding of vital proteins and their reported relationship with thiamin metabolism. These diseases are termed proteopathies and there are at least 50 different conditions in which the mechanism is importantly related to a misfolded protein. In the brain, thiamin deficiency causes a cascade of events involving mild impairment of oxidative metabolism, neuroinflammation and neurodegeneration, including the pathology of Alzheimer's disease, Parkinson's and Huntington's diseases, all of which are examples of proteopathies. Prion diseases are fatal neurodegenerative disorders related to the conformational alteration of the prion protein (PrP C) into a pathogenic and protease-resistant isoform (PrPSc). The physiological form (PrP C) is a cell surface glycoprotein expressed mainly in the central nervous system. Despite numerous efforts to elucidate its role, the exact biological function remains unknown. Prion-induced diseases, due to the conformational change in the protein, are a global health problem, with lack of effective therapy and 100% mortality. Thiamin and its derivatives bind the prion protein and intermolecular actions have been noted between thiamin and other thiamin-binding proteins, although the exact importance of this is conjectural.

The role of endogenous thiamine produced via THIC in root nodule symbiosis in Lotus japonicus.

Thiamine is a pivotal primary metabolite which is indispensable to all organisms. Although its biosynthetic pathway has been well documented, the mechanism by which thiamine influences the legume-rhizobium symbiosis remains uncertain. Here, we used overexpressing transgenic plants, mutants and grafting experiments to investigate the roles played by thiamine in Lotus japonicus nodulation. ljthic mutants displayed lethal phenotypes and the defect could be overcome by supplementation of thiamine or by overexpression of LjTHIC. Reciprocal grafting between L. japonicus wild-type Gifu B-129 and ljthic showed that the photosynthetic products of the aerial part made a major contribution to overcoming the nodulation defect in ljthic. Overexpression of LjTHIC in Lotus japonicus (OE-LjTHIC) decreased shoot growth and increased the activity of the enzymes 2-oxoglutarate dehydrogenase and pyruvate dehydrogenase. OE-LjTHIC plants exhibited an increase in the number of infection threads and also developed more nodules, which were of smaller size but unchanged nitrogenase activity compared to the wildtype. Taken together, our results suggest that endogenous thiamine produced via LjTHIC acts as an essential nutrient provided by the host plant for rhizobial infection and nodule growth in the Lotus japonicus - rhizobium interaction.

Thiamine status, metabolism and application in dairy cows: a review.

As the co-enzyme of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, thiamine plays a critical role in carbohydrate metabolism in dairy cows. Apart from feedstuff, microbial thiamine synthesis in the rumen is the main source for dairy cows. However, the amount of ruminal thiamine synthesis, which is influenced by dietary N levels and forage to concentrate ratio, varies greatly. Notably, when dairy cows are overfed high-grain diets, subacute ruminal acidosis (SARA) occurs and results in thiamine deficiency. Thiamine deficiency is characterised by decreased ruminal and blood thiamine concentrations and an increased blood thiamine pyrophosphate effect to >45 %. Thiamine deficiency caused by SARA is mainly related to the increased thiamine requirement during high grain feeding, decreased bacterial thiamine synthesis in the rumen, increased thiamine degradation by thiaminase, and decreased thiamine absorption by transporters. Interestingly, thiamine deficiency can be reversed by exogenous thiamine supplementation in the diet. Besides, thiamine supplementation has beneficial effects in dairy cows, such as increased milk and component production and attenuated SARA by improving rumen fermentation, balancing bacterial community and alleviating inflammatory response in the ruminal epithelium. However, there is no conclusive dietary thiamine recommendation for dairy cows, and the impacts of thiamine supplementation on protozoa, solid-attached bacteria, rumen wall-adherent bacteria and nutrient metabolism in dairy cows are still unclear. This knowledge is critical to understand thiamine status and function in dairy cows. Overall, the present review described the current state of knowledge on thiamine nutrition in dairy cows and the major problems that must be addressed in future research.

Thiamine Levels in Muscle and Eggs of Adult Pacific Salmon from the Fraser River, British Columbia.

Multiple species and stocks of Pacific salmon Oncorhynchus spp. have experienced large declines in the number of returning adults over a wide region of the Pacific Northwest due to poor marine survival (low smolt-to-adult survival rates). One possible explanation for reduced survival is thiamine deficiency. Thiamine (vitamin B1 ) is an essential vitamin with an integral role in many metabolic processes, and thiamine deficiency is an important cause of salmonid mortality in the Baltic Sea and in the Laurentian Great Lakes. To assess this possibility, we (1) compared muscle thiamine content over time in a holding experiment using Fraser River (British Columbia) Sockeye Salmon O. nerka to establish whether adults that died during the holding period had lower thiamine levels than survivors, (2) measured infectious loads of multiple pathogens in held fish, and (3) measured egg thiamine content from four species of Pacific salmon collected on Fraser River spawning grounds. Chinook Salmon O. tshawytscha had the lowest egg thiamine, followed by Sockeye Salmon; however, egg thiamine concentrations were above levels known to cause overt fry mortality. Thiamine vitamers in the muscle of Fraser River adult Sockeye Salmon shifted over a 13-d holding period, with a precipitous decline in thiamine pyrophosphate (the active form of thiamine used in enzyme reactions) in surviving fish. Survivors also carried lower loads of Flavobacterium psychrophilum than fish that died during in the holding period. Although there is no evidence of thiamine deficiency in the adults studied, questions remain about possible thiamine metabolism-fish pathogen relationships that influence survival.

Interactions of endoplasmic reticulum and mitochondria Ca(2+) stores with capacitative calcium entry.

Thiamine dependent enzymes are diminished in Alzheimer's disease (AD). Thiamine deficiency in vitro and in rodents is a useful model of this reduction. Thiamine interacts with cellular calcium stores. To directly test the relevance of the thiamine dependent changes to dynamic processes in AD, the interactions must be studied in cells from patients with AD. These studies employed fibroblasts. Mitochondrial dysfunction including reductions in thiamine dependent enzymes and abnormalities in calcium homeostasis and oxidative processes occur in fibroblasts from Alzheimer's Disease (AD) patients. Bombesin-releasable calcium stores (BRCS) from the endoplasmic reticulum (ER) are exaggerated in fibroblasts from patients with AD bearing a presenilin-1 (PS-1) mutation and in control fibroblasts treated with oxidants. ER calcium regulates calcium entry into the cell through capacitative calcium entry (CCE), which is reduced in fibroblasts and neurons from mice bearing PS-1 mutations. Under physiological conditions, mitochondria and ER play important and interactive roles in the regulation of Ca(2+) homeostasis. Thus, the interactions of mitochondria and oxidants with CCE were tested. Inhibition of ER Ca(2+)-ATPase by cyclopiazonic acid (CPA) stimulates CCE. CPA-induced CCE was diminished by inhibition of mitochondrial Ca(2+) export (-60%) or import (-40%). Different aspects of mitochondrial Ca(2+) coupled to CPA-induced-CCE were sensitive to select oxidants. The effects were very different when CCE was examined in the presence of InsP3, a physiological regulator of ER calcium release, and subsequent CCE. CCE under these conditions was only mildly reduced (20-25%) by inhibition of mitochondrial Ca(2+) export, and inhibition of mitochondrial Ca(2+) uptake exaggerated CCE (+53%). However, t-BHP reversed both abnormalities. The results suggest that in the presence of InsP3, mitochondria buffer the local Ca(2+) released from ER following rapid activation of InsP3R and serve as a negative feedback to the CCE. The results suggest that mitochondrial Ca(2+) modifies the depletion and refilling mechanism of ER Ca(2+) stores.

[Vitamin B1 (thiamine)]. / Vitamine B1 (thiamine).

Vitamin B1 (or thiamine) plays a key role in energy production from glucose. Since the main fuel of the nervous system is glucose, thiamine deficiency causes severe neurological symptoms. The biological exploration of vitamin B1 status is based on the measurement of thiamine pyrophosphate concentration or of the activity of a thiamine-dependent enzyme, transketolase, in erythrocytes. Severe deficiency states can be observed in chronic alcoholics, after protracted vomiting during pregnancy and after bariatric surgery. Mild deficiencies are common in the general population, but their clinical consequences are still unclear.

The beneficial role of thiamine in Parkinson disease.

Parkinson disease (PD) is the second most common form of neurodegeneration among elderly individuals. PD is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. In this paper, we review the evidence for an association between PD and thiamine. Interestingly, a significant association has been demonstrated between PD and low levels of serum thiamine, and thiamine supplements appear to have beneficial clinical effects against PD. Multiple studies have evaluated the connection between thiamine and PD pathology, and candidate pathways involve the transcription factor Sp1, p53, Bcl-2, caspase-3, tyrosine hydroxylase, glycogen synthase kinase-3ß, vascular endothelial growth factor, advanced glycation end products, nuclear factor kappa B, mitogen-activated protein kinase, and the reduced form of nicotinamide adenine dinucleotide phosphate. Thus, a review of the literature suggests that thiamine plays a role in PD, although further investigation into the effects of thiamine in PD is needed.

The role of thiamine in HIV infection.

Patients infected with HIV have a high prevalence of thiamine deficiency. Genetic studies have provided the opportunity to determine which proteins link thiamine to HIV pathology, i.e., renin-angiotensin system, poly(ADP-ribosyl) polymerase 1, Sp1 promoter gene, transcription factor p53, apoptotic factor caspase 3, and glycogen synthetase kinase 3ß. Thiamine also affects HIV through non-genomic factors, i.e., matrix metalloproteinase, vascular endothelial growth factor, heme oxygenase 1, the prostaglandins, cyclooxygenase 2, reactive oxygen species, and nitric oxide. In conclusion, thiamine may benefit HIV patients, but further investigation of the role of thiamine in HIV infection is needed.

The role of B vitamins in the management of heart failure.

Heart failure (HF) is the leading cause of morbidity and mortality in industrialized countries, creating a significant burden on both the healthcare system and quality of life. Research efforts continue to explore new pharmaceutical or surgically based approaches to HF management, but the role of nutrition as an adjunct therapy has been largely ignored. Elderly age, anorexia, malabsorption, premature satiety, and disease severity are among the factors identified as contributing to reduced nutrient intakes in patients with HF. These factors suggest that patients with HF are at increased risk of multiple-nutrient deficiencies, including B vitamins. B vitamins may be of particular therapeutic interest because of their key roles as cofactors in energy-producing pathways. Recently, impaired stores of high-energy compounds have been linked with myocardial dysfunction and prognosis in patients with HF. Therefore, deficiencies of B vitamins might contribute to reduced energy stores and disease progression. This review summarizes the existing literature both with respect to the prevalence of B vitamin deficiency as well as evidence from supplementation trials in patients with HF. The findings suggest that most of the literature in this area has focused on thiamin deficiency in patients with HF, whereas other B vitamins remain largely unstudied. Although few sporadic trials suggest a role for B vitamins in the management of HF, none are conclusive. Therefore, there is a need for larger, more robust trials to assist in defining the B vitamin requirements as well as the impact of supplementation on both morbidity and mortality in patients with HF.

New considerations on the neuromodulatory role of thiamine.

BACKGROUND: A nonmetabolic role for thiamine in cholinergic neurotransmission has long been suggested. The mechanism remains unclear. We sought to extend our previous research to elucidate the effect of the thiamine metabolic antagonist, oxythiamine, on the release of acetylcholine from the brain. METHODS: The potassium-stimulated release of acetylcholine from superfused rat brain slices was determined. Hand-cut slices of cerebral cortex were preincubated with tritiated choline to label acetylcholine stores. Two periods of stimulation (S1, S2) with 50 mmol/l solution for 3.5 min were performed as superfusate was collected. During S1, only 50 mmol/l potassium-containing Krebs-bicarbonate buffer with 2 mmol/l calcium was used. Using a two-by-two design, S2 consisted of exposure to 50 mmol/l potassium with or without 10(-4) mol/l oxythiamine, with or without calcium. The S2/S1 ratio was calculated. RESULTS: Oxythiamine enhanced the potassium-evoked release of acetylcholine by 60% but only when calcium was present in the superfusing medium. CONCLUSION: These data confirm earlier findings with oxythiamine on the calcium-mediated synaptic transmission of acetylcholine and support a possible neuromodulatory role for thiamine distinct from its actions as a cofactor during metabolic processes.

Thiamin(e): the spark of life.

One of the earliest vitamins to be discovered and synthesized, thiamin was originally spelled with an "e". The terminal "e" was dropped when it was found that it was not an amine. It is still spelled with and without the "e" depending on the text. This chapter provides a brief historical review of the association of thiamin with the ancient scourge of beriberi. It emphasizes that beriberi is the model for high calorie malnutrition because of its occurrence in predominantly white rice consuming cultures. Some of the symptomatology of this ancient scourge is described, emphasizing the difference from that seen in starvation. High calorie malnutrition, due to excessive ingestion of simple carbohydrates, is widely encountered in the U.S.A. today. Thiamin deficiency is commonly associated with this, largely because of its cofactor status in the metabolism of glucose. The biochemistry of the three phosphorylated esters of thiamin and the transporters are discussed and the pathophysiology of thiamin deficiency reviewed. The role of thiamin, and particularly its synthetic derivatives as therapeutic agents, is not fully appreciated in Western civilization and a clinical section describes some of the unusual cases described in the scientific literature and some experienced by the author. The possible role of high calorie malnutrition and related thiamin deficiency in juvenile crime is hypothesized.

Frontiers in vitamin research: new antibodies, new data.

Since 2004, the anatomical distribution of vitamins in the monkey brain, studied using immunohistochemical techniques and new tools (specific antisera that discriminate different vitamins reasonably well), has been an ongoing research field. The visualization of immunoreactive structures containing vitamins (folic acid, riboflavin, thiamine, pyridoxal, and vitamin C) has recently been reported in the monkey brain (Macaca fascicularis), all these vitamins showing a restricted or very restricted distribution. Folic acid, thiamine, and riboflavin have only been observed in immunoreactive fibers, vitamin C has only been found in cell bodies (located in the primary somatosensory cortex), and pyridoxal has been found in both fibers and cell bodies. Perikarya containing pyridoxal have been observed in the paraventricular hypothalamic nucleus, the periventricular hypothalamic region, and in the supraoptic nucleus. The fibers containing vitamins are thick, smooth (without varicosities), and are of medium length or long, whereas immunoreactive cell bodies containing vitamins are round or triangular. At present, there are insufficient data to elucidate the roles played by vitamins in the brain, but the anatomical distribution of these compounds in the monkey brain provides a general idea (although imprecise and requiring much more study) about the possible functional implications of these molecules. In this sense, here the possible functional roles played by vitamins are discussed.

Grazers and vitamins shape chain formation in a bloom-forming dinoflagellate, Cochlodinium polykrikoides.

Predators influence the phenotype of prey through both natural selection and induction. We investigated the effects of grazers and nutrients on chain formation in a dinoflagellate, Cochlodinium polykrikoides, which forms dense blooms and has deleterious effects on marine ecosystems around the world. Field populations of C. polykrikoides formed longer chains than laboratory cultures without grazers. In the field, chain length of C. polykrikoides was positively correlated with the abundance of the copepod Acartia tonsa. Chain length of C. polykrikoides increased when exposed to live females of A. tonsa or its fresh (<24 h post-isolation) exudates for 48 h. These results suggest that dissolved chemical cues released by A. tonsa induce chain formation in C. polykrikoides. Ingestion rate of A. tonsa on four-cell chains of C. polykrikoides was lower than on single cells, suggesting that chain formation may be an effective anti-grazing defense. Finally, nutrient amendment experiments demonstrated that vitamins (B(1), B(7), and B(12)) increased the chain length of C. polykrikoides both singly and collectively, while trace metals and inorganic nutrients did not, showing that vitamins may also influence chain formation in this species.

Nutrient provisioning facilitates homeostasis between tsetse fly (Diptera: Glossinidae) symbionts.

Host-associated microbial interactions may involve genome complementation, driving-enhanced communal efficiency and stability. The tsetse fly (Diptera: Glossinidae), the obligate vector of African trypanosomes (Trypanosoma brucei subspp.), harbours two enteric Gammaproteobacteria symbionts: Wigglesworthia glossinidia and Sodalis glossinidius. Host coevolution has streamlined the Wigglesworthia genome to complement the exclusively sanguivorous tsetse lifestyle. Comparative genomics reveal that the Sodalis genome contains the majority of Wigglesworthia genes. This significant genomic overlap calls into question why tsetse maintains the coresidence of both symbionts and, furthermore, how symbiont homeostasis is maintained. One of the few distinctions between the Wigglesworthia and Sodalis genomes lies in thiamine biosynthesis. While Wigglesworthia can synthesize thiamine, Sodalis lacks this capability but retains a thiamine ABC transporter (tbpAthiPQ) believed to salvage thiamine. This genetic complementation may represent the early convergence of metabolic pathways that may act to retain Wigglesworthia and evade species antagonism. We show that thiamine monophosphate, the specific thiamine derivative putatively synthesized by Wigglesworthia, impacts Sodalis thiamine transporter expression, proliferation and intracellular localization. A greater understanding of tsetse symbiont interactions may generate alternative control strategies for this significant medical and agricultural pest, while also providing insight into the evolution of microbial associations within hosts.

[Vitamin B1: metabolism and functions].

The review highlights metabolism and biological functions of vitamin B1 (thiamine). Thiamine transport systems, enzymes of its biosynthesis and degradation in various organisms, as well as molecular basis of thiamine-dependent hereditary patologies are considered. A special emphasis is given to discuss the role of thiamine triphosphate and adenylated thiamine triphosphate, a new thiamine derivative recently discovered in living cells.

Different apoptotic responses of human and bovine pericytes to fluctuating glucose levels and protective role of thiamine.

BACKGROUND: Vascular cells in diabetes are subjected to daily fluctuations from high to low glucose. We aimed at investigating whether pulsed exposure to different glucose concentrations influences apoptosis in human retinal pericytes (HRP) versus bovine retinal pericytes (BRP), with consequences on the onset of diabetic retinopathy, and the possible protective role of thiamine. METHODS: BRP and HRP (wild-type and immortalized) were grown in physiological/high glucose for 7 days, and then returned to physiological glucose for another 24, 48 or 72 h. Cells were also kept intermittently at 48-h intervals in high/normal glucose for 8 days, with/without thiamine/benfotiamine. Apoptosis was determined through ELISA, TUNEL, Bcl-2, Bax and p53 expression/concentration. RESULTS: Continuous exposure to high glucose increased apoptosis in BRP, but not HRP. BRP apoptosis normalized within 24 h of physiological glucose re-entry, while HRP apoptosis increased within 24-48 h of re-entry. Intermittent exposure to high glucose increased apoptosis in HRP and BRP. Bcl-2/Bax results were consistent with DNA fragmentation, while p53 was unchanged. Thiamine and benfotiamine countered intermittent high glucose-induced apoptosis. CONCLUSIONS: Human pericytes are less prone to apoptosis induced by persistently high glucose than bovine cells. However, while BRP recover after returning to physiological levels, HRP are more vulnerable to both downwardly fluctuating glucose levels and intermittent exposure. These findings reinforce the hypotheses that (1) glycaemic fluctuations play a role in the development of diabetic retinopathy and (2) species-specific models are needed. Thiamine and benfotiamine prevent human pericyte apoptosis, indicating this vitamin as an inexpensive approach to the prevention and/or treatment of diabetic complications.

Characteristics of thiamin and its relevance to the management of heart failure.

Heart failure (HF) is a major public health problem in the United States that puts a significant burden on both patients and the healthcare system. The prevalence of malnutrition in HF patients is well-known and correlates with a dramatic decline in quality of life and disease progression, and is associated with high morbidity and mortality rates. The implication of HF on micronutrient status is underrecognized in the quest to offer "best practice" medical, device, and surgical interventions to this population. The micronutrient thiamin is of particular interest in the management of HF for several reasons: (a) HF is a disease of the elderly whose micronutrient status is in need of attention; (b) HF patients tend to have inadequate nutrient intake, which has been associated with thiamin deficiency; (c) thiamin deficiency (wet beriberi) impairs cardiac performance and can mimic the signs and symptoms of HF thereby potentially exacerbating the underlying disease; (d) use of loop diuretics to manage fluid and sodium imbalances associated with HF may cause the hyperexcretion of thiamin, thereby increasing the risk of deficiency; and (e) the prevention of thiamin deficiency should be a routine component in the overall management of this disease.

A theoretical argument for inherited thiamine insensitivity as one possible biological cause of familial alcoholism.

Thiamine deficiency has been specifically linked to the development of Wernicke-Korsakoff syndrome (WK)--a degenerative brain disorder that is typically associated with alcoholic drinking. Alcoholism-related thiamine deficiency is a major cause of WK. However, an inherited abnormality in thiamine utilization has been identified in some WK patients that may predispose heavy drinkers to this severe neurological syndrome. Individuals who possess this variant require more thiamine throughout their lives to prevent them from experiencing thiamine deficiency. Recent prospective studies have implicated early childhood nutritional and environmental influences in the etiology of alcoholism in adults. These studies have suggested that developmental abnormalities involving brain white matter growth might precipitate the later development of alcoholism possibly by altering the emerging reward-related brain systems. Brain white matter growth is highly sensitive to nutritional deficiency (including thiamine deficiency) and oxidative injury, especially during the perinatal period. The proposed model of familial alcoholism hypothesizes that an inherited insensitivity to thiamine can precipitate brain abnormalities very early in life that will greatly increase the risk of developing alcoholism in adulthood. This paper offers a heuristic model of a possible mechanism by which both inherited and environmental factors related to thiamine utilization might coaggregate to cause alcoholism.