Metabolic failure due to thiamine deficiency during critical illness.

PURPOSE OF REVIEW: Thiamine is a crucial component in cellular energy metabolism, serving as a cofactor for multiple enzymatic processes and also having a role in regulating neuronal and neuromuscular transmission. Also it exerts antioxidant proprieties. The objective of this review is to consolidate and assess the most recent research concerning the consequences of insufficient thiamine levels for critically ill patients and to examine thiamine-related interventions. RECENT FINDINGS: Recent studies have unveiled a noteworthy association between thiamine deficiency and unfavorable consequences, such as heightened morbidity and fatality rates. The aforementioned deficiency exhibits a significant presence in medical situations such as starvation and alcohol use disorder, but also in patients during critical illness. Thiamine deficiency can have significant metabolic implications resulting in compromised energy generation and organ dysfunction, warranting prompt recognition and management. SUMMARY: Thiamine deficiency may not be recognized in critical care. Timely identification and management are imperative to mitigate adverse outcomes and improve patient prognosis. Thiamine may offer benefits for specific patient groups at higher risk of deficiency. Future studies should focus to establish optimal dosing, timing, and monitoring strategies on understanding the pathophysiological changes associated with thiamine deficiency in ICU patients and clarify its role in improving clinical outcomes.

Effects of Marginal Zn Excess and Thiamine Deficiency on Microglial N9 Cell Metabolism and Their Interactions with Septal SN56 Cholinergic Cells.

Mild thiamine deficiency aggravates Zn accumulation in cholinergic neurons. It leads to the augmentation of Zn toxicity by its interaction with the enzymes of energy metabolism. Within this study, we tested the effect of Zn on microglial cells cultivated in a thiamine-deficient medium, containing 0.003 mmol/L of thiamine vs. 0.009 mmol/L in a control medium. In such conditions, a subtoxic 0.10 mmol/L Zn concentration caused non-significant alterations in the survival and energy metabolism of N9 microglial cells. Both activities of the tricarboxylic acid cycle and the acetyl-CoA level were not decreased in these culture conditions. Amprolium augmented thiamine pyrophosphate deficits in N9 cells. This led to an increase in the intracellular accumulation of free Zn and partially aggravated its toxicity. There was differential sensitivity of neuronal and glial cells to thiamine-deficiency-Zn-evoked toxicity. The co-culture of neuronal SN56 with microglial N9 cells reduced the thiamine-deficiency-Zn-evoked inhibition of acetyl-CoA metabolism and restored the viability of the former. The differential sensitivity of SN56 and N9 cells to borderline thiamine deficiency combined with marginal Zn excess may result from the strong inhibition of pyruvate dehydrogenase in neuronal cells and no inhibition of this enzyme in the glial ones. Therefore, ThDP supplementation can make any brain cell more resistant to Zn excess.

Neuroinflammation regulates the balance between hippocampal neuron death and neurogenesis in an ex vivo model of thiamine deficiency.

BACKGROUND: Thiamine (vitamin B1) is a cofactor for enzymes of central energy metabolism and its deficiency (TD) impairs oxidative phosphorylation, increases oxidative stress, and activates inflammatory processes that can lead to neurodegeneration. Wernicke-Korsakoff syndrome (WKS) is a consequence of chronic TD, which leads to extensive neuronal death, and is associated with neuropathological disorders, including cognitive deficits and amnesia. The hippocampus is one of the brain areas most affected by WKS. B1 replacement may not be enough to prevent the irreversible cognitive deficit associated with WKS. MATERIALS AND METHODS: An organotypic hippocampal slice culture (OHC) model was developed to investigate, using immunofluorescence and confocal microscopy and transcriptome analysis, the molecular mechanisms underlying the neurodegeneration associated with TD. The effect of anti-inflammatory pharmacological intervention with resveratrol (RSV) was also assessed in B1-deprived OHCs. RESULTS: In OHCs cultured without B1, neuronal density decayed after 5 days and, on the 7th day, the epigenetic markings H3K4me3 and H3K9me3 were altered in mature neurons likely favoring gene transcription. Between the 7th and the 14th day, a pulse of neurogenesis was observed followed by a further massive neuron loss. Transcriptome analysis at day nine disclosed 89 differentially expressed genes in response to B1 deprivation. Genes involved in tryptophan metabolism and lysine degradation KEGG pathways, and those with Gene Ontology (GO) annotations related to the organization of the extracellular matrix, cell adhesion, and positive regulation of synaptic transmission were upregulated. Several genes of the TNF and FoxO signaling pathways and with GO terms related to inflammation were inhibited in response to B1 deprivation. Nsd1, whose product methylates histone H3 lysine 36, was upregulated and the epigenetic marking H3K36me3, associated with negative regulation of neurogenesis, was increased in neurons. Treating B1-deprived OHCs with RSV promoted an earlier neurogenesis pulse. CONCLUSION: Neuroregeneration occurs in B1-deficient hippocampal tissue during a time window. This phenomenon depends on reducing neuroinflammation and, likely, on metabolic changes, allowing acetyl-CoA synthesis from amino acids to ensure energy supply via oxidative phosphorylation. Thus, neuroinflammation is implicated as a major regulator of hippocampal neurogenesis in TD opening a new search space for treating WKS.

Thiamine insufficiency induces Hypoxia Inducible Factor-1α as an upstream mediator for neurotoxicity and AD-like pathology.

Insufficiencies of the micronutrient thiamine (Vitamin B1) have been associated with inducing Alzheimer's disease (AD)-like neuropathology. The hypometabolic state associated with chronic thiamine insufficiency (TI) has been demonstrated to be a contributor towards the development of amyloid plaque deposition and neurotoxicity. However, the molecular mechanism underlying TI induced AD pathology is still unresolved. Previously, we have established that TI stabilizes the metabolic stress transcriptional factor, Hypoxia Inducible Factor-1α (HIF1α). Utilizing neuronal hippocampal cells (HT22), TI-induced HIF1α activation triggered the amyloidogenic cascade through transcriptional expression and increased activity of ß-secretase (BACE1). Knockdown and pharmacological inhibition of HIF1α during TI significantly reduced BACE1 and C-terminal Fragment of 99 amino acids (C99) formation. TI also increased the expression of the HIF1α regulated pro-apoptotic protein, BCL2/adenovirus E1B 19 kDa protein-interacting protein (BNIP3). Correspondingly, cell toxicity during TI conditions was significantly reduced with HIF1α and BNIP3 knockdown. The role of BNIP3 in TI-mediated toxicity was further highlighted by localization of dimeric BNIP3 into the mitochondria and nuclear accumulation of Endonuclease G. Subsequently, TI decreased mitochondrial membrane potential and enhanced chromatin fragmentation. However, cell toxicity via the HIF1α/BNIP3 cascade required TI induced oxidative stress. HIF1α, BACE1 and BNIP3 expression was induced in 3xTg-AD mice after TI and administration with the HIF1α inhibitor YC1 significantly attenuated HIF1α and target genes levels in vivo. Overall, these findings demonstrate a critical stress response during TI involving the induction of HIF1α transcriptional activity that directly promotes neurotoxicity and AD-like pathology.

The Dichotomous Effect of Thiamine Supplementation on Tumorigenesis: A Systematic Review.

The malignant neoplastic cell is characterized by its diverse metabolic changes. It occurs in order to maintain the high rate of proliferation. The possibility of new pharmacological targets has inserted tumor metabolism as a target for recent research, emphasizing the enzymatic activity of thiamin. This review aims to elucidate the behavior of thiamin against tumor development. This is a systematic review in which studies indexed in Pubmed, Scopus, SciELO and BVS were searched using the descriptors (Thiamin OR Vitamin B1) AND (Cancer OR Malignant neoplasia) AND (Tumor metabolism). Title and abstract were read. Duplicates, literary reviews, books, conference abstracts, editorials, and papers published prior to 2010 were eliminated. 23 records were included in this review. Low doses of thiamin have been shown to be enough to stimulate tumor growth. Another population studies has shown evidence of tumor regression after correction of vitamin B1 deficiency. There is an open path for the development of new research to better assess the influence of thiamin on cancer cells. Once the connections between thiamin and the metabolism of cancer cells are fully established, new opportunities for therapeutic intervention and dietary modification will appear to reduce the progression of the disease in patients with cancer.

Protection of Cholinergic Neurons against Zinc Toxicity by Glial Cells in Thiamine-Deficient Media.

Brain pathologies evoked by thiamine deficiency can be aggravated by mild zinc excess. Cholinergic neurons are the most susceptible to such cytotoxic signals. Sub-toxic zinc excess aggravates the injury of neuronal SN56 cholinergic cells under mild thiamine deficiency. The excessive cell loss is caused by Zn interference with acetyl-CoA metabolism. The aim of this work was to investigate whether and how astroglial C6 cells alleviated the neurotoxicity of Zn to cultured SN56 cells in thiamine-deficient media. Low Zn concentrations did not affect astroglial C6 and primary glial cell viability in thiamine-deficient conditions. Additionally, parameters of energy metabolism were not significantly changed. Amprolium (a competitive inhibitor of thiamine uptake) augmented thiamine pyrophosphate deficits in cells, while co-treatment with Zn enhanced the toxic effect on acetyl-CoA metabolism. SN56 cholinergic neuronal cells were more susceptible to these combined insults than C6 and primary glial cells, which affected pyruvate dehydrogenase activity and the acetyl-CoA level. A co-culture of SN56 neurons with astroglial cells in thiamine-deficient medium eliminated Zn-evoked neuronal loss. These data indicate that astroglial cells protect neurons against Zn and thiamine deficiency neurotoxicity by preserving the acetyl-CoA level.

Thiamine deficiency in rats affects thiamine metabolism possibly through the formation of oxidized thiamine pyrophosphate.

BACKGROUND: Thiamine deficiency (TD) has a number of features in common with the neurodegenerative diseases development and close relationship between TD and oxidative stress (OS) has been repeatedly reported in the literature. The aim of this study is to understand how alimentary TD, accompanied by OS, affects the expression and level of two thiamine metabolism proteins in rat brain, namely, thiamine transporter 1 (THTR1) and thiamine pyrophosphokinase (TPK1), and what factors are responsible for the observed changes. METHODS: The effects of OS caused by TD on the THTR1and TPK1 expression in rat cortex, cerebellum and hippocampus were examined. The levels of active and oxidized forms of ThDP (enzymatically measured) in the blood and brain, ROS and SH-groups in the brain were also analyzed. RESULTS: TD increased the expression of THTR1 and protein level in all studied regions. In contrast, expression of TPK1 was depressed. TD-induced OS led to the accumulation of ThDP oxidized inactive form (ThDPox) in the blood and brain. In vitro reduction of ThDPox by dithiothreitol regenerates active ThDP suggesting that ThDPox is in disulfide form. A single high-dose thiamine administration to TD animals had no effect on THTR1 expression, partly raised TPK1 mRNA and protein levels, but is unable to normalize TPK1 enzyme activity. Brain and blood ThDP levels were increased in these conditions, but ThDPox was not decreased. GENERAL SIGNIFICANCE: It is likely, that the accumulation of ThDPox in tissue could be seen as a potential marker of neurocellular dysfunction and thiamine metabolic state.

The impact of thiamine deficiency and benfotiamine treatment on Nod-like receptor protein-3 inflammasome in microglia.

Thiamine-dependent processes are critical in cerebral glucose metabolism, it is abnormity induces oxidative stress, inflammation and neurodegeneration. Nod-like receptor protein-3 (NLRP3) inflammasome-mediated inflammation is closely related to neurologic diseases and can be activated by oxidative stress. However, the impact of thiamine deficiency on NLRP3 inflammasome activation remains unknown. In this study, we found that NLRP3 inflammasomes were significantly activated in the microglia of thiamine deficiency mice model. In contrast, benfotiamine dampened inflammation NLRP3 mediated in BV2 cells stimulated with LPS and ATP through reducing mitochondrial reactive oxygen species levels and mitigating autophagy flux defect. These data identify an important role of thiamine metabolism in NLRP3 inflammasome activation, and correcting thiamine metabolism through benfotiamine provides a new therapeutic strategy for NLRP3 inflammasome related neurological, metabolic, and inflammatory diseases.

Sex differences in cholinergic circuits and behavioral disruptions following chronic ethanol exposure with and without thiamine deficiency.

BACKGROUND: Few studies have investigated differences in the vulnerabilities of males and females to alcohol use disorder and alcohol-related brain damage (ARBD). According to epidemiological and clinical findings, females appear to be more sensitive to the effects of alcohol and thiamine deficiency and have a worse prognosis in recovery from neurocognitive deficits compared with males. This study aimed to characterize the effects of chronic ethanol (EtOH) toxicity and thiamine deficiency across the sexes using rodent models. METHODS: Male and female Sprague Dawley rats were assigned to chronic forced EtOH treatment (CET), pyrithiamine-induced thiamine deficiency (PTD), combined CET-PTD, or pair-fed (PF) control treatment conditions. Following treatments, spatial working memory was assessed during a spontaneous alternation task while measuring acetylcholine (ACh) in the prefrontal cortex (PFC) and the hippocampus (HPC). The animals also underwent an operant-based attentional set-shifting task (ASST) for the analysis of behavioral flexibility. RESULTS: Female and male rats did not differ in terms of EtOH consumption; however, the CET and CET-PTD-treated female rats had lower BECs than male rats. Compared with the PF group, the CET, PTD, and CET-PTD groups exhibited spatial working memory impairments with corresponding reductions in ACh efflux in the PFC and HPC. The ASST revealed that CET-PTD-treated males and females displayed impairments marked by increased latency to make decisions. Thalamic shrinkage was prominent only in the CET-PTD and PTD treatment conditions, but no sex-specific effects were observed. CONCLUSIONS: Although the CET and CET-PTD-treated females had lower BECs than the males, they demonstrated similar cognitive impairments. These results provide evidence that female rats experience behavioral and neurochemical disruptions at lower levels of alcohol exposure than males and that chronic EtOH and thiamine deficiencies produce a unique behavioral profile.

Region-selective permeability of the blood-brain barrier to α-aminoisobutyric acid during thiamine deficiency and following its reversal.

Thiamine deficiency (TD) results in focal lesions in several regions of the rat brain including the thalamus and inferior colliculus. Since alterations in blood-brain barrier (BBB) integrity may play a role in this damage, we have examined the influence of TD on the unidirectional blood-to-brain transfer constant (Ki) of the low molecular weight species α-aminoisobutyric acid (AIB) in vulnerable and non-vulnerable brain regions at different stages during progression of the disorder, and following its reversal with thiamine. Analysis of the regional distribution of Ki values showed early (day 10) increased transfer of [14C]-AIB across the BBB in the vulnerable medial thalamus as well as the non-vulnerable caudate and hippocampus. At the acute symptomatic stage (day 14), more widespread BBB permeability changes were detected in most areas including the lateral thalamus, inferior colliculus, and non-vulnerable cerebellum and pons. Twenty-four hours following thiamine replenishment, a heterogeneous pattern of increased BBB permeability was observed in which many structures maintained increased uptake of [14C]-AIB. No increase in the [3H]-dextran space, a marker of intravascular volume, was detected in brain regions during the progress of TD, suggesting that BBB permeability to this large tracer was unaffected. These results indicate that BBB opening i) occurs early during TD, ii) is not restricted to vulnerable areas of the brain, iii) is progressive, iv) persists for at least 24 h following treatment with thiamine, and v) is likely selective in nature, depending on the molecular species being transported.

Aggravated effects of coexisting marginal thiamine deficits and zinc excess on SN56 neuronal cells.

Objectives: Zinc excitotoxicity and thiamine pyrophosphate deficiency (TD) are known pathogenic signals contributing to mechanism of different encephalopathies through inhibition of enzymes responsible for energy metabolism such as pyruvate dehydrogenase, aconitase or ketoglutarate dehydrogenase. The aim of this work was to investigate whether subclinical Zn excess and TD, frequent in aging brain, may combine yielding overt neuronal impairment.Results: Clonal SN56 cholinergic neuronal cells of septal origin were used as the model of brain cholinergic neurons, which are particularly susceptible to neurodegeneration in the course of Alzheimer's disease, hypoxia and other dementia-linked brain pathologies. Neither subtoxic concentration of Zn (0.10 mM) nor mild 20-25% TD deficits alone caused significant negative changes in cultured cholinergic neurons viability and their acetyl-CoA/acetylcholine metabolism. However, cells with mild TD accumulated Zn in excess, which impaired their energy metabolism causing a loss of neurons viability and their function as neurotransmitters. These negative effects of Zn were aggravated by amprolium which is an inhibitor of thiamine intracellular transport.Conclusion: Our data indicate that TD may amplify otherwise non-harmful border-line Zn excitotoxic signals yielding progress of neurodegeneration.

Erythrocyte transketolase activity coefficient (ETKAC) assay protocol for the assessment of thiamine status.

Vitamin B1 (thiamine) is an essential nutrient that acts as a cofactor for a number of metabolic processes, particularly in energy metabolism. Symptoms of classic thiamine deficiency are recognized as beriberi, although clinical symptoms are nonspecific and recognition of subclinical deficiency is difficult. Therefore, reliable biomarkers of thiamine status are required. Thiamine diphosphate is a cofactor for transketolase, including erythrocyte transketolase (ETK). The ETK activity assay as an indirect, functional marker of thiamine status has been used for over 50 years. The ETK activity assay provides a sensitive and specific biomarker of thiamine status; however, there is a lack of consensus over the cutoffs for deficiency, partly due to a lack of assay harmonization. Here, we provide a step-by-step protocol for the measurement of ETK activity and the calculation of the ETK activity coefficient, including detailed explanations of equipment and chemicals required and guidance for quality control procedures. Harmonization of the protocol will provide the basis for the development of internationally recognized cutoffs for thiamine insufficiency. The establishment of quality control materials and a quality assurance scheme are recommended to provide reliability. This will ensure that the ETK activity assay remains an important method for the assessment of thiamine status.

Does thiamine protect the brain from iron overload and alcohol-related dementia?

Alcohol-related dementia (ARD) is a common and severe co-morbidity in alcohol use disorder (AUD). We propose brain iron overload (BIO) to be an important and previously neglected pathogenic process, accelerating cognitive decline in AUD. Furthermore, we suggest thiamine, which is frequently depleted in AUD, to be a key modulator in this process: Thiamine deficiency impairs the integrity of the blood-brain barrier, thereby enabling iron to pass through and accumulate in the brain. This hypothesis is based on findings from animal, translational, and neuroimaging studies, discussed in this article. To validate this hypothesis, translational studies focusing on brain iron homeostasis in AUD, as well as prospective clinical studies investigating prevalence and clinical impact of BIO in AUD, should be conducted. If proven right, this would change the understanding of ARD and may lead to novel therapeutic interventions in prevention and treatment of ARD.

Novel p.P298L SURF1 mutation in thiamine deficient Leigh syndrome patients compromises cytochrome c oxidase activity.

SURF1 is a nuclear gene and encodes for an important assembly factor for cytochrome c oxidase enzyme. A number of mutations in SURF1 gene render cytochrome c oxidase deficiency, a major causative factor for Leigh syndrome. We screened all the 9 exons and exon-intron boundaries of SURF1 gene in 165 Indian Leigh syndrome patients who were thiamine responsive too. Consequently, we identified several novel and reported nucleotide variations in this gene. The nucleotide changes were analysed by using different in-silico tools for predicting their pathogenicity. Based upon the predictions, we further validated the analyzed functional significance of p.N249D and p.P298L mutations in SURF1 protein using COS-7 cells. Though, both the mutations did not affect the localization of SURF1protein into the mitochondria. But, interestingly the novel mutation p.P298L was reported to significantly compromise the COX activity in these cells.

Severe thiamine deficiency in eastern Baltic cod (Gadus morhua).

The eastern Baltic cod (Gadus morhua) population has been decreasing in the Baltic Sea for at least 30 years. Condition indices of the Baltic cod have decreased, and previous studies have suggested that this might be due to overfishing, predation, lower dissolved oxygen or changes in salinity. However, numerous studies from the Baltic Sea have demonstrated an ongoing thiamine deficiency in several animal classes, both invertebrates and vertebrates. The thiamine status of the eastern Baltic cod was investigated to determine if thiamine deficiency might be a factor in ongoing population declines. Thiamine concentrations were determined by chemical analyses of thiamine, thiamine monophosphate and thiamine diphosphate (combined SumT) in the liver using high performance liquid chromatography. Biochemical analyses measured the activity of the thiamine diphosphate-dependent enzyme transketolase to determine the proportion of apoenzymes in both liver and brain tissue. These biochemical analyses showed that 77% of the cod were thiamine deficient in the liver, of which 13% had a severe thiamine deficiency (i.e. 25% transketolase enzymes lacked thiamine diphosphate). The brain tissue of 77% of the cod showed thiamine deficiency, of which 64% showed severe thiamine deficiency. The thiamine deficiency biomarkers were investigated to find correlations to different biological parameters, such as length, weight, otolith weight, age (annuli counting) and different organ weights. The results suggested that thiamine deficiency increased with age. The SumT concentration ranged between 2.4-24 nmol/g in the liver, where the specimens with heavier otoliths had lower values of SumT (P = 0.0031). Of the cod sampled, only 2% of the specimens had a Fulton's condition factor indicating a healthy specimen, and 49% had a condition factor below 0.8, indicating poor health status. These results, showing a severe thiamine deficiency in eastern Baltic cod from the only known area where spawning presently occurs for this species, are of grave concern.

Understanding and Eliminating the Detrimental Effect of Thiamine Deficiency on the Oleaginous Yeast Yarrowia lipolytica.

Thiamine is a vitamin that functions as a cofactor for key enzymes in carbon and energy metabolism in all living cells. While most plants, fungi, and bacteria can synthesize thiamine de novo, the oleaginous yeast Yarrowia lipolytica cannot. In this study, we used proteomics together with physiological characterization to elucidate key metabolic processes influenced and regulated by thiamine availability and to identify the genetic basis of thiamine auxotrophy in Y. lipolytica Specifically, we found that thiamine depletion results in decreased protein abundance for the lipid biosynthesis pathway and energy metabolism (i.e., ATP synthase), leading to the negligible growth and poor sugar assimilation observed in our study. Using comparative genomics, we identified the missing 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate synthase (THI13) gene for the de novo thiamine biosynthesis in Y. lipolytica and discovered an exceptional promoter, P3, that exhibits strong activation and tight repression by low and high thiamine concentrations, respectively. Capitalizing on the strength of our thiamine-regulated promoter (P3) to express the missing gene from Saccharomyces cerevisiae (scTHI13), we engineered a thiamine-prototrophic Y. lipolytica strain. By comparing this engineered strain to the wild-type strain, we revealed the tight relationship between thiamine availability and lipid biosynthesis and demonstrated enhanced lipid production with thiamine supplementation in the engineered thiamine-prototrophic Y. lipolytica strain.IMPORTANCE Thiamine plays a crucial role as an essential cofactor for enzymes involved in carbon and energy metabolism in all living cells. Thiamine deficiency has detrimental consequences for cellular health. Yarrowia lipolytica, a nonconventional oleaginous yeast with broad biotechnological applications, is a native thiamine auxotroph whose affected cellular metabolism is not well understood. Therefore, Y. lipolytica is an ideal eukaryotic host for the study of thiamine metabolism, especially because mammalian cells are also thiamine auxotrophic and thiamine deficiency is implicated in several human diseases. This study elucidates the fundamental effects of thiamine deficiency on cellular metabolism in Y. lipolytica and identifies genes and novel thiamine-regulated elements that eliminate thiamine auxotrophy in Y. lipolytica Furthermore, the discovery of thiamine-regulated elements enables the development of thiamine biosensors with useful applications in synthetic biology and metabolic engineering.

Nutritional neuropathies.

Neuropathies associated with nutritional deficiencies are routinely encountered by the practicing neurologist. Although these neuropathies assume different patterns, most are length-dependent, sensory axonopathies. Cobalamin deficiency neuropathy is the exception, often presenting with a non-length-dependent sensory neuropathy. Patients with cobalamin and copper deficiency neuropathy characteristically have concomitant myelopathy, whereas vitamin E deficiency is uniquely associated with a spinocerebellar syndrome. In contrast to those nutrients for which deficiencies produce neuropathies, pyridoxine toxicity results in a non-length-dependent sensory neuronopathy. Deficiencies occur in the context of malnutrition, malabsorption, increased nutrient loss (such as with dialysis), autoimmune conditions such as pernicious anemia, and with certain drugs that inhibit nutrient absorption. When promptly identified, therapeutic nutrient supplementation may result in stabilization or improvement of these neuropathies.

Influence of Glucose Dosage in Parenteral Nutrition on Body Thiamine Levels in Rats.

The objective of this study was to determine the relationship between glucose dosage in parenteral nutrition and reductions in levels of body thiamine in rats. Vitamin-free infusions with differing amounts of glucose were administered to normal or thiamine-deficient rats for 5 days, after which urinary thiamine excretion and the amounts of thiamine in the blood, liver, brain, and skeletal muscles were measured. The total energy dosage was set at three levels (98, 140, and 196 kcal/kg), and the dose of amino acids was constant among all groups. Urinary thiamine excretions on Day 5 decreased with increasing glucose dosage in the infusions. In normal rats, the amount of thiamine in the blood and all organs decreased compared with the diet group; however, no significant differences were found among the infusion groups. In thiamine-deficient rats, on the other hand, the amount of thiamine in the liver and skeletal muscles did not differ significantly among infusion groups; however, the amount of thiamine in the brain and blood decreased with increasing glucose dosage. An organ-specific correlation was found between glucose dosage in infusions and reductions in levels of thiamine. To prevent thiamine deficiencies from affecting the central nervous system, greater caution must be exercised during high-caloric parenteral nutrition. However, a constant supply of thiamine seemed to be essential, irrespective of the amount of energy supplied via parenteral nutrition, to maintain a sufficient level of thiamine in the body.

A Pivotal Role for Thiamine Deficiency in the Expression of Neuroinflammation Markers in Models of Alcohol-Related Brain Damage.

BACKGROUND: Alcohol-related brain damage (ARBD) is associated with neurotoxic effects of heavy alcohol use and nutritional deficiency, in particular thiamine deficiency (TD), both of which induce inflammatory responses in brain. Although neuroinflammation is a critical factor in the induction of ARBD, few studies have addressed the specific contribution(s) of ethanol (EtOH) versus TD. METHODS: Adult rats were randomly divided into 6 conditions: chronic EtOH treatment (CET) where rats consumed a 20% v/v solution of EtOH for 6 months; CET with injections of thiamine (CET + T); severe pyrithiamine-induced TD (PTD); moderate PTD; moderate PTD during CET; and pair-fed controls. After the treatments, the rats were split into 3 recovery phase time points: the last day of treatment (time point 1), acute recovery (time point 2: 24 hours posttreatment), and delayed recovery (time point 3: 3 weeks posttreatment). At these time points, vulnerable brain regions (thalamus, hippocampus, frontal cortex) were collected and changes in neuroimmune markers were assessed using a combination of reverse transcription polymerase chain reaction and protein analysis. RESULTS: CET led to minor fluctuations in neuroimmune genes, regardless of the structure being examined. In contrast, PTD treatment led to a profound increase in neuroimmune genes and proteins within the thalamus. Cytokine changes in the thalamus ranged in magnitude from moderate (3-fold and 4-fold increase in interleukin-1ß [IL-1ß] and IκBα) to severe (8-fold and 26-fold increase in tumor necrosis factor-α and IL-6, respectively). Though a similar pattern was observed in the hippocampus and frontal cortex, overall fold increases were moderate relative to the thalamus. Importantly, neuroimmune gene induction varied significantly as a function of severity of TD, and most genes displayed a gradual recovery across time. CONCLUSIONS: These data suggest an overt brain inflammatory response by TD and a subtle change by CET alone. Also, the prominent role of TD in the immune-related signaling pathways leads to unique regional and temporal profiles of induction of neuroimmune genes.