Ameliorative effects of thiamin on learning behavior and memory dysfunction in a rat model of hypothyroidism: implication of oxidative stress and acetylcholinesterase.

Hypothyroidism causes learning and memory impairment. Considering the neuroprotective properties of thiamine (Vitamin B1), this study was conducted to investigate the effects of thiamine on acetylcholinesterase (AChE) activity, oxidative damage, and memory deficits in hypothyroid rats.In this study, 50 rats (21 days old) were randomly divided into 5 groups and treated with propylthiouracil (0.05% in drinking water) and thiamine (50, 100, and 200 mg/kg, oral) for 7 weeks. Following that, Morris water maze (MWM) and passive avoidance (PA) tests were performed. Finally, oxidative stress indicators and AChE activity were measured in brain tissue.Treatment of hypothyroid rats with thiamine, especially at 100 and 200 mg/kg, alleviated the ability to remember the location of the platform as reflected by less time spent and distance to reach the platform, during the MWM test (P < 0.05 to P < 0.001). In the PA test, the latency to enter the dark chamber and light stay time were increased in rats who received thiamine compared to the hypothyroid group (P < 0.05 to P < 0.001). In addition, thiamine increased the levels of total thiol groups and superoxide dismutase while decreasing the levels of malondialdehyde and AChE.Our results suggest that thiamine supplementation could effectively improve memory loss in a rat model of hypothyroidism. The positive effects of thiamin on the learning and memory of hypothyroid rats may be due to amelioration of redox hemostasis and cholinergic disturbance.

Thiamine for the Treatment of Cardiac Arrest-Induced Neurological Injury: A Randomized, Blinded, Placebo-Controlled Experimental Study.

Background Thiamine supplementation has demonstrated protective effects in a mouse model of cardiac arrest. The aim of this study was to investigate the neuroprotective effects of thiamine in a clinically relevant large animal cardiac arrest model. The hypothesis was that thiamine reduces neurological injury evaluated by neuron-specific enolase levels. Methods and Results Pigs underwent myocardial infarction and subsequently 9 minutes of untreated cardiac arrest. Twenty minutes after successful resuscitation, the pigs were randomized to treatment with either thiamine or placebo. All pigs underwent 40 hours of intensive care and were awakened for assessment of functional neurological outcome up until 9 days after cardiac arrest. Nine pigs were included in both groups, with 8 in each group surviving the entire intensive care phase. Mean area under the curve for neuron-specific enolase was similar between groups, with 81.5 µg/L per hour (SD, 20.4) in the thiamine group and 80.5 µg/L per hour (SD, 18.3) in the placebo group, with an absolute difference of 1.0 (95% CI, -57.8 to 59.8; P=0.97). Likewise, there were no absolute difference in neurological deficit score at the end of the protocol (2 [95% CI, -38 to 42]; P=0.93). There was no absolute mean group difference in lactate during the intensive care period (1.1 mmol/L [95% CI, -0.5 to 2.7]; P=0.16). Conclusions In this randomized, blinded, placebo-controlled trial using a pig cardiac arrest model with myocardial infarction and long intensive care and observation for 9 days, thiamine showed no effect in changes to functional neurological outcome or serum levels of neuron-specific enolase. Thiamine treatment had no effect on lactate levels after successful resuscitation.

Protocatechuic Acid Prevents Some of the Memory-Related Behavioural and Neurotransmitter Changes in a Pyrithiamine-Induced Thiamine Deficiency Model of Wernicke-Korsakoff Syndrome in Rats.

The purpose of this research was to investigate the effects of protocatechuic acid (PCA) at doses of 50 and 100 mg/kg on the development of unfavourable changes in cognitive processes in a pyrithiamine-induced thiamine deficiency (PTD) model of the Wernicke-Korsakoff syndrome (WKS) in rats. The effects of PCA were assessed at the behavioural and biochemical levels. Behavioural analysis was conducted using the Foot Fault test (FF), Bar test, Open Field test, Novel Object Recognition test (NOR), Hole-Board test and Morris Water Maze test (MWM). Biochemical analysis consisting of determination of concentration and turnover of neurotransmitters in selected structures of the rat CNS was carried out using high-performance liquid chromatography. PTD caused catalepsy (Bar test) and significantly impaired motor functions, leading to increased ladder crossing time and multiplied errors due to foot misplacement (FF). Rats with experimentally induced WKS showed impaired consolidation and recall of spatial reference memory in the MWM test, while episodic memory related to object recognition in the NOR was unimpaired. Compared to the control group, rats with WKS showed reduced serotonin levels in the prefrontal cortex and changes in dopamine and/or norepinephrine metabolites in the prefrontal cortex, medulla oblongata and spinal cord. PTD was also found to affect alanine, serine, glutamate, and threonine levels in certain areas of the rat brain. PCA alleviated PTD-induced cataleptic symptoms in rats, also improving their performance in the Foot Fault test. In the MWM, PCA at 50 and 100 mg/kg b.w. improved memory consolidation and the ability to retrieve acquired information in rats, thereby preventing unfavourable changes caused by PTD. PCA at both tested doses was also shown to have a beneficial effect on normalising PTD-disrupted alanine and glutamate concentrations in the medulla oblongata. These findings demonstrate that certain cognitive deficits in spatial memory and abnormalities in neurotransmitter levels persist in rats that have experienced an acute episode of PTD, despite restoration of thiamine supply and long-term recovery. PCA supplementation largely had a preventive effect on the development of these deficits, to some extent also normalising neurotransmitter concentrations in the brain.

Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation.

The complexity of affected brain regions and cell types is a challenge for Huntington's disease (HD) treatment. Here we use single nucleus RNA sequencing to investigate molecular pathology in the cortex and striatum from R6/2 mice and human HD post-mortem tissue. We identify cell type-specific and -agnostic signatures suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) are arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 are negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells shows decreased accessibility regulated by OL maturation genes. The data implicates glucose and lipid metabolism in abnormal cell maturation and identify PRKCE and Thiamine Pyrophosphokinase 1 (TPK1) as central genes. Thiamine/biotin treatment of R6/1 HD mice to compensate for TPK1 dysregulation restores OL maturation and rescues neuronal pathology. Our insights into HD OL pathology spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.

Dietary thiamine modulates carbohydrate metabolism, antioxidant status, and alleviates hypoxia stress in oriental river prawn Macrobrachium nipponense (de Haan).

Hypoxia is one of the challenges in prawns aquaculture. However, the role of thiamine, which is a coenzyme in carbohydrate metabolism with antioxidant properties, in reducing hypoxia in prawns aquaculture is currently unknown. We investigated the effects of thiamine on antioxidant status, carbohydrate metabolism and acute hypoxia in oriental river prawn, Macrobrachium nipponense. One thousand eight hundred prawns (0.123 ± 0.003 g) were fed five diets (60 prawns each tank, six replicates per diet) supplemented with graded thiamine levels (5.69, 70.70, 133.67, 268.33 and 532.00 mg/kg dry mater) for eight weeks and then exposed to hypoxia stress for 12 h followed by reoxyegnation for 12 h. The results showed that, under normoxia, prawns fed the 133.67 or 268.33 mg/kg thiamine diet had significantly lower glucose 6-phosphatedehydrogenase, succinate dehydrogenase and phosphoenolpyruvate carboxykinase activities than those fed the other diets. Moreover, total antioxidant capacity (T-AOC) increased significantly when prawns were fed the 133.67 mg/kg thiamine diet. Superoxide dismutase (SOD) activity and malonaldehyde (MDA) content also increased significantly when prawns were fed the 268.33 or 532.00 mg/kg thiamine diet under hypoxia. And the significantly increased SOD activity and MDA level also observed in prawns fed 532.00 mg/kg thiamine under reoxygenation. Under normoxia, prawns fed the 70.70 or 133.67 mg/kg thiamine diet decreased the mRNA expressions of AMP-activated protein kinase-alpha (AMPK-α), pyruvate dehydrogenase-E1-α subunit (PDH-E1-α) and hypoxia-inducible factor-1s (HIF-1α, HIF-1ß), but increased the mRNA expressions of phosphofructokinase (PFK) significantly. After 12 h of hypoxia, the energy metabolism related genes (AMPK-ß, AMPK-γ, PFK, PDH-E1-α), hypoxia-inducible factor related genes (HIF-1α, HIF-1ß) and thiamine transporter gene (SLC19A2) were up-regulated significantly in prawns fed the 133.67 or 268.33 mg/kg thiamine diets. After 12 h of reoxygenation, prawns fed the 133.67 or 268.33 mg/kg diet significantly decreased the SOD activity, MDA level and SLC19A2 mRNA expression compared with other diets. The optimum thiamine was 161.20 mg/kg for minimum MDA content and 143.17 mg/kg for maximum T-AOC activity based on cubic regression analysis. In summary, supplementing 143.17 to 161.20 mg/kg thiamine in the diets for M. nipponense improves the antioxidant capacity under normoxia and reduces the oxidative damage under hypoxia stress.

Benfotiamine protects against hypothalamic dysfunction in a STZ-induced model of neurodegeneration in rats.

The neurodegeneration of Alzheimer's disease (AD) affects not only brain structures associate with cognition early in the progression of the disease, but other areas such as the hypothalamus, a region involved in the control of metabolism and appetite. In this context, we evaluated the effects of benfotiamine (BFT), a vitamin B1 analog that is being proposed as a therapeutical approach for AD-related cognitive alterations, which were induced by intracerebroventricular injection of streptozotocin (STZ). In addition to the already described effect of STZ on cognition, we show that this drug also causes metabolic changes which are linked to changes in hypothalamic insulin signaling and orexigenic and anorexigenic circuitries, as well as a decreased cellular integrated stress response. As expected, the supplementation with 150 mg/kg of BFT for 30 days increased blood concentrations of thiamine and its phosphate esters. This led to the prevention of body weight and fat loss in STZ-ICV-treated animals. In addition, we also found an improvement in food consumption, despite hypothalamic gene expression linked to anorexia after STZ exposure. Additionally, decreased apoptosis signaling was observed in the hypothalamus. In in vitro experiments, we noticed a high ability of BFT to increase insulin sensitivity in hypothalamic neurons. Furthermore, we also observed that BFT decreases the mitochondrial unfolded stress response damage by preventing the loss of HSP60 and reversed the mitochondria dysfunction caused by STZ. Taken together, these results suggest that benfotiamine treatment is a potential therapeutic approach in the treatment of hypothalamic dysfunction and metabolic disturbances associated with sporadic AD.

Therapeutic potential of vitamin B1 derivative benfotiamine from diabetes to COVID-19.

Benfotiamine (S-benzoylthiamine-O-monophosphate), a unique, lipid-soluble derivative of thiamine, is the most potent allithiamine found in roasted garlic, as well as in other herbs of the genus Allium. In addition to potent antioxidative properties, benfotiamine has also been shown to be a strong anti-inflammatory agent with therapeutic significance to several pathological complications. Specifically, over the past decade or so, benfotiamine has been shown to prevent not only various secondary diabetic complications but also several inflammatory complications such as uveitis and endotoxemia. Recent studies also demonstrate that this compound could be used to prevent the symptoms associated with various infectious diseases such as HIV and COVID-19. In this review article, the authors discuss the significance of benfotiamine in the prevention of various pathological complications.

Anti-inflammatory and antioxidative effects of thiamin supplements in patients with gestational diabetes mellitus.

OBJECTIVE: The aim of this study was to evaluate the effects of thiamin supplementation on biomarkers of inflammation and oxidative stress in patients with gestational diabetes mellitus (GDM). METHODS: This randomized, double-blind, placebo-controlled trial was conducted among 60 patients with GDM. Patients were randomly allocated into two groups to receive either 100 mg/day thiamin supplements (n = 30) or placebo (n = 30) for 6 weeks. RESULTS: Thiamin supplementation significantly decreased serum high-sensitivity C-reactive protein (hs-CRP) (ß - 0.98 mg/L; 95% CI, -1.54, -0.42; p = .001) and plasma malondialdehyde (MDA) levels (ß - 0.86 µmol/L; 95% CI, -1.15, -0.57; p < .001) when compared with the placebo. In addition, thiamin supplementation downregulated gene expression of tumor necrosis factor-alpha (TNF-α) (p = .002) in peripheral blood mononuclear cells of patients with GDM. Thiamin supplementation did not affect other biomarkers of inflammation and oxidative stress. CONCLUSION: Overall, thiamin supplementation for 6 weeks to patients with GDM significantly reduced hs-CRP and MDA levels, and gene expression of TNF-α, but did not affect other biomarkers of inflammation and oxidative stress. CLINICAL TRIAL REGISTRATION NUMBER: Clinical Trials.govIdentifier no. http://www.irct.ir: IRCT20170513033941N58.

Interactions between dietary carbohydrate and thiamine: implications on the growth performance and intestinal mitochondrial biogenesis and function of Megalobrama amblycephala.

A12-week experiment was conducted to evaluate the influences of thiamine ongrowth performance, and intestinal mitochondrial biogenesis and function of Megalobramaamblycephala fed a high-carbohydrate (HC) diet. Fish (24·73 (sem 0·45) g) were randomly assigned to one of four diets: two carbohydrate (CHO) levels (30 and 45 %) and two thiamine levels (0 and 1·5 mg/kg). HC diets significantly decreased DGC, GRMBW, FIMBW, intestinal activities of amylase, lipase, Na+, K+-ATPase, CK, complexes I, III and IV, intestinal ML, number of mitochondrial per field, ΔΨm, the P-AMPK: T-AMPK ratio, PGC-1ß protein expression as well as the transcriptions of AMPKα1, AMPKα2, PGC-1ß, mitochondrial transcription factor A, Opa-1, ND-1 and COX-1 and 2, while the opposite was true for ATP, AMP and reactive oxygen species, and the transcriptions of dynamin-related protein-1, fission-1 and mitochondrial fission factor. Dietarythiamine concentrations significantly increased DGC, GRMBW, intestinal activities of amylase, Na+, K+-ATPase, CK, complexes I and IV, intestinal ML, number of mitochondrial per field, ΔΨm, the P-AMPK:T-AMPK ratio, PGC-1ß protein expression as well as the transcriptions of AMPKα1, AMPKα2, PGC-1ß, Opa-1, ND-1, COX-1 and 2, SGLT-1 and GLUT-2. Furthermore, a significant interaction between dietary CHO and thiamine was observed in DGC, GRMBW, intestinal activities of amylase, CK, complexes I and IV, ΔΨm, the AMP:ATP ratio, the P-AMPK:T-AMPK ratio, PGC-1ß protein expression as well as the transcriptions of AMPKα1, AMPKα2, PGC-1ß, Opa-1, COX-1 and 2, SGLT-1 and GLUT-2. Overall, thiamine supplementation improved growth performance, and intestinal mitochondrial biogenesis and function of M. amblycephala fed HC diets.

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.

B Vitamins Supplementation Can Improve Cognitive Functions and May Relate to the Enhancement of Transketolase Activity in A Rat Model of Cognitive Impairment Associated with High-fat Diets.

OBJECTIVE: To determine whether B vitamin treatment was sufficient to reduce cognitive impairment associated with high-fat diets in rats and to modulate transketolase (TK) expression and activity. METHODS: To test this, we separated 50 rats into five groups that were either fed a standard chow diet (controls) or a high-fat diet (experimental groups H0, H1, H2, and H3). H0 group animals received no additional dietary supplementation, while H1 group animals were administered 100 mg/kg body weight (BW) thiamine, 100 mg/kg BW riboflavin, and 250 mg/kg BW niacin each day, and group H2 animals received daily doses of 100 mg/kg BW pyridoxine, 100 mg/kg BW cobalamin, and 5 mg/kg BW folate. Animals in the H3 group received the B vitamin regimens administered to both H1 and H2 each day. RESULTS: Over time, group H0 exhibited greater increases in BW and fat mass relative to other groups. When spatial and memory capabilities in these animals were evaluated via conditioned taste aversion (CTA) and Morris Water Maze (MWM), we found B vitamin treatment was associated with significant improvements relative to untreated H0 controls. Similarly, B vitamin supplementation was associated with elevated TK expression in erythrocytes and hypothalamus of treated animals relative to those in H0 (P<0.05). CONCLUSION: Together, these findings suggest B vitamin can modulate hypothalamic TK activity to reduce the severity of cognitive deficits in a rat model of obesity. As such, B vitamin supplementation may be a beneficial method for reducing cognitive dysfunction in clinical settings associated with high-fat diets.

Role of pyruvate in maintaining cell viability and energy production under high-glucose conditions.

Pyruvate functions as a key molecule in energy production and as an antioxidant. The efficacy of pyruvate supplementation in diabetic retinopathy and nephropathy has been shown in animal models; however, its significance in the functional maintenance of neurons and Schwann cells under diabetic conditions remains unknown. We observed rapid and extensive cell death under high-glucose (> 10 mM) and pyruvate-starved conditions. Exposure of Schwann cells to these conditions led to a significant decrease in glycolytic flux, mitochondrial respiration and ATP production, accompanied by enhanced collateral glycolysis pathways (e.g., polyol pathway). Cell death could be prevented by supplementation with 2-oxoglutarate (a TCA cycle intermediate), benfotiamine (the vitamin B1 derivative that suppresses the collateral pathways), or the poly (ADP-ribose) polymerase (PARP) inhibitor, rucaparib. Our findings suggest that exogenous pyruvate plays a pivotal role in maintaining glycolysis-TCA cycle flux and ATP production under high-glucose conditions by suppressing PARP activity.

Multilevel Approach for the Treatment of Giardiasis by Targeting Arginine Deiminase.

Giardiasis represents a latent problem in public health due to the exceptionally pathogenic strategies of the parasite Giardia lamblia for evading the human immune system. Strains resistant to first-line drugs are also a challenge. Therefore, new antigiardial therapies are urgently needed. Here, we tested giardial arginine deiminase (GlADI) as a target against giardiasis. GlADI belongs to an essential pathway in Giardia for the synthesis of ATP, which is absent in humans. In silico docking with six thiol-reactive compounds was performed; four of which are approved drugs for humans. Recombinant GlADI was used in enzyme inhibition assays, and computational in silico predictions and spectroscopic studies were applied to follow the enzyme's structural disturbance and identify possible effective drugs. Inhibition by modification of cysteines was corroborated using Ellman's method. The efficacy of these drugs on parasite viability was assayed on Giardia trophozoites, along with the inhibition of the endogenous GlADI. The most potent drug against GlADI was assayed on Giardia encystment. The tested drugs inhibited the recombinant GlADI by modifying its cysteines and, potentially, by altering its 3D structure. Only rabeprazole and omeprazole decreased trophozoite survival by inhibiting endogenous GlADI, while rabeprazole also decreased the Giardia encystment rate. These findings demonstrate the potential of GlADI as a target against giardiasis.

Ex Vivo Evaluation of the Sepsis Triple Therapy High-Dose Vitamin C in Combination with Vitamin B1 and Hydrocortisone in a Human Peripheral Blood Mononuclear Cells (PBMCs) Model.

Sepsis is an extremely complex clinical syndrome, usually involving an excessive inflammatory response including an overshooting cytokine release that damages tissue and organs of the patient. Due to the severity of this condition, it is estimated that over 11 million people die from sepsis each year. Despite intensive research in the field, there is still no specific therapy for sepsis. Many sepsis patients show a marked deficiency of vitamin C. 9 out of 10 sepsis patients have a hypovitaminosis C, and every third patient even shows a clinical deficiency in the scurvy range. In addition, low vitamin C levels of intensive care sepsis patients correlate with a higher need for vasopressors, higher Sequential Organ Failure Assessment (SOFA) scores, and increased mortality. Based on this observation and the conducted clinical trials using vitamin C as sepsis therapy in intensive care patients, the aim of the present ex vivo study was to evaluate the effects of high-dose vitamin C alone and in a triple combination supplemented with vitamin B1 (thiamine) and hydrocortisone on the lipopolysaccharide (LPS)-induced cytokine response in peripheral blood mononuclear cells (PBMCs) from healthy human donors. We found that all corticosteroid combinations strongly reduced the cytokine response on RNA- and protein levels, while high-dose vitamin C alone significantly diminished the PBMC mediated secretion of the cytokines interleukin (IL)-10, IL-23, and monocyte chemo-attractant protein (MCP-1), which mediate the inflammatory response. However, vitamin C showed no enhancing effect on the secretion of further cytokines studied. This data provides important insights into the possible immunomodulatory function of vitamin C in an ex vivo setting of human PBMCs and the modulation of their cytokine profile in the context of sepsis. Since vitamin C is a vital micronutrient, the restoration of physiologically adequate concentrations should be integrated into routine sepsis therapy, and the therapeutic effects of supraphysiological concentrations of vitamin C in sepsis patients should be further investigated in clinical trials.

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.

The modulator action of thiamine against pentylenetetrazole-induced seizures, apoptosis, nitric oxide, and oxidative stress in rats and SH-SY5Y neuronal cell line.

Accumulating evidences indicate that thiamine plays a vital role in the nervous system. However, questions exist as to how it causes epilepsy, neuronal damage, and antiepileptic mechanisms. The study looked at how the thiamine supplement impacted pentylenetetrazole (PTZ)-induced seizures in rats and pentylenetetrazole-induced neurotoxicity in the SH-SY5Y cell line. We used twenty-four male rats and they were randomly divided into 4 groups as control, saline (1 mL/kg/day serum physiologic) + PTZ, thiamine (50 mg/kg/day) + PTZ, and thiamine (50 mg/kg/day) for 10 days. PTZ (45 mg/kg) was given to activate the seizure on day 10. Memory efficiency was measured by using passive avoidance. The brain levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), caspase-3, nitric oxide (NO), and cyclic guanosine monophosphate (cGMP) were analyzed by using ELISA kits. SH-SY5Y cells were treated with/without thiamine for 1 h, followed by PTZ (30 µm) at a medium level to trigger neurotoxicity. Cell viability, total antioxidant status, total oxidant status, and apoptosis were assayed in the SH-SY5Y cells. Thiamine delayed the initiation of epileptic seizures and increased memory damage. In addition, 8-OHdG, caspase-3, NO, and cGMP levels were significantly reduced in the brain and prevented pentylenetetrazole-induced neurotoxicity, apoptosis, enhanced antioxidant, and reduced oxidant in SH-SY5Y cells. Thiamine dramatically altered seizures, memory loss, oxidative stress, and apoptosis. Thiamine has a preventative effect on PTZ-induced seizures in rats and PTZ-induced neurotoxicity in SH-SY5Y neuroblastoma cells. It could prevent oxidative stress and signaling of NO/cGMP. Thiamine supplement could be used as an additional therapeutic agent in epilepsy.

Thiamine Treatment and Favorable Outcome in an Infant with Biallelic TPK1 Variants.

Episodic encephalopathy due to mutations in the thiamine pyrophosphokinase 1 (TPK1) gene is a rare autosomal recessive metabolic disorder. Patients reported so far have onset in early childhood of acute encephalopathic episodes, which result in a progressive neurologic dysfunction including ataxia, dystonia, and spasticity. Here, we report the case of an infant with TPK1 deficiency (compound heterozygosity for two previously described pathogenic variants) presenting with two encephalopathic episodes and clinical stabilization under oral thiamine and biotin supplementation. In contrast to other reported cases, our patient showed an almost normal psychomotor development, which might be due to an early diagnosis and subsequent therapy.

Thiamine Pyrophosphokinase Deficiency due to Mutations in the TPK1 Gene: A Rare, Treatable Neurodegenerative Disorder.

TPK deficiency due to TPK1 mutations is a rare neurodegenerative disorder, also known as thiamine metabolism dysfunction syndrome 5 (OMIM no.: 614458). Here, we report a new patient with compound heterozygous TPK1 mutations, of which one has not been described so far. The individual reported here suffered from acute onset encephalopathy, ataxia, muscle hypotonia, and regression of developmental milestones in early infancy, repeatedly triggered by febrile infections. Initiation of high-dose thiamine and magnesium supplementation led to a marked and sustained improvement of alertness, ataxia, and muscle tone within days. Contrary to the described natural history of patients with TPK deficiency, the disease course was favorable under thiamine treatment without deterioration or developmental regression during the follow-up period. TPK deficiency is a severe neurodegenerative disease. This case report demonstrates that this condition is potentially treatable. High-dose thiamine treatment should therefore be initiated immediately after diagnosis or even upon suspicion.

Oral benfotiamine reverts cognitive deficit and increase thiamine diphosphate levels in the brain of a rat model of neurodegeneration.

It is well known that patients with Alzheimer's disease (AD) have imbalances in blood thiamine concentrations and lower activity of thiamine-dependent enzymes. Benfotiamine, a more bioavailable thiamine analog, has been proposed as an alternative to counteract these changes related to thiamine metabolism. Thus, our study aimed to analyze the effects of benfotiamine supplementation on brain thiamine absorption, as well as on parameters related to neuronal energy metabolism and disease progression in an experimental model of sporadic AD induced by intracerebroventricular injection of streptozotocin (STZ) in rats. The supplementation with 150 mg/kg of benfotiamine for 30 days increased the concentrations of thiamine diphosphate in the hippocampus and entorhinal cortex. This led to an improvement in mitochondria enzymes and insulin signaling pathway, with inactivation of GSK3α/ß and ERK1/2, which are two tau-kinases related to the progression of AD, which could decrease tau hyperphosphorylation and apoptosis signaling. Besides, we observed an increased amount of Glun2b subunit of NMDA receptors, decreased inflammation, and improvement of cognitive deficit. Together, these results suggest that benfotiamine could be a potential therapeutic approach in the treatment of sporadic AD.

Allithiamine Alleviates Hyperglycaemia-Induced Endothelial Dysfunction.

Diabetes mellitus-related morbidity and mortality is a rapidly growing healthcare problem, globally. Several nutraceuticals exhibit potency to target the pathogenesis of diabetes mellitus. The antidiabetic effects of compounds of garlic have been extensively studied, however, limited data are available on the biological effects of a certain garlic component, allithiamine. In this study, allithiamine was tested using human umbilical cord vein endothelial cells (HUVECs) as a hyperglycaemic model. HUVECs were isolated by enzymatic digestion and characterized by flow cytometric analysis using antibodies against specific marker proteins including CD31, CD45, CD54, and CD106. The non-cytotoxic concentration of allithiamine was determined based on MTT, apoptosis, and necrosis assays. Subsequently, cells were divided into three groups: incubating with M199 medium as the control; or with 30 mMol/L glucose; or with 30 mMol/L glucose plus allithiamine. The effect of allithiamine on the levels of advanced glycation end-products (AGEs), activation of NF-κB, release of pro-inflammatory cytokines including IL-6, IL-8, and TNF-α, and H2O2-induced oxidative stress was investigated. We found that in the hyperglycaemia-induced increase in the level of AGEs, pro-inflammatory changes were significantly suppressed by allithiamine. However, allithiamine could not enhance the activity of transketolase, but it exerts a potent antioxidant effect. Collectively, our data suggest that allithiamine could alleviate the hyperglycaemia-induced endothelial dysfunction due to its potent antioxidant and anti-inflammatory effect by a mechanism unrelated to the transketolase activity.