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.

Furosemide-related thiamine deficiency in hospitalized hypervolemic patients with renal failure and heart failure.

BACKGROUND: We aimed to describe the thiamine status in hospitalized hypervolemic heart failure (HF) and/or renal failure (RF) patients treated with furosemide and to investigate whether there was a difference in furosemide-related thiamine deficiency between patients with RF and HF. METHODS: Patients who were diagnosed as hypervolemia and treated with intravenous furosemide (at least 40mg/day) were included in this prospective observational study. Whole blood thiamine concentrations were measured 3 times during hospital follow-up of patients. RESULTS: We evaluated 61 hospitalized hypervolemic patients, of which 22 (36%) were men and 39 (64%) were women, with a mean age of 69.00±10.39 (45-90) years. The baseline and post-hospital admission days 2 and 4 mean thiamine levels were 51.71±20.66ng/ml, 47.64±15.43ng/ml and 43.78±16.20ng/ml, respectively. Thiamine levels of the hypervolemic patients decreased significantly during the hospital stay while furosemide treatment was continuing (p=0.029). There was a significant decrease in thiamine levels in patients who had HF (p=0.026) and also, thiamine was significantly lower in HF patients who had previously used oral furosemide before hospitalization. However, these findings were not present in patients with RF. CONCLUSIONS: Thiamine substantially decreases in most hypervolemic patients receiving intravenous furosemide treatment during the hospital stay. Thiamine levels were significantly decreased with furosemide treatment in especially HF patients, but the decrease in thiamine levels did not detected at the same rate in RF patients. Diuretic-induced thiamine loss may be less likely in RF patients, probably due to a reduction in excretion.

Cardiac Dysfunction Due to Thiamine Deficiency after Hemodialysis for Biguanide-related Lactic Acidosis.

Biguanide is an ideal drug for the treatment of type 2 diabetes mellitus. When used appropriately, the incidence of lactic acidosis is reported to be very low. Risk factors associated with biguanide-related lactic acidosis include chronic kidney disease, congestive heart failure, alcohol use, severe dehydration, shock, hypoxic states, sepsis, and advanced age. We herein report a case of cardiac dysfunction due to thiamine deficiency after hemodialysis in a patient with suspected biguanide-related lactic acidosis. Patients who develop severe lactic acidosis while taking biguanides should be given a large dose of thiamine without delay, given the possibility of thiamine deficiency as a complication.

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.

The Effects of Genetic Mutations and Drugs on the Activity of the Thiamine Transporter, SLC19A2.

A rare cause of megaloblastic anemia (MA) is thiamine-responsive megaloblastic anemia (TRMA), a genetic disorder caused by mutations in SLC19A2 (encoding THTR1), a thiamine transporter. The study objectives were to (1) functionally characterize selected TRMA-associated SLC19A2 variants and (2) determine whether current prescription drugs associated with drug-induced MA (DIMA) may act via inhibition of SLC19A2. Functional characterization of selected SLC19A2 variants was performed by confocal microscopy and isotopic uptake studies of [3H]-thiamine in HEK293 cells. Sixty-three drugs associated with DIMA were screened for SLC19A2 inhibition in isotopic uptake studies. Three previously uncharacterized SLC19A2 variants identified in TRMA patients exhibited disrupted localization to the plasma membrane along with near-complete loss-of-function. Ten of 63 drugs inhibited SLC19A2-mediated thiamine transport ≥ 50% at screening concentrations; however, with the exception of erythromycin, none was predicted to inhibit SLC19A2 at clinically relevant unbound plasma concentrations. Data from electronic health records revealed reduced levels of thiamine pyrophosphate (TPP) in patients prescribed erythromycin, consistent with inhibition of SLC19A2-mediated thiamine transport. Here, we confirmed the role of three SLC19A2 variants in TRMA pathology. Additionally, we report that inhibition of SLC19A2 is a potential, but uncommon mechanism for DIMA.

Hyperemesis-induced Wernicke-Korsakoff Syndrome due to Hypergastrinemia during Long-term Treatment with Proton Pump Inhibitors.

We herein report a patient with Wernicke-Korsakoff syndrome (WKS) who had neither a history of alcoholism or of history of gastric surgery. A 56-year-old woman was transferred to our hospital because of the loss of consciousness and she was diagnosed to have Wernicke encephalopathy. She showed proton pump inhibitor-induced refractory hypergastrinemia with the subsequent development of hyperemesis and a vitamin B1 deficiency.

Thiamine Deficiency Modulates p38MAPK and Heme Oxygenase-1 in Mouse Brain: Association with Early Tissue and Behavioral Changes.

Thiamine deficiency (TD) produces severe neurodegenerative lesions. Studies have suggested that primary neurodegenerative events are associated with both oxidative stress and inflammation. Very little is known about the downstream effects on intracellular signaling pathways involved in neuronal death. The primary aim of this work was to evaluate the modulation of p38MAPK and the expression of heme oxygenase 1 (HO-1) in the central nervous system (CNS). Behavioral, metabolic, and morphological parameters were assessed. Mice were separated into six groups: control (Cont), TD with pyrithiamine (Ptd), TD with pyrithiamine and Trolox (Ptd + Tr), TD with pyrithiamine and dimethyl sulfoxide (Ptd + Dmso), Trolox (Tr) and DMSO (Dmso) control groups and treated for 9 days. Control groups received standard feed (AIN-93M), while TD groups received thiamine deficient feed (AIN-93DT). All the groups were subjected to behavioral tests, and CNS samples were collected for cell viability, histopathology and western blot analyses. The Ptd group showed a reduction in weight gain and feed intake, as well as a reduction in locomotor, grooming, and motor coordination activities. Also, Ptd group showed a robust increase in p38MAPK phosphorylation and mild HO-1 expression in the cerebral cortex and thalamus. The Ptd group showed a decreased cell viability, hemorrhage, spongiosis, and astrocytic swelling in the thalamus. Groups treated with Trolox and DMSO displayed diminished p38MAPK phosphorylation in both the structures, as well as attenuated thalamic lesions and behavioral activities. These data suggest that p38MAPK and HO-1 are involved in the TD-induced neurodegeneration in vivo, possibly modulated by oxidative stress and neuroinflammation.

Thiamine deficiency and oxidative stress induced by prolonged metronidazole therapy can explain its side effects of neurotoxicity and infertility in experimental animals: Effect of grapefruit co-therapy.

We aimed to explore the possible neurotoxicity and infertility mechanisms of prolonged metronidazole (MTZ) use and the effects of antioxidant grapefruit (GP) co-therapy on MTZ-induced complications. Sixty male albino Wistar rats were divided into four groups (n = 15 each). Group I (control group) received 1% dimethyl sulfoxide (27 ml/ kg/day), group II (MTZ group) received MTZ (400 mg/kg/day), group III (MTZ + GP) received MTZ (400 mg/kg/ day) plus GP juice (27 ml/kg/ day) and group IV (GP group) received GP juice (27 ml/kg) for 60 days. Semen analyses were performed. Free testosterone, gonadotrophin (follicle-stimulating hormone (FSH) and luteinizing hormone) and thiamine levels were measured. Samples of cerebellar, testicular and epididymal tissues were used for both colorimetric assays of oxidative stress markers and histopathological examinations. Significant decreases in the sperm count, percent total sperm motility, serum thiamine levels, free testosterone levels and FSH levels were observed in the MTZ and MTZ + GP groups (p < 0.05 for all parameters). Significantly higher oxidative stress levels (p < 0.05) were observed in the cerebellar and testicular tissue homogenates of these groups than in those of the control group, and associated disruptions in the cerebellar, testicular and epididymal structures were apparent compared to those of the control group. Although the GP group showed a significantly higher sperm count and significantly lower oxidative stress than the control group (p < 0.05), with histological similarity to the control group, the GP group exhibited significantly higher prolactin levels and lower free testosterone and FSH levels than the control group (p < 0.05). Oxidative stress and decreased thiamine levels could explain the MTZ-induced neurotoxicity and infertility side effects that aggravated by GP co-administration.

Early recognition of thiamine deficiency: ocular motor deficits in a patient with nutritional deprivation due to persistent antibiotic-related nausea.

CASE DESCRIPTION: A 73-year-old male presented with new onset dizziness and a 22-kg weight loss due to antibiotic-induced nausea/vomiting. Due to gaze-evoked nystagmus (GEN), thiamine deficiency was suspected. Within 12 h after replacement, his GEN decreased. CONCLUSION: In patients with nutritional deprivation, new onset GEN should prompt further diagnostics and immediate thiamine supplementation to avoid disease progression.

Thiamin Status in Adults Receiving Chronic Diuretic Therapy Prior to Admission to a Medical Intensive Care Unit: A Pilot Study.

BACKGROUND: The aim of the study was to determine serum thiamin concentrations in critically ill medical patients who required chronic diuretic drug treatment before admission to a medical intensive care unit (ICU). METHODS: This prospective study was performed in a medical ICU. Subjects who received diuretic drug therapy for at least 6 months prior to ICU admission constituted the diuretic group. The control group was clinically matched adults admitted to the same ICU but without a history of diuretic therapy. RESULTS: A total of 50 subjects were included (25 subjects in each of the diuretic and control groups). In the diuretic group, daily dose of furosemide prior to admission was 40 mg/d (range of 20-160 mg/d). In all subjects, the ICU admission baseline blood thiamin concentrations were 31.2 ± 27.1 ng/mL. In the diuretic group, the baseline whole blood thiamin level was significantly lower compared with levels in the control group (15.5 ± 10.7 vs 46.8 ± 29.5 ng/mL; P < 0.001). On day 2 after entry, thiamin levels remained low (23.2 ± 15.4 ng/mL in the diuretic group vs 49 ± 38 ng/mL in the control group; P = 0.003). Low thiamin levels were found in 96% of patients at baseline and in 72% of patients on the second day in the diuretic group. CONCLUSION: Adults receiving chronic diuretic therapy and then requiring medical ICU care commonly exhibit thiamin depletion on admission to the ICU and during the initial days of ICU care.

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.

Telomere shortening in alcohol dependence: Roles of alcohol and acetaldehyde.

Heavy drinking leads to premature aging and precipitates the onset of age-related diseases. Acetaldehyde (AcH), a toxic metabolite of ethanol, has been implicated in various types of cancer. However, whether alcohol accelerates biological aging at a cellular level is controversial and the mechanism involved is unclear. We addressed these questions by measuring telomere length (TL) in peripheral blood leukocytes of Japanese patients with alcohol dependence (AD) and examined the association between TL, genetic variants of alcohol dehydrogenase (ADH)1B and aldehyde dehydrogenase (ALDH)2, and other clinical characteristics. A total of 134 male AD patients and 121 age- and sex-matched healthy controls were evaluated. All patients received endoscopic screening for cancer of the upper aerodigestive tract (UADT). TL was almost 50% shorter in AD patients relative to controls. There were no significant differences in TL between AD patients with and without UADT cancer, and no associations between ADH1B and ALDH2 genotypes and TL. AD patients with thiamine (vitamin B1) deficiency at admission had significantly shorter TL than those with normal thiamine status. Although the exact mechanism underlying the shorter TL in AD patients remain unclear, our findings suggest that alcohol rather than AcH is associated with telomere shortening in AD, which may be accelerated by thiamine deficiency. Future studies should also focus on the association between telomere shortening and TD in the context of oxidative stress.

Microglial activation and vascular responses that are associated with early thalamic neurodegeneration resulting from thiamine deficiency.

Thiamine/vitamin B1 deficiency can lead to behavioral changes and neurotoxicity in humans. This may due in part to vascular damage, neuroinflammation and neuronal degeneration in the diencephalon, which is seen in animal models of pyrithiamine-enhanced thiamine deficiency. However, the time course of the progression of these changes in the animal models has been poorly characterized. Therefore, in this study, the progression of: 1) activated microglial association with vasculature; 2) neurodegeneration; and 3) any vascular leakage in the forebrain during the progress of thiamine deficiency were determined. A thiamine deficient diet along with 0.25 mg/kg/d of pyrithiamine was used as the mouse model. Vasculature was identified with Cd31 and microglia with Cd11b and Iba1 immunoreactivity. Neurodegeneration was determined by FJc labeling. The first sign of activated microglia within the thalamic nuclei were detected after 8 d of thiamine deficiency, and by 9 d activated microglia associated primarily with vasculature were clearly present but only in thalamus. At the 8 d time point neurodegeneration was not present in thalamus. However at 9 d, the first signs of neurodegeneration (FJc + neurons) were seen in most animals. Over 80% of the microglia were activated at 10 d but almost exclusively in the thalamus and the number of degenerating neurons was less than 10% of the activated microglia. At 10 d, there were sporadic minor changes in IgG presence in thalamus indicating minor vascular leakage. Dizocilpine (0.2-0.4 mg/kg) or phenobarbital (10-20 mg/kg) was administered to groups of mice from day 8 through day 10 to block neurodegeneration but neither did. In summary, activated microglia start to surround vasculature 1-2 d prior to the start of neurodegeneration. This response may be a means of controlling or repairing vascular damage and leakage. Glutamate excitotoxicity and vascular leakage likely only play a minor role in the early neurodegeneration resulting from thiamine deficiency. However, failure of dysfunctional vasculature endothelium to supply sufficient nutrients to neurons could be contributing to the neurodegeneration.

The Dramatic Recovery of a Patient with Biguanide-associated Severe Lactic Acidosis Following Thiamine Supplementation.

Biguanides are a drug of choice for the treatment of type 2 diabetes mellitus. Although they can cause lactic acidosis in susceptible patients with predisposing risk factors, the incidence of lactic acidosis is reported to be very low when they are used properly. We herein present a case of biguanide-associated severe lactic acidosis complicated with thiamine deficiency that was provoked without predisposing factors for thiamine deficiency. Diabetic patients taking biguanide may be predisposed to thiamine deficiency, even when there is no evidence of risk factors, and the high-dose administration of thiamine may be essential in the treatment of this otherwise under-recognized disorder.

BDNF regains function in hippocampal long-term potentiation deficits caused by diencephalic damage.

Thiamine deficiency (TD), commonly associated with chronic alcoholism, leads to diencephalic damage, hippocampal dysfunction, and spatial learning and memory deficits. We show a decrease in the magnitude of long-term potentiation (LTP) and paired-pulse facilitation (PPF) at CA3-CA1 synapses, independent of sex, following diencephalic damage induced by TD in rats. Thus, despite a lack of extensive hippocampal cell loss, diencephalic brain damage down-regulates plastic processes within the hippocampus, likely contributing to impaired hippocampal-dependent behaviors. However, both measures of hippocampal plasticity (LTP, PPF) were restored with brain-derived neurotrophic factor (BDNF), revealing an avenue for neural and behavioral recovery following diencephalic damage.

Treatment of rats with the JAK-2 inhibitor fedratinib does not lead to experimental Wernicke's encephalopathy.

Recent clinical trials suggest that patients with myelofibrosis can develop Wernicke's encephalopathy (WE) when treated with fedratinib, a specific Janus kinase-2 (JAK-2) inhibitor. To investigate this issue, we have examined (1) if fedratinib can produce or alter the course of this disorder, (2) its effects on thiamine-dependent enzyme activity and thiamine status, and (3) its influence on the uptake of thiamine. Animals administered fedratinib for 28days at a comparable dose used to treat human cases of myelofibrosis showed no evidence of clinical signs of thiamine deficiency (TD). Rats treated with a combination of fedratinib and TD exhibited no neurological differences in their progress to the symptomatic stage when compared to thiamine-deficient animals only. Treatment with the JAK-2 inhibitor did not compromise erythrocyte transketolase activity, and thiamine status was not affected in a major way unlike animals with TD. In addition, treatment of cultured astrocytes with fedratinib did not diminish the uptake of thiamine into these cells. Our findings suggest that treatment with fedratinib does not lead to or alter the progress of TD, and do not support the notion that administration of this JAK-2 inhibitor directly results in the development of WE due to inhibition of thiamine transport. Known adverse effects of fedratinib involving compromised gastrointestinal function may be an important indirect contributing factor to previously reported cases of WE in patients with myelofibrosis.

Thiamine Levels During Intensive Insulin Therapy in Critically Ill Patients.

INTRODUCTION: Thiamine is an essential cofactor in carbohydrate metabolism, and deficiency can therefore cause various organ dysfunctions. Little is known about the prevalence and possible worsening of thiamine deficiency in critically ill patients. In this study, we investigated the prevalence of thiamine deficiency at admission to the intensive care unit (ICU) and hypothesized that intensive insulin therapy, aimed at regulating glucose levels, increases thiamine utilization and therefore might cause or worsen deficiency in patients with limited thiamine stores. MATERIALS AND METHODS: An observational prospective cohort study was carried out in a medical-surgical ICU in a general teaching hospital in Apeldoorn, the Netherlands. All adults who were treated during that time with intensive insulin therapy were included. Deficiency was defined as a thiamine level <100 nmol/L. No thiamine supplementation was administered except for normal amounts present in standard enteral feeding. RESULTS: A total of 58 patients were available for analysis. Median thiamine level at admission was 111 nmol/L. Deficiency was present in 39.7% of patients and was significantly associated with the presence of gastrointestinal pathology and with recent surgery. Thiamine levels increased a median of 14 nmol/L in 48 hours. Only 3.4% of patients showed a predefined relevant decline in thiamine levels. CONCLUSION: Intensive insulin therapy does not appear to cause or worsen thiamine deficiency. However, based on the high prevalence of deficiency at admission, it might be warranted to supplement thiamine in all patients admitted to the ICU, especially when there is an underlying gastrointestinal disease or recent surgery.

Brain endothelial dysfunction following pyrithiamine induced thiamine deficiency in the rat.

Prolonged vitamin B1 (thiamine) deficiency can lead to neurological disorders such as Wernicke's encephalopathy and Wernicke-Korsakoff Syndrome (WKS) in humans. These thiamine deficiency disorders have been attributed to vascular leakage, blood-brain barrier breakdown and neuronal loss in the diencephalon and brain stem. However, endothelial dysfunction following thiamine deficiency and its relationship to the phenomenon of neurodegeneration has not been clearly elucidated. The present study sought to begin to address this issue by evaluating vascular morphology and integrity in a pyrithiamine (PT)-induced rat model of thiamine deficiency. Adjacent brain sections were used to either assess vascular integrity through immunohistochemical localization of rat endothelial cell antigen (RECA-1) and endothelial brain barrier antigen (EBA-1) or neurodegeneration using the de Olmos cupric silver method. GFAP and CD11b immunolabeling was used to evaluate astrocytic and microglial/macrophagic changes. Extensive neurodegeneration occurred concomitant with both vascular damage (thinning and breakage) and microglial activation in the inferior olive, medial thalamic area, and medial geniculate nuclei of pyrithiamine treated rats. Likewise, glucose transporter-1 (Glut-1), which is mostly expressed in endothelial cells, was also severely decreased in this pyrithiamine induced thiamine deficient rat model. MRI scans of these animals prior to sacrifice show that the pyrithiamine induced thiamine deficient animals have abnormal T2 relaxation values, which are commensurate with, and possibly predictive of, the neurodegeneration and/or endothelial dysfunction subsequently observed histologically in these same animals.

Vitamin B1-deficient mice show impairment of hippocampus-dependent memory formation and loss of hippocampal neurons and dendritic spines: potential microendophenotypes of Wernicke-Korsakoff syndrome.

Patients with severe Wernicke-Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation.