Increased neuronal cell survival after L-deprenyl treatment in experimental thiamine deficiency

Experimental thiamine deficiency results in a reproducible pattern of selective neuronal cell death. Events such as blood-brain barrier breakdown, N-methyl-D-aspartic acid (NMDA) receptor-mediated excitotoxicity, and increased reactive oxygen species have been implicated in thiamine deficiency-induced neural loss. L-deprenyl protects dopaminergic, noradrenergic, and acetylcholinergic neurons from neurotoxic, mechanical, and excitotoxic damage. In the present study, the effects of l-deprenyl on neuronal cell survival were examined in rats made thiamine deficient by daily administration of the central thiamine antagonist pyrithiamine (0.5 mg/kg s.c.). Rats assigned to thiamine deficient or control groups received daily injections of l-deprenyl (0.25, 0.5, or 1.0 mg/kg/day i.p.) or vehicle until they reached a state of severe thiamine deficiency (loss of righting reflex). At this stage, thiamine status was restored by daily injections of thiamine (10 mg/kg s.c.) for 3 days, after which the animals were killed, and their brains were processed for neuronal cell counts (cresyl violet staining), astrocytic proliferation [glial fibrillary acidic protein (GFAP) immunohistochemistry], and monoamine oxidase B (MAO-B) activity. All rats receiving l-deprenyl (all doses) had significantly decreased neuronal cell loss in thalamic nuclei, in the inferior colliculus, and in the inferior olive and had a concomitant decrease in reactive astrocytic proliferation compared with the thiamine-deficient, vehicle-treated rats. The neuroprotective effects of l-deprenyl in thiamine deficiency induced brain damage most likely result from its properties other than its effects as an MAO-B inhibitor. J. Neurosci. Res. 52:240–246, 1998. © 1998 Wiley-Liss, Inc.     

非酒精性Wernicke脑病临床特征分析

目的 总结非酒精性Wernicke脑病的临床特点及诊断和治疗策略。方法 收集16例非酒精性Wernicke脑病患者，其中男7例，女9例，年龄28~77（56.3±15.2）岁。16例患者均无长期饮酒史、均存在硫胺素缺乏的病因，10例为胃肠道手术后，3例为恶性肿瘤化疗，1例为慢性结肠炎呕吐，1例为神经性厌食，1例为妊娠呕吐。总结16例患者临床表现、辅助检查资料、治疗及转归情况。结果 16例患者临床表现为有明确营养不良史14例，眼征12例，共济失调9例，精神障碍10例。有典型"三主征"的患者3例（18.8%）。8例出现颅MRI特征性表现。给予大剂量维生素B1治疗后症状完全缓解12例，部分缓解4例。结论 对可能存在硫胺素缺乏的患者需要高度警惕并发非酒精性Wernicke脑病，临床诊断不应局限于经典的"三主征"，尽早识别及足量应用维生素B1是治疗非酒精性Wernicke脑病的关键。     

Identification and characterization of the human and mouse SLC19A3 gene: a novel member of the reduced folate family of micronutrient transporter genes

We report here the isolation, characterization, and chromosomal localization of the genes encoding the human and corresponding murine orthologue of solute carrier family 19A member 3 (SLC19A3). Human SLC19A3 encodes a 496-amino-acid residue protein with a predicted molecular weight of 56 kDa that shares sequence similarity to both SLC19A1 (reduced folate transporter (RFC-1)) and SLC19A2 (high affinity thiamine transporter (THTR-1)). Like the SLC19A1 and SLC19A2 proteins, SLC19A3 contains 12 putative transmembrane domains. The human SLC19A3 gene is widely expressed, with the most abundant expression observed in placenta, kidney, and liver, and has been mapped to chromosome 2q37. The murine SLC19A3 gene maps to central chromosome 1 in the region defined as a seizure susceptibility locus in the DBA/2J mouse strain. This article describes the identification of SLC19A3, a gene encoding a novel solute transporter, and establishes murine SLC19A3 as a candidate gene for seizures in the DBA/2J mouse.     

维生素B_1对乙醇发育毒性的拮抗作用

目的:探讨维生素B1(VB1)对乙醇发育毒性的拮抗效果及可能机制。方法:以器官发生期小鼠体外全胚胎培养模型为基础,以4.0mg/ml乙醇诱导胚胎致畸模型,以0.25,0.5,1.0μg/mlVB1进行干预,通过对胚胎整体生长和各个器官发育指标的测量,评价VB1对乙醇发育毒性的拮抗效果。分离培养后的胚胎中脑细胞,检测细胞焦磷酸硫胺素(thiamine pyrophosphate,TPP)和硫胺素焦磷酸激酶(thiamine pyrophosphokinase,TPK)活性,分析VB1拮抗乙醇发育毒性的可能机制。结果:VB1对乙醇的发育毒性具有一定的拮抗作用,主要表现为卵黄囊、中枢神经系统和下颌突的发育改善。4.0mg/ml乙醇暴露能显著降低胚胎中脑组织TPP含量,而补充VB1能够逆转TPP含量的降低。在本次实验的剂量范围内,补充VB1对胚胎中脑组织TPK活性没有显著影响。结论:一定剂量的VB1在体外能够拮抗乙醇的发育毒性,增加细胞内TPP含量可能是其机制之一。     

Nervous tissue thiamine metabolism in vivo. II. Thiamine and its phosphoesters dynamics in different brain regions and sciatic nerve of the rat

Different steps of the metabolism of thiamine (T), thiamine mono- (TMP), pyro- (TPP) and triphosphate (TTP) in the cerebellum, brainstem, cerebral cortex and the sciatic nerve were evaluated in the rat in vivo. The radioactivity of T and its phosphoesters was determined at fixed time intervals (0.5–240 h) after an intraperitoneal injection of [¹⁴C]T (30μg:1.25 μCi), under steady state conditions. The dynamics of thiamine compounds was evaluated using a compartmental mathematical model that allowed the fractional rate constants (FRC), turnover rates (TR) and turnover times to be calculated. The phosphorylation of T to TPP and the dephosphorylations of TPP to TMP and TMP to T could be estimated in all the structures investigated. Their turnover rates were found to be ordered in the sequence: cerebellum > brainstem > cerebral cortex > sciatic nerve. The transphosphorylation of TPP to TTP was so small that it could not be determined in a reliable way. Regional differences were found both in the rate and in the composition of T and TMP mixture released from nervous structures. The shortest turnover time of TPP was found in the cerebellum, while the sciatic nerve exhibited the fastest renewal of T and TMP. In all the structures investigated TPP had a rather short turnover time, suggesting that its function might be associated to a rapid conversion into chemically different forms.The possible relationships between the rates of turnover of T compounds are the sensitivity of the nervous structures to T deficiency are discussed.     

A novel mutation in the SLC19A2 gene in a Tunisian family with thiamine-responsive megaloblastic anaemia, diabetes and deafness syndrome

Thiamine-responsive megaloblastic anaemia (TRMA) syndrome with diabetes and deafness was found in two patients from a Tunisian kindred. The proband was homozygous for a novel mutation, 287delG, in the high-affinity thiamine transporter gene, SLC19A2. We demonstrated that fibroblasts from this patient exhibited defective thiamine transport. These data confirm that the SLC19A2 gene is the high-affinity thiamine carrier and that this novel mutation is responsible for TRMA syndrome.     

Pericyte adhesion is impaired on extracellular matrix produced by endothelial cells in high hexose concentrations

Aims/hypothesis: Thickening of the basement membrane and selective loss of pericytes are early events in diabetic retinopathy. We aimed at checking whether pericyte interaction with extracellular matrix produced by endothelial cells is influenced by the hexose concentrations in which endothelial cells are cultured. Methods: Conditioned extracellular matrixes were obtained by growing human umbilical vein endothelial cells in media containing 28 mmol/l hexoses (d-glucose, d-galactose, l-glucose), which undergo different intracellular processing, before and after adding the inhibitors of protein glycation thiamine or aminoguanidine. Having removed the endothelium, bovine retinal pericytes were grown on such matrixes and, in separate experiments, on laminin, fibronectin or type IV collagen. Pericyte adhesion was determined by cell counts 18 h after seeding. Results: Reduced adhesion was observed on matrixes produced in high d-glucose, high d-galactose and high l-glucose. Both thiamine and aminoguanidine restored impaired pericyte adhesion when added to high d-glucose and high d-galactose, but not l-glucose. Laminin, fibronectin and type IV collagen did not consistently modify pericyte adhesion. Conclusions/interpretations: Pericyte adhesion is impaired on extracellular matrix produced by endothelium in high hexose concentrations. This could result from excess protein glycation, corrected by aminoguanidine and thiamine, rather than altered glycoprotein composition. [Diabetologia (2002) 45: 416–419] Received: 28 June 2001 and in revised form: 16 November 2001     

Thiamine-dependent enzyme changes in temporal cortex of patients with Alzheimer's disease

Activites of thiamine-dependent enzymes [pyruvate dehydrogenase (PDHC), -ketoglutarate dehydrogenase (KGDH), and transketolase (TK)] were measured in autopsied samples of temporal cortex from six patients with Alzheimer's disease and from eight age-matched control subjects who were free from neurological or psychiatric diseases. Times from death to freezing of dissected material at –70°C were matched. Significant decreases in PDHC (decreased by 70%;P<0.01), KGDH (decreased by 70%; p<0.01), and TK (decreased by 52%;P<0.01) were observed in brain tissue from patients with Alzheimer's disease. In contrast, activities of glutamate dehydrogenase were within normal limits. These findings suggest a possible role for alterations of brain thiamine metabolism or utilization in Alzheimer's disease     

Wernicke Encephalopathy Presenting with Dysphagia: A Case Report and Systematic Literature Review

Wernicke encephalopathy (WE) is a well-known neurological condition caused by thiamine (vitamin B1) deficiency that occurs in both alcoholic and non-alcoholic populations. We aimed to report a case of a patient with WE who presented with dysphagia and dysphonia and later developed typical symptoms of thiamine deficiency and to conduct a systematic review of the literature on this rare presentation of WE. We searched two databases (PubMed and Scopus) and included publications up to November 2022. We found 12 cases of WE and dysphagia, aged between 12 and 81 years; swallowing problems presented at the onset in nine patients (including the current case report). Our findings suggest that thiamine deficiency should be suspected in patients with dysphagia of unknown cause, even in the absence of alcohol abuse. In contrast to most WE patients, the majority of patients included in this review presented with dysphagia at the onset of their disease, even in the absence of the classic triad of cognitive impairment, ataxia, and oculomotor abnormalities, indicating that there could be varying susceptibilities to clinical manifestations of thiamine deficiency in different brain regions.