Disease relevance of 2-[1-[(4-amino-2-methyl-pyrimidin-5-yl)methyl]-6-methyl-pyridin-5-yl]ethanol

• After a week on a thiamine-free diet and daily injections of pyrithiamine hydrobromide, a group of rats began to lose weight; soon thereafter hypothermia, piloerection, and ataxia developed, followed by convulsions and death [1].
• To understand the chemical basis of thi-box pyrophosphate specificity, we have determined crystal structures of an E. coli thi-box bound to thiamine pyrophosphate, thiamine monophosphate, and the structural analogs benfotiamine and pyrithiamine [2].
• Thus, there are some reductions in ACh levels and utilization that are unique to pyrithiamin induced deficiency and as such are distinct from oxythiamin/undernutrition related reductions [3].
• Autoradiographic studies reveal that increased densities of binding sites for the astrocytic ligand 3H-PK11195 closely parallel the topographic distribution of reactive gliosis and neuronal loss in selective brain regions of pyrithiamine-induced thiamine-deficient rats [4].
• The effects of thiamine deficiency and of the antithiamine drug pyrithiamine on the C-6 glioma and the C-1300 neuroblastoma cell lines have been studied [5].

Psychiatry related information on 2-[1-[(4-amino-2-methyl-pyrimidin-5-yl)methyl]-6-methyl-pyridin-5-yl]ethanol

• Pyrithiamine induced acute thiamine deficient encephalopathy in the mouse is one of the possible animal models of human Wernicke-Korsakoff syndrome [6].
• Reversible alterations of cerebral gamma-aminobutyric acid in pyrithiamine-treated rats: implications for the pathogenesis of Wernicke's encephalopathy [7].
• Response latency and accuracy on a pretrained nonmatching-to-sample task in rats recovered from pyrithiamine-induced thiamine deficiency [8].
• The pyrithiamine-injections induced several M74-like symptoms including incoordination, lethargy, whitened liver and yolk-sac precipitates [9].

High impact information on 2-[1-[(4-amino-2-methyl-pyrimidin-5-yl)methyl]-6-methyl-pyridin-5-yl]ethanol

• Second, an analysis of the reaction mixture by mass spectrometry directly identified pyrithiamine pyrophosphate in the reaction mixture [10].
• Three lines of evidence support the ability of thiamine pyrophosphokinase to form pyrithiamine pyrophosphate [10].
• However, the mechanism by which pyrithiamine interferes with cellular thiamine phosphoester homeostasis is not entirely clear [10].
• Experiments with sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that the treatment with pyrithiamin decreased the phosphorylation by [gamma-32P]ATP of alpha (+) in a dose-dependent manner while it had little effect on that of alpha [11].
• Quantitative receptor autoradiography was used to evaluate the density of high-affinity binding sites for the "peripheral-type" benzodiazepine receptor (PTBR) ligand [3H]PK11195 in brain regions of the rat at different stages of pyrithiamine-induced thiamine deficiency encephalopathy, an experimental model of the Wernicke-Korsakoff syndrome (WKS) [12].

Chemical compound and disease context of 2-[1-[(4-amino-2-methyl-pyrimidin-5-yl)methyl]-6-methyl-pyridin-5-yl]ethanol

• Using T2-weighted Magnetic Resonance Imaging (MRI) in a pyrithiamin-treated, thiamin deficient (TD) rat model of Wernicke's encephalopathy (WE), we have observed hyperintensity in the thalamus, hypothalamus, collicular bodies and hippocampus which was enhanced 40 min after a glucose load [13].
• Phospholipase C from Clostridium welchii inhibited the activities of the enzymes treated with and without pyrithiamin or N-ethylmaleimide, a preferential inhibitor of the alpha (+) form, but the extent of the inhibition was higher in the control enzyme than in the treated enzymes [14].

Biological context of 2-[1-[(4-amino-2-methyl-pyrimidin-5-yl)methyl]-6-methyl-pyridin-5-yl]ethanol

• Pyrithiamine inhibition is an indication of prior activation of the Na+,K+-ATPase alpha + catalytic subunit by insulin [15].
• The results indicate an accumulation of lactate and severe impairment of the lipid metabolism in the edematous lesion of the cerebral cortex among the pyrithiamine-treated rats [16].
• In the present study, diurnal rhythm and regulation of body temperature were monitored during and several weeks following pyrithiamine-induced thiamine deficiency (PTD group, n=8) or pairfeeding (control group, n=9) [17].
• Pyrithiamine (10 mM) reduced the rising rate of the action potential without affecting the membrane and threshold potential [18].
• In contrast, pyrithiamine drastically decreases the oxidative decarboxylation of pyruvate by rat liver [19].

Anatomical context of 2-[1-[(4-amino-2-methyl-pyrimidin-5-yl)methyl]-6-methyl-pyridin-5-yl]ethanol

• Treatment with pyrithiamine, a central thiamine antagonist, resulted in a 71 and 55% decrease in protein levels of the astrocyte glutamate transporters GLT-1 and GLAST, respectively, by immunoblotting in the medial thalamus of day 14 symptomatic rats at loss of righting reflexes [20].
• Treatment of rats with pyrithiamine resulted in moderate reductions of glutamate in thalamus and pons and in generalized severe reductions of aspartate in pons (by 89%, p less than 0.01), thalamus (by 83%, p less than 0.01), cerebellum (by 53%, p less than 0.01), and cerebral cortex (by 33%, p less than 0.05) [21].
• Kinetic analysis shows that they compete mainly for the saturable component of thiamine flux across the blood-brain barrier, with only a slight inhibition of the non-saturable component, most clearly seen with pyrithiamine [22].
• In contrast, alpha2 and beta2 isoform expression and Na+,K+-ATPase activity sensitive to pyrithiamine (a specific inhibitor of the alpha2 isoform) were markedly increased in Schwann cells in the distal segment of the injured sciatic nerve [23].
• The pyrithiamine-treated rats produced by our method histopathologically exhibited the edematous lesion not only around the third ventricle and at the tegmentum of pons, as expected, but also in the cerebral cortex [16].

Associations of 2-[1-[(4-amino-2-methyl-pyrimidin-5-yl)methyl]-6-methyl-pyridin-5-yl]ethanol with other chemical compounds

• In both preparations, thiamin transport was inhibited competitively by unlabeled thiamin, pyrithiamin, amprolium and, to a lesser extent, oxythiamin, the inhibiting effect being always more marked in erythrocytes than in ghosts [24].
• We examined changes in 5-hydroxytriptamine (5-HT, serotonin) neurons in pyrithiamine-induced thiamine deficiency in mice immunohistochemically [25].
• ACh utilization was significantly reduced in the midbrain, striatum and hippocampus of pyrithiamin treated rats, but was reduced only in the striatum of oxythiamin treated rats compared to controls [3].
• Cellular uptake of this vitamin was estimated by directly comparing venous dilution profiles of (14C) and (3H) radioactivities in the absence and presence of unlabelled thiamin hydrochloride and pyrithiamin hydrobromide [26].
• In S. uvarum IFO 1265, the synthesis of vitamin B6 was maximally inhibited by the addition of thiamin (1.5 nmol ml-1) to the growth medium without affecting cell growth, whereas the amounts of cellular vitamin B6 increased in the presence of the thiamin antagonist, pyrithiamin or oxythiamin, at concentrations that did not affect growth [27].

Gene context of 2-[1-[(4-amino-2-methyl-pyrimidin-5-yl)methyl]-6-methyl-pyridin-5-yl]ethanol

• Pyrithiamine resistance was shown to be a recessive, single gene trait that resulted from the mutation of the thiamine transporter gene, as suggested by previous work [28].
• Pyrithiamine as a substrate for thiamine pyrophosphokinase [10].
• The brains of rats exposed to an early symptomatic stage of pyrithiamine-induced thiamine deficiency, 12-13 days of treatment, contained degenerating axons in corpus callosum, anterior commissure, external and internal capsules, optic and olfactory tracts, and fornix and mammillothalamic tracts [29].
• Daily pyrithiamine treatment led within 3 weeks to loss of righting reflex and convulsions and to decreased blood transketolase of a comparable magnitude to that observed in chronic thiamine-deprived rats [30].
• Biochemical studies of pyrithiamine-resistant mutants of Escherichia coli K12 [31].

Analytical, diagnostic and therapeutic context of 2-[1-[(4-amino-2-methyl-pyrimidin-5-yl)methyl]-6-methyl-pyridin-5-yl]ethanol

• We used kinetic assays coupled with mass spectrometry of the reaction products and x-ray crystallography of an equilibrium reaction mixture of thiamine pyrophosphokinase, pyrithiamine, and Mg2+/ATP to elucidate the mechanism by which pyrithiamine inhibits the enzymatic production of thiamine pyrophosphate [10].
• Microdialysis in the awake, freely moving rat was used to determine the effect of pyrithiamine-induced thiamine deficiency on the levels of amino acids in the brain [32].
• To help clarify the biochemical basis for these disorders, a cell culture system has been established in which pyrithiamine, a potent thiamine transport inhibitor, was used to mimic different degrees of thiamine deficiency within human lymphoblasts [33].
• Consequences of long-term consumption of alcohol (20 months) and of pyrithiamine-induced blockade of vitamin-B1-uptake on the shape of individual brain structures and on the acquisition of two learning tasks have been investigated in 3 groups of rats (alcohol group, AL; thiamine-deficient group, TH; control group, CG) [34].
• To assess retrograde retention of spatial information, half of the rats were pre-trained on the maze before the treatment manipulations of pyrithiamine (PT)-induced thiamine deficiency and post-tested after treatment (pre-trained group) [35].

References