Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyrithiamine induced acute thiamine deficient encephalopathy in the mouse is one of the possible animal models of human Wernicke-Korsakoff syndrome. In this experiment, the adult male Swiss Mice, treated with a daily subcutaneous injection of pyrithiamine in conjunction with a thiamine deficient diet, abruptly developed unique encephalopathic signs on day 10. In the animals sacrificed immediately after the onset of the disease, the gross examination of the brains revealed a small number of minute hemorrhagic lesions in the thalamus, mammilary bodies and pontine tegmentum, including the medial and lateral vestibular nuclei. When spared the hemorrhage, these regions appear intact grossly and in paraffin sections, but were found to be significantly altered in Epon sections. In semithin Epon sections of the pontine tegmentum, there was edematous swelling of all the astrocytes and oligodendrocytes and occasional myelin sheaths. By electron microscopy, the edema of astrocytes involved both nucleus and cytoplasm extensively. The oligodendroglial edema was severe in the peripheral cytoplasm, particularly in the inner loops of the myelin sheaths and only moderately in the nuclei, perinuclear cytoplasm and outer loops. Disintegration of the myelin lamellae occurred when edema of the inner loops had advanced. The axis cylinders surrounded by the edematous loops were essentially intact. In contrast to such glial cell damage, the nerve cells and blood vessels were not altered. These findings suggest that (1) astroglia and oligodendroglia are the cells most sensitive to thiamine deficiency and (2) the resultant glial cell injury is the initial change of thiamine deficient encephalopathy in man and in experimental animals.
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PMID:Early edematous lesion of pyrithiamine induced acute thiamine deficient encephalopathy in the mouse. 68 83

Pyrithiamine-induced thiamine-deficiency encephalopathy in the rat shows many neuropathological and biochemical similarities to Wernicke's encephalopathy in humans. 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). Alanine concentrations were concomitantly increased. Activities of the thiamine-dependent enzyme alpha-ketoglutarate dehydrogenase (alpha KGDH) were decreased in parallel with the aspartate decreases; pyruvate dehydrogenase complex activities were unchanged in all brain regions. Following thiamine administration to symptomatic pyrithiamine-treated rats, neurological symptoms were reversed and concentrations of glutamate, aspartate, and alanine, as well as alpha KGDH activities, were restored to normal in cerebral cortex and pons. Aspartate levels and alpha KGDH activities remained below normal values, however, in thalamus. Thus, pyrithiamine treatment leads to reductions of cerebral alpha KGDH and (1) decreased glucose (pyruvate) oxidation resulting in accumulation of alanine and (2) decreased brain content of glutamate and aspartate. Such changes may be of key significance in the pathophysiology of the reversible and irreversible signs of Wernicke's encephalopathy in humans.
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PMID:Effect of pyrithiamine treatment and subsequent thiamine rehabilitation on regional cerebral amino acids and thiamine-dependent enzymes. 256 21

Chronic alcoholism results in thiamine deficiency as a consequence of inadequate dietary intake and of impaired absorption of the vitamin. In addition, there is evidence to suggest that alcohol reduces thiamine phosphorylation to thiamine pyrophosphate (TPP) in brain. TPP is a cofactor for the pyruvate dehydrogenase complex (PDHC), alpha-ketoglutarate dehydrogenase (alpha KGDH) and transketolase (TK), three enzymes involved in cerebral glucose and energy metabolism. Pyrithiamine-induced thiamine deficiency in the rat results in early, selective, reversible reductions of alpha KGDH in brain; PDHC activities are unaffected. Reductions of alpha KGDH are accompanied by decreased aspartate, glutamate and GABA and by concomitantly increased alanine in the brain of thiamine-deficient animals. It is suggested that decreased alpha KGDH, rather than decreased PDHC constitutes 'the biochemical lesion' in thiamine deficiency encephalopathy first enunciated by Peters in the 1930s. If sufficiently prolonged and severe, thiamine deficiency results in brain cell death. Possible mechanisms involved include compromised cerebral energy metabolism and focal accumulation of lactate, both of which could result from decreased activities of alpha KGDH. In addition, it is proposed that brain cell death in severe thiamine deficiency may result from excessive release of excitotoxic amino acids. Comparable mechanisms could be involved in the cell death and in the pathogenesis of the thiamine-unresponsive symptoms of the Wernicke-Korsakoff Syndrome in humans.
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PMID:Effects of thiamine deficiency on brain metabolism: implications for the pathogenesis of the Wernicke-Korsakoff syndrome. 267 60

Pyrithiamine-induced acute thiamine-deficient encephalopathy was produced in adult male Wistar rats. Twenty-four hours before the onset of neurological signs the brain showed no morphological abnormalities. Encephalopathic rats had symmetrical lesions of edematous necrosis localized in the thalamus, mammillary body, and pontine tegmentum. Biochemically, encephalopathic rats had brain thiamine levels less than 20% of controls. For the assay of the concentrations of adenosine triphosphate (ATP) and phosphocreatine, the brains were fixed using 5 KW microwave irradiation and were divided into four parts: cerebral cortex, diencephalon, lower brainstem, and cerebellum. In the lower brainstem of the encephalopathic rats ATP concentrations were 89.5% of normal controls. Phosphocreatine levels were lowered to 70% of controls in the diencephalon and to 75% in the lower brainstem. Total high energy phosphate levels were decreased to 89% of controls in the diencephalon and 91% in the lower brainstem before the onset of neurological signs and to 76% and 79%, respectively, after the onset. In the cerebral cortex and cerebellum high energy phosphates were not significantly reduced. Lower high energy phosphate levels and the distribution of edematous lesions were coincident in the brain. These findings suggest that a low energy state is closely related to the formation of edematous lesions in thiamine-deficient encephalopathy.
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PMID:Low energy levels in thiamine-deficient encephalopathy. 672 85

Pyrithiamine-induced thiamin deficiency has been used in rat as an experimental form of Wernicke-Korsakoff encephalopathy, a disease associated with chronic alcoholism. Although the main etiological factor is known to be the lack of thiamin, the biochemical mechanisms involved in the pathogenesis remain unclear. Thiamin-dependent enzymes were studied in brain mitochondria: alpha-ketoglutarate dehydrogenase activity exhibited 40% reduction, whereas pyruvate dehydrogenase did not change significantly. Polarographic recordings of mitochondrial respiration revealed a decreased State 3, when using pyruvate/malate, alpha-ketoglutarate or glutamine as a substrate, but the respiration rates remained unchanged with glutamate or succinate. This fall in pyruvate oxidation may be due to the impairment of alpha-ketoglutarate dehydrogenase, which follows pyruvate dehydrogenase in the metabolic pathway. A time course of lactate concentration showed dramatic increases in thalamus, mid brain, hypothalamus and colliculli, consistent with the anatomopathological findings. No increases were found before the onset of neurological symptoms.
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PMID:Brain pyruvate oxidation in experimental thiamin-deficiency encephalopathy. 893 Apr 10

The possible involvement of blood-brain barrier (BBB) breakdown in the pathogenesis of thiamine deficiency encephalopathy was investigated in RBE4 cells, an immortalized rat brain endothelial cell line. The effects of thiamine deficiency produced by addition of pyrithiamine and by reduction of thiamine in the culture medium, on the metabolism and permeability of the RBE4 monolayer was examined. Pyrithiamine treatment in low thiamine medium (M199) for 7 days caused cytotoxic effects on RBE4 cells at all concentrations (10-50 microg/ml). Pyrithiamine caused a concentration- and time-dependent decrease in MTT reduction and a significant increase in glucose consumption and lactate production compared to controls. Pyrithiamine treatment for 3 days caused a significant decrease in MTT reduction at 50 microg/ml only. In contrast, increased glucose consumption and lactate production by the RBE4 cells was observed after treatment for 3 days with concentrations of 25 microg/ml pyrithiamine and above. The permeability of RBE4 cell monolayers to [14C]sucrose (Mw 342), but not FITC-dextran (Mw 4000) was significantly increased by treatment with pyrithiamine concentrations of 25 microg/ml and above for 3 days. These effects were not accompanied by detectable changes in F-actin distribution or content, although F-actin content was significantly reduced by 7 days exposure to pyrithiamine. These results suggest that metabolic and permeability changes in thiamine-deficient RBE4 cells may be important early events in thiamine-deficiency encephalopathy. The relative role of the BBB in the pathogenesis of thiamine deficiency is discussed.
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PMID:Metabolic and permeability changes caused by thiamine deficiency in immortalized rat brain microvessel endothelial cells. 918 23

Chronic alcoholism results in thiamine deficiency as a result of poor nutrition and impaired gastrointestinal absorption of the vitamin. Pyrithiamine-induced thiamine deficiency in the rat reproduces a neurological syndrome and ultimately neuropathological damage of a nature and distribution that is similar to that encountered in Wernicke's encephalopathy in humans. Pyrithiamine-induced thiamine deficiency results in selective reversible decreases in activity of the thiamine-dependent enzyme alpha-ketoglutarate dehydrogenase and concomitant reversible changes in brain amino acids. It is proposed that these changes constitute "the biochemical lesion" in thiamine deficiency encephalopathy. If sufficiently severe and prolonged, decreased activities of alpha-ketoglutarate dehydrogenase may result in compromised brain energy metabolism and in lactate accumulation in brain, both of which could be responsible for neuronal cell death in this condition. In addition, it has been suggested that cell death results from NMDA-receptor mediated excitotoxic damage. Similar pathophysiologic mechanisms could be responsible for brain cell death in Wernicke's encephalopathy in humans.
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PMID:Pathophysiologic mechanisms responsible for the reversible (thiamine-responsive) and irreversible (thiamine non-responsive) neurological symptoms of Wernicke's encephalopathy. 1684 Feb 90