Lead induced thiamine deficiency in the brain decreased the threshold of electroshock seizure in rat.

Many neurological disorders that occur frequently in lead intoxicated animals, have also been observed in thiamine deficient animals. To test whether lead intoxication could decrease the thiamine status and thresholds of electroshock seizure in rats, 3-week-old Wistar rats were treated with lead or lead plus thiamine. For comparison, a thiamine deficient group was included. Thiamine contents and transketolase activity, one of the thiamine dependent enzymes in the brain regions were significantly lowered by lead intoxication and thiamine deficiency. In both cases, thresholds of the electroshock seizure were significantly decreased. Thiamine supplementation reversed these signs and decreased the brain lead concentration in the lead treated group. The results from the present study suggest that the increased seizure susceptibility induced by lead intoxication in rats may be mediated at least in part through the changes of thiamine status.

Brain pyruvate oxidation in experimental thiamin-deficiency encephalopathy.

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.

Na+,K(+)-ATPase activity is selectively increased in thalamus in thiamine deficiency prior to the appearance of neurological symptoms.

The relationship between progression of neurological status and the activities of both Na+,K(+)- and Mg(2+)-dependent-ATPase (adenosine 5'-triphosphate phosphohydrolase) was investigated in brain regions of pyrithiamine-induced thiamine deficient rats. Thalamic Na+,K(+)-ATPase activity was selectively increased by 200% (P < 0.01) prior to the appearance of symptoms of thiamine deficiency and normalized in symptomatic rats. This selective transitory activation precludes a mediation by brain soluble fraction Na+,K(+)-ATPase modifiers as does the unaltered distribution in regional high-affinity [3H]ouabain binding densities observed throughout the time-course used in these experiments. Na+,K(+)-ATPase maintains cellular ionic gradients and has been implicated in neurotransmitter uptake and release mechanisms. The fact that the increased thalamic Na+,K(+)-ATPase activity coincides with the early alterations in serotonin metabolism observed in similarly treated animals and the concomitantly early increase in glucose utilization previously observed in the thalamus of thiamine-deficient rats is discussed.

Thiamine deficiency and Wernicke's encephalopathy in AIDS.

Several neuropathological reports in the last 5 years have described brain lesions characteristic of Wernicke's Encephalopathy in patients with AIDS. Using the erythrocyte transketolase activation assay, we now report biochemical evidence of thiamine deficiency in 9/39 (23%) of patients with AIDS or AIDS-related complex. In no cases was there history of alcohol abuse nor were there clinical signs of Wernicke's Encephalopathy. Thiamine deficiency in these patients most likely results from the cachexia and catabolic state characteristic of AIDS. In view of (i) the confirmed neuropathological evidence of Wernicke's Encephalopathy in AIDS patients, (ii) the significant thiamine deficiency in these patients and (iii) the difficulties of clinical diagnosis of Wernicke's Encephalopathy, it is recommended that dietary thiamine supplementation be initiated in all newly diagnosed cases of AIDS or AIDS-related complex.

Natural establishment of thiaminase activity in the alimentary tract of newborn lambs and effects on thiamine status and growth rates.

Thiaminase activity was detected in the faeces of lambs at 2 to 5 days of age. Levels of activity increased for 10 days and then declined over the next 3 to 4 weeks. Decreased erythrocyte transketolase activity indicated thiamine insufficiency in lambs with high thiaminase activity. Mean growth rates were 17% less in lambs with high thiaminase activity than in lambs with zero or low thiaminase activity. Bacillus thiaminolyticus was the only organism isolated which produced thiaminase. Treatment of newborn lambs with intramuscular injections of sulphadoxine did not prevent them from excreting thiaminase in their faeces. It is proposed that oral thiamine supplementation of lambs at 2 to 3 weeks of age may be the most appropriate prevention and treatment for subclinical thiamine deficiency of the cause described.

Neuroanatomical consequences of thiamine deficiency: a comparative analysis.

In this paper, the neuroanatomical locus of lesions produced by thiamine deficiency was examined. An attempt was made to analyse the relationship between the pattern of development of neuropathological lesions and such experimental variables as length of deficiency, species, and method of deprivation. There is evidence in all species studied that certain structures are selectively vulnerable to thiamine deficiency. Current theories concerning the pathogenesis of lesions, including metabolic, neurophysiological, and genetic mechanisms were also discussed. It was concluded that the selective vulnerability of certain structures to thiamine deficiency is the result of a complex interaction between cellular, neurochemical, and metabolic properties of various brain regions which make them more susceptible to a breakdown in thiamine-dependent systems.

The effect of reduced dietary protein level on the activity of transketolase and glutathione reductase in pig erythrocytes.

The effect was investigated of decreased protein level in a food ration on covering the requirements for vitamins B1 and B2. Two feeding experiments were conducted, each on 32 fattening pigs of Polish Landrace breed. The activity of transketolase and glutathione reductase in erythrocytes and vitamin B1 and B2 level in blood and liver were determined. It was shown that a reduction of the diatery protein level by 25% caused a decrease of thiamine utilization by pigs. It indicates the necessity of a dietary supplementation with a synthetic vitamin B1 preparation in such a condition. A reduced activity of glutathione reductase, indicating a riboflavin deficiency, was observed only when the low protein diet was additionally deprived of a vitamin-mineral premix containing a fodder B2 preparation. Reduction of the dietary protein level by 25% was not associated with the risk of riboflavin deficiency, provided that the ration was supplemented with a standard dose of synthetic vitamin B2.

Ruminant thiamine requirement in perspective.

Thiaminases play an important role in the aetiology of CCN being responsible for the state of thiamine-deficiency which is an essential feature of the disease, evidence for which is presented here. These studies have led to a greater appreciation of the role of thiamine and thiaminases in ruminant nutrition especially as ruminal thiaminase activity is not confined to clinically affected animals but is of wider distribution. The importance of thiaminases in intensive beef production and the possibility of the need for thiamine supplementation in the form of a thiaminase resistant derivative is discussed.

Comparative histochemical and immunofluorescent observations in thiamine deficient encephalopathies.

Histochemical and immunohistological examinations were carried out at different stages of thiamine-deficient encephalopathy in rats. The respiratory enzymatic activity decreased in the most damaged area correlating well with the neuropathological findings. There was an inverse relationship between the damaged area and its marginal zone; the latter showed an increase of the same enzymatic activity. The capillary network and the activity of the vessel walls seemed to be almost unimpaired. The immunohistological investigations showed only a moderate extravasation of the plasma proteins.

Red blood cell transketolase activity and the effect of thiamine supplementation in patients with chronic liver disease.

Biochemical evidence of thiamine deficiency was found in 58% of patients with chronic liver disease, the incidence being higher in alcoholic than in non-alcoholic patients. Daily supplementation with high doses of thiamine hydrochloride (200 mg/day) for one week restored levels of thiamine pyrophosphate (TPP), the active co-enzyme form of thiamine, to normal in all cases. Such supplementation also stimulated synthesis of the TPP dependent enzyme transketolase. Because of the essential role of TPP as a co-factor in intermediary metabolism, it is concluded that high doses of thiamine should be included in the routine nutritional management of patients with severe chronic liver disease.

Evaluation of methods of coenzyme activation of erythrocyte enzymes for detection of deficiency of vitamins B1, B2, and B6.

We describe optimized, ultraviolet spectrophotometric procedures for determination of erythrocyte transketolase, glutathione reductase, and aspartate aminotransferase activity, and their activation by their respective coenzymes--thiamine pyrophosphate, flavin-adenine dinucleotide, and pyridoxal-5-phosphate--as tests for vitamin B1, B2, and B6 deficiency. With these procedures we have investigated healthy subjects on normal and vitamin-supplemented diets, and a series of (mainly) alcoholic hospital in-patients. The enzyme procedures described have good precision and can be readily carried out in the routine laboratory. Abnormal transketolase activation correlated well with clinical evidence of vitamin B1 deficiency.

Influence of the oral contraceptive, menstranol, on drug-metabolizing enzymes of female rats in thiamin-supplemented and deficiency states.

The administration of a diet deficient in thiamin results in elevated hepatic microsomal activity of aniline hydroxylase, ethylmorphone demethylase, NADPH cytochrome c reductase and cytochrome P-450 when compared to similar female rats fed diets supplemented with thiamin. Accompanying these differences in enzyme activity are increased concentrations of microsomal docosahexaenoic acid and arachidonic acid. Binding of aniline to microsomes from rats fed high levels of thiamin is decreased due to a decrease in cytochrome P-450. On the other hand, the binding of ethylmorphine to P-450 is decreased by feeding high levels of thiamin. The daily administration of mestranol enhanced ethylmorphine and aniline metabolism to a greater extent in rats fed thiamin-rich diet than in rats fed thiamin-deficient diet or laboratory chow. This treatment did not increase cytochrome P-450 cytochrome c reductase or microsomal protein nor does it appear to affect the binding of aniline to cytochrome P-450. Ethylmorphine binding is generally decreased by this treatment. Alterations in the Michaelis constants for these reactions were limited to an increase in the Ks for aniline in pair-fed animals and in the Ks for ethylmorphine in thiamin-deficient rats receiving 1.0 mg mestranol per day.

PIP: The effect of mestranol on drug-metabolizing enzymes was studied in female rats receiving either deficient or thiamin-supplemented diets. Rats on the deficient diet showed increased hepatic microsomal activity of aniline hydroxylase, ethylmorphine demethylase, NADPH cytochrome c reductase, and cytochrome P-450. There were also increased concentrations of microsomal docosahexaenoic acid and arachidinic acid. Rats on the thiamin-supplemented diet showed decreased binding of aniline to microsomes, which was due to decreased levels of cytochrome P-450. However, high levels of thiamin decreased the binding of ethylmorphine to P-450. Mestranol increased ethylmorphine and aniline metabolism to a greater degree in animals receiving the thiamin-supplemented diet than those receiving the deficient diet or laboratory feed. However, levels of cytochrome P-450, cytochrome c reductase, or microsomal proteins were not increased, and the binding of aniline to cytochrome P-450 was not affected. Generally, treatment with mestranol decreased the binding of ethylmorphine. It appears that mestranol alters the Type I binding site on cytochrome P-450, but has no effect on the Type II binding site.