Thiamine-deficient Diet Research Articles

Changes in Brain Lipid Composition in Thiamine Deficient Rats

Brain lipid composition was studied in thiamine deficient rats treated with thiamine antimetabolites (oxythiamine: OT, and pyrithiamine: PT) and thiamine deficient diet (TDD). After intraperitoneal injection of OT (40 mg/kg/day) or TDD feeding for 6 days, body weight gain decreased. However, the PT (500 μg/kg/day) treated rats or the pair fed control (PFC: TDD+thiamine of 5 mg/kg, i.p.) showed no decrease in body weight gain compared with the regular diet control (C). Brain lipid levels (total lipid, total cholesterol, triglyceride, phospholipid, sphingomyelin and cerebroside) were examined in four brain regions (cerebral cortex, subcortical structure, brain stem and cerebellum). Total lipid level increased in four regions in OT or TDD treated rats, but total lipid level in the cerebellum in PT treated rats decreased. Total cholesterol level increased in all treated rats, while the triglyceride level in the brain stem decreased dramatically in OT or TDD treated rats. Cerebroside levels of four regions in the PT, OT or TDD group remarkably decreased, and PFC rats showed a significant improvement of the decrease in cerebroside level. It is conceivable that these changes in brain lipid composition provided some clues for the histological and morphological changes of the brain as manifested by the myelin degradation in acute thiamine deficiency.

Delayed auditory brainstem response in thiamin-deficient rats.

We recorded the auditory brainstem responses of rats fed a thiamin-deficient diet. The interpeak latencies between waves I and III, as well as those between waves I and IV, were significantly prolonged from day 24, while the latency of wave I was prolonged on day 26 of the thiamin-deficient diet. These delayed responses were corrected in 2 to 4 days after the initiation of daily intraperitoneal thiamin injections from day 32. The rats that were fed the thiamin-deficient diet, and then sacrificed on day 32, showed a decrease of total thiamin levels in the brain (26% of the level in control rat brains). Based on these results, we emphasize the value of the auditory brainstem response to detect thiamin deficiency.

Effects of Thiamine Administration on Hypothermia and Hypothalamic Histamine Levels in Dietary-Induced Thiamine Deficient Rats

The rats maintained on a thiamine-deficient diet for 30 days showed hypothermia, and their histamine levels increased significantly in both the anterior and posterior hypothalamus. When these rats were administered, thiamine disulfide and/or provided with thiamine-added diet for a further 30 days, the rats recovered from hypothermia, and histamine levels were decreased to the normal level. Thus, it is probable that the increased histamine levels in the hypothalamus, especially those in its anterior region, are closely related to the hypothermia in thiamine-deficient rats.

Thiamine deficiency in utero alters response to ethanol in adulthood

To determine whether prenatal thiamine deficiency, a frequent concomitant of alcoholism, reduces the response to ethanol during adulthood in the rat as does ethanol exposure in utero (Abel et al. 1981), pregnant Sprague-Dawley rats received either control or thiamine deficient diets together with daily injections of the thiamine antagonist pyrithiamine. At 7 months of age, male offspring were exposed to precisely regulated ethanol vapor concentrations in an inhalation chamber for 24 h and blood ethanol concentrations (BECs) and ethanol-induced intoxication were determined. Prenatally thiamine deficient rats and controls were indistinguishable in terms of appearance, body and liver weights, and the ratios of liver to body weight and brain to liver weight. However, total body water was significantly greater, and BECs and behavioral impairment were decreased, in the experimental rats. These findings indicate that prenatal thiamine deprivation is associated with reduced pharmacologic effect of ethanol as a result of increases in its volume of distribution and rate of metabolism.

Branched-chain alpha-ketoacids and related acids in thiamin-deprived rats.

We showed elevated plasma levels of branched-chain amino acids, alpha-ketoacids, alpha-hydroxyacids in thiamin-deprived rats, which had decreased liver thiamin levels (2.4% of control) after 4 weeks of feeding of thiamin-deficient diet. The ratios of mean levels of these acids in thiamin-deficient rats to those in control rats were as follows: total branched-chain amino acids 1.6; total branched-chain alpha-ketoacids 2.7; total branched-chain alpha-hydroxyacids 3.6; pyruvic acid 1.6. The plasma level of total branched-chain alpha-hydroxyacids was correlated to liver thiamin concentration (r = -0.67, p less than 0.01), but those of the other two acids were not correlated. Although the increased levels of branched-chain acids in thiamin-deprived rats were less remarkable than those of ill patients with maple syrup urine disease, they reflect the reportedly decreased branched-chain alpha-ketoacid dehydrogenase activities (about 40% of control), and we discussed whether the toxic effects of individual branched-chain acid could be demonstrated by its administration to the thiamin-deprived rats.

Long-lasting changes in regional brain amino acids and monoamines in recovered pyrithiamine treated rats

Rats were subjected to a severe bout of thiamine deficiency induced by daily pyrithiamine + a thiamine deficient diet, reversed by thiamine administration and allowed to recover. Pyrithiamine treated animals demonstrated impaired retention of a 24 h recall of passive avoidance. Regional brain concentration of norepinephrine, dopamine, serotonin, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, GABA, glutamate, aspartate, glutamine, and glycine were determined after 2 and 9 weeks of nutritional recovery. A significant increase in NE content of cerebellum from the pyrithiamine treated animals was observed at both 2 and 9 week recovery periods. The concentrations of serotonin and its metabolite were significantly elevated in midbrain-thalamus and striatum. Significant reductions of GABA and glutamate were also observed in midbrain-thalamus. Amino acid levels in all other brain areas were unchanged from pair-fed controls. These results suggest regionally specific, chronic alterations in GABA, glutamate, serotonin, and norepinephrine activity following recovery from an acute bout of pyrithiamine-induced thiamine deficiency. The absence of a permanent reduction of cortical norepinephrine similar to that observed in an earlier study is discussed.

The influence of thiamine deficiency and ethanol on rat brain catecholamines

In rats treated with a thiamine deficient diet for 30 days the brain content of total thiamine decreased by 27–50%. Thiamine deficiency decreased the dopamine (DA) concentration of the striatum indicating a reduced synthesis of DA. In the hypothalamus the levels of the catecholamine metabolites homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenyl glycol (HMPG) were reduced indicating a reduced DA and noradrenaline (NA) turnover. Animals on a diet containing 5% ethanol had increased concentrations of HVA and HMPG in rest brain indicating an increased DA and NA turnover. The concentration of 1-carboxysalsolinol (1-CSAL) and salsolinol (SAL) in the brain stem was increased in animals receiving ethanol. Thus, both thiamine deficiency and ethanol treatment influenced the catecholamine system in a complex region-dependent way. In the brain regions most susceptible to brain damage in thiamine deficiency, i.e., hypothalamus and brain stem, 1-CSAL and SAL increased most following thiamine deficiency combined with ethanol intake.

The effect of thiamine deficiency on the structure and physiology of the rat forebrain

Dietary thiamine deficiency, enhanced by pyrithiamine administration in adult rats, produces overt lesions in the brain that are especially prominent in the thalamus. The present study was undertaken to determine whether the thalamic lesions could be correlated with alterations in the physiological properties of neurons in the thalamus and somatosensory cortex. The regimen for experimentally inducing thiamine deficiency produced large lesions in the thalamus of every case; the lesions included most, if not all, of the neurons in the intralaminar thalamic nuclei. The extent of the lesion in the intralaminar thalamus was highly correlated with the loss of bilaterally synchronous spontaneous activity in the cerebral cortex. This correlation was seen in animals analyzed as early as 1-18 hr after the appearance of opisthotonus, the crisis state of thiamine deficiency, and as late as 2-9 weeks of recovery following thiamine replacement therapy. The loss of bilateral synchronous bursting neuronal activity following intralaminar thalamic lesions is consistent with the proposed role of the intralaminar thalamus as a pacemaker for rhythmic cortical activity (Armstrong-James et al., Exp. Brain Res., 1985; Fox and Armstrong-James, Exp. Brain Res. 63: 505-518, 1986). The location and size of the central lesions within the thalamus suggest that the observed neuronal loss could result from a nonhemorrhagic infarction in the ventromedial branches of the superior cerebellar arteries. Experimental thiamine deficiency also produced alterations in the receptive field properties of the somatosensory cortex neurons in all animals examined. Changes in cortical receptive field properties were correlated with the destruction of sensory relay neurons in the thalamic ventrobasal complex. The loss of the central lateral thalamic input to the cortex and the loss of somatosensory relay neurons in the ventrobasal thalamus in experimental thiamine deficiency produce alterations in cortical function which may contribute to deficits in memory and cognition analogous to those which characterize Korsakoff's psychosis in humans.

Decrease of high affinity ouabain binding in rat cerebellum and hypothalamus by thiamin deficiency

The effect of dietary thiamin deficiency on high affinity [ 3H]ouabain binding was examined in different regions of rat brain. The binding activity in the cerebellum and hypothalamus was significantly lower in the thiamin-deficient group than in the pair-fed control and freely fed control groups. The decrease was due to a change in B max but not in K d. The results suggest a possible involvement of (Na +, K +)-ATPase in neurological manifestations of thiamin deficiency.

Persistence of habituation deficits after neurological recovery from severe thiamine deprivation

Rats were fed a thiamine-deficient diet for 4 weeks and injected daily with pyrithiamine during the last two weeks of the diet. This regime induced severe neurological anomalies such as ataxia, loss of righting reflex and visual place reflex, and finally full tonic-clonic seizures. These symptoms are reminiscent of the clinical Wernicke-Korsakoff syndrome. Injection of thiamine dramatically reversed these symptoms within one or two hours as seen in Wernicke patients. Six weeks later these rats showed a marked deficit in habituation of exploratory behavior and of the auditory orienting response. To what extent this chronic deficit in habituation contributes to the cognitive dysfunctions seen in Wernicke-Korsakoff patients is discussed. Histological examination of the brains of 6 of the rats revealed a heterogeneous pattern of damage to the brainstem, including mamillary bodies and several thalamic nuclei, reminiscent of that seen in Korsakoff patients. In addition there were many dark abnormal cells in limited fields of hippocampus neocortex and thalamus in almost all animals.

Monoamines and metabolites in cortex and subcortical structures: normal regional distribution and the effects of thiamine deficiency in the rat

The present study measured the concentration of monoamines, metabolites and estimates of turnover rate in eighteen separate brain regions from controls and a rat model of Korsakoff's disease induced by a two week bout of pyrithiamine and thiamine deficient diet (PTD). A behaviorally tested control ( n = 12) and PTD ( n = 17) group, and a non-behaviorally tested PTD group ( n = 8) were sacrificed 7 months after recovery from treatment. The brains were dissected into nine cortical areas and nine subcortical regions. In behaviorally tested PTD animals, a significant reduction of NE was observed in entorhinal cortex. Diminished norepinephrine (NE) concentration was also observed in entorhinal, hippocampal, septal and olfactory areas of the non-behaviorally tested PTD group. Serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were increased in several brain areas, particularly midbrain-thalamus, striatum, of both groups of recovered PTD animals. These findings are discussed with respect to results and hypotheses presented in our previous study of this animal model. Significant differences in monoamine, metabolite and turnover estimates were also observed among cortical areas of the control animals. Entorhinal cortex contained the highest concentration of NE and 5-hydroxytryptamine (5-HT), while DA was highest in somatosensory cortex. The distribution of 5-HT and 5-HIAA were more homogeneous and displayed a rostral-caudal decline in concentration.

Comparison of Transketolase Activity and Thiamin Pyrophosphate Levels in Erythrocytes and Liver of Rainbow Trout (Salmo gairdneri) as Indicators of Thiamin Status

Yearling rainbow trout (Salmo gairdneri) were fed a purified diet with and without thiamin supplementation for 30 wk, at which time overt signs of thiamin deficiency appeared in the deficient group. Overt signs of thiamin deficiency were anorexia, darkening and ataxia. Death rapidly followed the development of overt thiamin deficiency. Transketolase activity and thiamin pyrophosphate levels were measured monthly in erythrocyte and liver samples. Significant differences in erythrocyte tranketolase activity between fish fed the thiamin-deficient and control diets were measured after 24 wk of feeding. No significant difference in liver transketolase activity was found between trout fed diets with or without thiamin supplementation. Thiamin pyrophosphate levels were significantly lower in erythrocytes and liver of fish fed the thiamin-deficient diet after 16 wk of feeding. Thiamin pyrophosphate levels in erythrocytes and liver were found to be a more sensitive indicator of thiamin status of rainbow trout than erythrocyte or liver transketolase activity.

Suppressive effects of intraventricular injected dopamine and nomifensine on muricide induced by thiamine deficiency

The effects of dopamine (DA) and nomifensine (NF) on muricide activity induced by thiamine deficiency were examined. The chronic administration of L-dopa and nomifensine during feeding of thiamine deficient diet attenuated the muricide activity. Moreover, acute administration of L-dopa or nomifensine (IP) and dopamine or nomifensine (ICV) suppressed the thiamine deficiency-induced muricide activity dose-dependently. Small doses of apomorphine inhibited the muricide response significantly. The suppressive effects of dopamine and nomifensine were antagonized by pretreatment with 6-hydroxydopamine, but were not changed by pretreatment with p-chlorophenylalanine. These results suggest that the dopaminergic system has an important role in the regulation to the thiamine deficiency-induced muricide response.

Neuro-toxic interaction in alcohol-treated, thiamine-deficient mice.

Groups of adult male mice were either fed a thiamine-deficient diet for 10 weeks and thereafter treated with ethanol by making them inhale vapourized cane spirit for 10 weeks, or given both treatments simultaneously. The brains of these mice were then searched for degeneration using both light and electron microscopy. No degenerating nerve cells were observed in any animal in the cerebral cortex, hippocampus, cerebellum, olfactory bulbs, midbrain or hindbrain. However, axon terminal degeneration was seen in the olfactory bulbs and deep cerebellar nuclei in mice given the combined treatment. No cerebellar degeneration was found and only little degeneration was present in the olfactory bulbs of mice given the two treatments at different times. Thus, the combined treatment of alcohol and thiamine deficiency produced more brain damage than the sum of that produced by the two treatments given separately. This represents the first experimental in vivo demonstration of a biochemical interaction between these two factors in alcohol-related brain damage. The findings of long-term animal treatment with models using thiamine antagonists are compared.

Oxalate metabolism in thiamine-deficient rats.

Male weanling rats were maintained on a thiamine-deficient diet for 4 weeks, and compared with ad libitum and pair-fed controls. Thiamine deficiency led to slow growth and finally a decrease in body weight. Liver and kidney weights of the deficient rats were low, but appropriate to the body weight. Thiamine deficiency also caused a significant decrease in erythrocyte transketolase levels. The decarboxylation of glyoxylate both via the glyoxylate oxidation cycle and alpha-ketoglutarate:glyoxylate (alpha-KG:GA) carboligase was significantly lower in the liver and kidney mitochondria, leading to accumulation of glyoxylate in the tissues and its excretion in the urine. Part of the accumulated glyoxylate is converted to oxalate, causing hyperoxaluria.

Influence of dietary supplementation with thiamine on lead intoxication in rats

The influence of dietary supplementation with thiamine on lead (Pb) contents in blood and tissues, blood δ-aminolevulinic acid dehydratase (δ-ALAD) activity, and urinary excretion of δ-aminolevulinic acid (δ-ALA) was evaluated in male Sprague-Dawley rats. Groups of randomly selected animals were given a thiamine-deficient diet, a diet containing normal thiamine (20 mg/kg), or a thiamine-supplemented diet (50 mg/kg), along with control drinking water or water containing 100 ppm Pb, for 4 mo. Animals fed the thiamine-supplemented diet (50 mg/kg) and Pb showed decreased urinary excretion of δ-ALA and a decreased inhibition of δ-ALAD activity in blood compared to those given Pb with normal thiamine diet. The liver, kidney, and blood of rats receiving supplemental thiamine also contained significantly less Pb than the other two treatment groups given Pb-containing water. The protective effect of thiamine against Pb toxicity may be attributed to its interference with retention of the metal in body tissue, possibly resulting from the formation of excretable thiamine-lead complexes.

GABA-transaminase and glutamic acid decarboxylase changes in the brain of rats treated with pyrithiamine.

Pyrithiamine, a thiamine phosphokinase inhibitor, was fed to rats on a thiamine-deficient diet, producing weight loss, ataxia and loss of righting reflex in 10 days. Some rats were then sacrificed; others were returned to a normal diet, to be sacrificed only when their weight had returned to pre-experimental levels. Rats were sacrificed for assay of glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) activities in homogenates of eight brain regions or were perfused for gamma-aminobutyric acid transaminase (GABA-T) histochemistry. GAD activity was significantly reduced in symptomatic rats in the thalamus greater than cerebellum greater than midbrain greater than pons/medulla. GABA-T staining was similarly reduced, with greatest losses in the thalamus greater than inferior colliculus greater than pons greater than medulla. ChAT activity was not significantly altered in any brain area. Following return to a normal diet. GAD activity was significantly recovered in all areas except the thalamus. GABA-T staining recovered, at least partially, in all areas affected.

Activities of thiamine-dependent enzymes in two experimental models of thiamine-deficiency encephalopathy: 1. The pyruvate dehydrogenase complex.

Chronic thiamine deprivation in the rat leads to selective neuropathological damage in brainstem structures whereas treatment with the central thiamine antagonist, pyrithiamine, results in more widespread damage. In order to further elucidate the neurochemical mechanisms responsible for this selective damage, the thiamine-dependent enzyme complex pyruvate dehydrogenase (PDHC) was measured in 10 brain structures in the rat during progression of thiamine deficiency produced by chronic deprivation or by pyrithiamine treatment. Feeding of a thiamine-deficient diet to adult rats resulted in 5-7 weeks in ataxia and loss of righting reflex accompanied by decreased blood transketolase activities. PDHC activities were selectively decreased by 15-30% in midbrain and pons (lateral vestibular nucleus). Thiamine treatment of symptomatic rats led to reversal of neurological signs and to concomitant reductions of the cerebral PDHC abnormalities. 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. No significant regional alterations of PDHC, however, were observed in pyrithiamine-treated rats.

THE WERNICKE-KORSAKOFF SYNDROME IN QUEENSLAND, AUSTRALIA: ANTECEDENTS AND PREVENTION

The Wernicke-Korsakoff (W-K) syndrome is commonplace in Queensland, Australia. In a population of mental hospital inpatients with the W-K syndrome, males, particularly single males and widowers, and subjects who had undergone partial gastrectomy were over-represented. Some possible antecedents of the W-K syndrome are examined by focusing, not on W-K patients, but on problem drinkers. The results of a cross-national comparison of drinkers from Queensland, Australia and Merseyside, in the United Kingdom, are presented. The data support the hypothesis that Queensland drinkers are comparatively less involved with their families than Merseyside drinkers. This parallels a social perspective which regards allegiance to a male drinking group as very important in confirming social solidarity and 'mateship' in Australia. Such groups attach no importance to eating, setting the stage for dietary neglect and thiamine deficiency of which the W-K syndrome may be the end result. The fortification of alcoholic beverages with thiamine in Queensland has been previously proposed and attracted much local publicity. It seems possible that this publicity may have contributed to an increased awareness by heavy drinkers in Queensland of the need for supplementary B vitamins. However, this awareness is not so complete as to rule out the need for further measures aimed at reducing the incidence of the W-K syndrome in that state.

Intrauterine growth retardation induced by thiamine deficiency and pyrithiamine during pregnancy in the rat

The role of nutritional factors in the development of prenatal and postnatal growth retardation is not well understood. We tested if thiamine deficiency may cause intrauterine growth retardation in rats. From the second day of gestation Sprague-Dawley rats were freely fed either a nutritionally complete or a thiamine-deficient diet. A similar group of rats was pair-fed with a complete or a thiamine-deficient diet and daily pyrithiamine injections (50 μg/100 gm of body weight) were given to precipitate thiamine deficiency during the short gestation of the rat. Maternal thiamine levels in blood and brain tissues, maternal erythrocyte transketolase activity with thiamine pyrophosphate effects, and fetal tissue thiamine levels were measured. The results indicate that feeding a thiamine-deficient diet in conjunction with pyrithiamine injections caused sufficient thiamine deficiency to induce intrauterine growth retardation in the progeny. We conclude that thiamine deficiency alone during in utero development in the rat may contribute to intrauterine growth retardation.