Acute nutritional axonal neuropathy.

INTRODUCTION: This study describes clinical, laboratory, and electrodiagnostic features of a severe acute axonal polyneuropathy common to patients with acute nutritional deficiency in the setting of alcoholism, bariatric surgery (BS), or anorexia. METHODS: Retrospective analysis of clinical, electrodiagnostic, and laboratory data of patients with acute axonal neuropathy. RESULTS: Thirteen patients were identified with a severe, painful, sensory or sensorimotor axonal polyneuropathy that developed over 2-12 weeks with sensory ataxia, areflexia, variable muscle weakness, poor nutritional status, and weight loss, often with prolonged vomiting and normal cerebrospinal fluid protein. Vitamin B6 was low in half and thiamine was low in all patients when obtained before supplementation. Patients improved with weight gain and vitamin supplementation, with motor greater than sensory recovery. DISCUSSION: We suggest that acute or subacute axonal neuropathy in patients with weight loss or vomiting associated with alcohol abuse, BS, or dietary deficiency is one syndrome, caused by micronutrient deficiencies. Muscle Nerve 57: 33-39, 2018.

Effects of maternal vitamin B6 deficiency and over-supplementation on DNA damage and oxidative stress in rat dams and their offspring.

Vitamin B6 is a cofactor for more than 140 essential enzymes and plays an important role in maternal health and fetal development. The goal of this study was to investigate the effects of maternal vitamin B6 on DNA damage and oxidative stress status in rat dams and their offspring. Female Wistar rats were randomly assigned to three dietary groups fed a standard diet (control diet), a diet supplemented with 30 mg/kg of vitamin B6, or a deficient diet (0 mg/kg of vitamin B6) for 10 weeks before and during mating, pregnancy and lactation. The dams were euthanized at weaning, and their male pups were euthanized either 10 days or 100 days after birth. We found that maternal vitamin B6 deficiency increased the micronucleus frequency in peripheral blood and bone marrow cells and also increased the concentration of hepatic TBARS (thiobarbituric acid reactive substances) in newborn pups (10 days old). In conclusion, maternal 5- to 6-fold over-supplementation of vitamin B6 had no adverse effects, however its deficiency may induce chromosomal damage and hepatic lipid peroxidation in the offspring.

Sphingosine 1-phosphate lyase inhibition by 2-acetyl-4-(tetrahydroxybutyl)imidazole (THI) under conditions of vitamin B6 deficiency.

Caramel food colorant 2-acetyl-4-(tetrahydroxybutyl)imidazole (THI) causes lymphopenia in animals through sphingosine 1-phosphate lyase (SPL) inhibition. However, this mechanism of action is partly still controversial because THI did not inhibit SPL in vitro either in cell-free or in cell-based systems. It is thought that the in vitro experimental conditions which have been used so far were not suitable for the evaluation of SPL inhibition, especially in case of cell-based experiments. We speculated that the key factor might be the coenzyme pyridoxal 5'-phosphate (PLP), an active form of vitamin B6 (VB6), because media used in cell-based assays usually contain an excess amount of VB6 which leads to the activation of SPL. By the use of VB6-deficient culture medium, we could regulate apo- (without PLP) and holo- (with PLP) SPL enzyme in cultured cells, resulting in the successful detection of SPL inhibition by THI. Although the observed inhibitory effect was not as strong as that of 4-deoxypyridoxine (a VB6 analog SPL inhibitor), these findings may be useful for further understanding the mechanism of action of THI.

Oral exposure to the anti-pyridoxine compound 1-amino D-proline further perturbs homocysteine metabolism through the transsulfuration pathway in moderately vitamin B6 deficient rats.

Pyridoxal 5'-phosphate (PLP; a B6 vitamer) serves as an important cofactor in a myriad of metabolic reactions, including the transsulfuration (TS) pathway, which converts homocysteine (Hcy) to cysteine. While overt vitamin B6 deficiency is rare, moderate deficiency is common and may be exacerbated by anti-pyridoxine factors in the food supply. To this end, we developed a model of moderate B6 deficiency and a study was conducted to examine the in vivo effect of 1-amino D-proline (1ADP), an anti-pyridoxine factor found in flaxseed, on indices of Hcy metabolism through the TS pathway in moderately B6 deficient rats. Male weaning rats received a semi-purified diet containing either 7 mg/kg (control; CD) or 0.7 mg/kg (moderately deficient; MD) diet of pyridoxine·hydrochloride (PN∙HCl), each with 1 of 4 levels of 1ADP, viz. 0, 0.1, 1 and 10 mg/kg diet for 5 weeks. Perturbations in vitamin B6 biomarkers were more pronounced in the MD group. Plasma PLP was significantly reduced, while plasma Hcy (8-fold) and cystathionine (11-fold) were increased in rats consuming the highest amount of 1ADP in the MD group. The activities of hepatic cystathionine ß-synthase and cystathionine γ-lyase enzymes were significantly reduced in rats consuming the highest 1ADP compared to the lowest, for both levels of PN∙HCl. Dilation of hepatic central veins and sinusoids, mild steatosis and increased liver triglycerides were present in MD rats consuming the highest 1ADP level. The current data provide evidence that the consumption of an anti-pyridoxine factor linked to flaxseed may pose a risk for subjects who are moderate/severe vitamin B6 deficient.

Sugar and chromosome stability: clastogenic effects of sugars in vitamin B6-deficient cells.

Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, has been implicated in preventing human pathologies, such as diabetes and cancer. However, the mechanisms underlying the beneficial effects of PLP are still unclear. Using Drosophila as a model system, we show that PLP deficiency, caused either by mutations in the pyridoxal kinase-coding gene (dPdxk) or by vitamin B6 antagonists, results in chromosome aberrations (CABs). The CAB frequency in PLP-depleted cells was strongly enhanced by sucrose, glucose or fructose treatments, and dPdxk mutant cells consistently displayed higher glucose contents than their wild type counterparts, an effect that is at least in part a consequence of an acquired insulin resistance. Together, our results indicate that a high intracellular level of glucose has a dramatic clastogenic effect if combined with PLP deficiency. This is likely due to an elevated level of Advanced Glycation End-products (AGE) formation. Treatment of dPdxk mutant cells with α-lipoic acid (ALA) lowered both AGE formation and CAB frequency, suggesting a possible AGE-CAB cause-effect relationship. The clastogenic effect of glucose in PLP-depleted cells is evolutionarily conserved. RNAi-mediated silencing of PDXK in human cells or treatments with PLP inhibitors resulted in chromosome breakage, which was potentiated by glucose and reduced by ALA. These results suggest that patients with concomitant hyperglycemia and vitamin B6 deficiency may suffer chromosome damage. This might impact cancer risk, as CABs are a well-known tumorigenic factor.

Mechanisms of the beneficial effects of vitamin B6 and pyridoxal 5-phosphate on cardiac performance in ischemic heart disease.

Although vitamin B6 and its metabolite, pyridoxal 5'-phosphate (PLP), have been shown to exert beneficial effects in ischemic heart disease, the mechanisms of their action are not fully understood. Some studies have shown that ventricular arrhythmias and mortality upon the occlusion of coronary artery were attenuated by pretreatment of animals with PLP. Furthermore, ischemia-reperfusion-induced abnormalities in cardiac performance and defects in sarcoplasmic reticular Ca2+-transport activities were decreased by PLP. The increase in cardiac contractile activity of isolated heart by ATP was reduced by PLP, unlike propranolol, whereas that by isoproterenol was not depressed by PLP. ATP-induced increase in [Ca2+]i, unlike KCl-induced increase in [Ca2+]i in cardiomyocytes was depressed by PLP. Both high- and low-affinity sites for ATP binding in sarcolemmal membranes were also decreased by PLP. These observations support the view that PLP may produce cardioprotective effects in ischemic heart disease by attenuating the occurrence of intracellular Ca2+ overload due to the blockade of purinergic receptors.

Vitamin-dependent methionine metabolism and alcoholic liver disease.

Emerging evidence indicates that ethanol-induced alterations in hepatic methionine metabolism play a central role in the pathogenesis of alcoholic liver disease (ALD). Because malnutrition is a universal clinical finding in this disease and hepatic methionine metabolism is dependent upon dietary folate and vitamins B-6 and B-12, ALD can be considered an induced nutritional disorder that is conditioned by alcohol abuse. The present review describes the etiologies of these 3 vitamin deficiencies in ALD and how they interact with chronic ethanol exposure to alter hepatic methionine metabolism. Subsequent sections focus on molecular mechanisms for the interactions of aberrant methionine metabolism with ethanol in the pathogenesis of ALD, in particular the role of S-adenosylmethionine (SAM) in regulating the epigenetic expressions of genes relevant to pathways of liver injury. The review will conclude with descriptions of studies on the efficacy of SAM in the treatment of ALD and with discussion of potentially fruitful future avenues of research.

Liver-specific increase of UTP and UDP-sugar concentrations in rats induced by dietary vitamin B6-deficiency and its relation to complex N-glycan structures of liver membrane-proteins.

This is the first known report on the influence of vitamin B6-deficiency on the concentration of UDP-sugars and other uracil nucleotides in rats. Animals aged 3 weeks or 2 months were fed a vitamin B6-free diet for periods varying from 3 days to 7 weeks. Nucleotides were quantified by enzymatic-photometry and by SAX-high precision liquid chromatography. In 3 week-old rats, vitamin B6-deficiency resulted in an up to 6.3-fold increase in the concentrations of UTP, UDP, UMP and UDP-sugars and less of CTP in rat liver, while no changes were observed in older rats. In young rats, the concentration of uracil nucleotides started to increase after 1 week diet, with a maximum after 2 weeks. After 5 weeks, the concentrations returned to normal values. In heart, lungs, kidney and brain, concentrations were measured after 2 weeks diet in young rats. In contrast to liver, the heart muscle uracil nucleotide concentrations were decreased by 40%. In kidney, the sum of UTP, UDP and UMP showed a decrease of 40%, whereas UDP-sugars were increased 1.4-fold. In the lungs, nucleotide concentrations were mostly unaffected by vitamin B6-deficiency, despite a 70% increase of UDP-GA. In brain, UDP-Glc, UDP-Gal and the sum of CTP and CDP showed an increase of 30-50%. We became surprised that the increased UDP-sugar concentrations did not influence the structure of liver plasma membrane-N-glycans. Despite the 4 to 6-fold increase of UTP and UDP-sugars, no changes in the complexity or sialylation of these N-glycans could be detected. This study demonstrates that, especially in liver, pyridoxal phosphate is closely involved in the control of uracil nucleotides during a defined period of development. In contrast to in vitro experiments, in vivo N-glycan biosynthesis in liver is regulated by a more complex or higher mechanism than substrate concentrations.

Effect of vitamin B6 deficiency on glyoxylate metabolism in rats with or without glyoxylate overload.

We examined the effect of vitamin B6 deficiency on glyoxylate metabolism and hepatic alanine: glyoxylate aminotransferase (AGT) activity in rats with normal or high glyoxylate intake. Male rats were divided into four groups: a control group, a vitamin B6-free diet group, a glyoxylate water group, and a vitamin B6-free diet + glyoxylate water group. Each group was given special diet (control or vitamin B6-deficient diet) and drinking water (plain or 0.5% glyoxylate water) for 4 weeks, after which biochemical parameters and hepatic AGT mRNA level were measured. Compared with control rats, the urinary oxalate/creatinine ratio was higher in each of the other 3 groups. The urinary glycolate/creatinine ratio was also higher in the vitamin B6-free diet group and the vitamin B6-free diet + glyoxylate water group than the control group, while the urinary glycine/creatinine and citrate/creatinine ratio was lower in both groups. The hepatic AGT mRNA level was reduced in the vitamin B6-free diet group, but was increased in the glyoxylate water group than the control group. These results suggest that vitamin B6 is necessary for glyoxylate metabolism as a coenzyme of AGT. Especially in the presence of a high glyoxylate intake, vitamin B6 deficiency leads to severe hyperoxaluria and hypocituria.

Effect of pyridoxine deficiency on the structural and functional development of hippocampus.

In this study it was attempted to understand the effect of pyridoxine deficiency on the structural and functional development of the hippocampus. Hippocampus has been closely associated with complex neuroendocrine control of physiological activities as well as behavioural responses including learning process and memory retention. Prenatal, preweanling and weanling deficiency of pyridoxine was induced in the experimental rats by feeding dams with diet deficient in pyridoxine during pregnancy and lactation. The general growth profile for pyridoxine deficient (PD) rats is compared with control ones. The structural changes in the hippocampus of pyridoxine deficient rats was investigated using the histological techniques. Hippocampal electrical activity was recorded from in vitro brain slice preparation. The study clearly showed the structural impairment in the hippocampus of PD rats. These anatomic anomalies might be related to poor neurointegrative development and neurophysiological deficits that occur in young one. The electrical activity recorded from hippocampal slices of PD rats showed significant variation when compared to controls. Pyridoxine deficiency is common in pregnant women who used anovulatory steroids before pregnancy. The pyridoxine deficiency of the mother may result in permanent behavioural abnormality and intellectual deficit in the progeny.

Experimental model of pyridoxine (B6) deficiency-induced neuropathy.

A pyridoxine (B6) dietary deficiency was studied in female adult Sprague-Dawley rats by hind-limb walking-track analysis. Serum levels of pyridoxine and three metabolites were quantified by high-pressure liquid chromatography with fluorescence measurement. Morphometric analysis of the sciatic and posterior tibial nerves (from within the tarsal tunnel) was performed after 1 year on a diet deficient in vitamin B6. The B6-deficient rats developed abnormal walking-track patterns by 8 months, and these track parameters were different from age- and sex-matched normal diet control rats at the p < 0.05 level. Adding B6 at 10 parts per million to the diet then partially corrected these parameters, whereas the addition of 30 parts per million B6 corrected the abnormal pattern completely. Serum pyridoxal concentration correlated with the functional parameters, dropping from a mean of 115 mg per liter to 39.5 mg per liter (p < 0.05), and correcting with the B6 additive. Morphometric analysis demonstrated that the B6-deficient nerve from the tarsal tunnel had a decreased nerve fiber density (p < 0.001), with a normal total myelinated nerve fiber number, and an increased axon-to-myelin ratio (p < 0.003). It is concluded that a diet totally deficient in vitamin B6 results in a peripheral neuropathy.

A cartilage matrix deficiency experimentally induced by vitamin B6 deficiency.

A vitamin B6-deficiency-induced disorder in avian articular cartilage resembling osteoarthritis has been further characterized. We measured several parameters of proteoglycan (PG) metabolism, i.e., fixed charge density and sulfated glycosaminoglycans (S-GAG) content in PN-deficient versus control articular cartilage and synovial fluid from the knee joint. Statistically significant changes were: 1) decreased content and increased extractability of total sulfated PGs from articular cartilage with guanidine HCl; 2) elevation of S-GAG concentration in synovial fluid; 3) increased plasma cystathionine (sulfur amino acid) levels. PG synthesis as assessed by 35SO4 incorporation into S-GAGs was not impaired. A lack of cartilage swelling in 0.15 M saline and the normal water content indicated that although disturbed, the collagen network was not disrupted. This finding was in agreement with a previous microscopic study that revealed no fissures in the articular cartilage. Previous findings of a normal aggregating PG size-distribution and absence of elevated metalloproteases made a disturbance of aggregating PG metabolism unlikely. Escape into the synovial fluid of small PGs, normally bound to articular collagen, was believed to result from an alteration in collagen molecular organization that could be secondary to elevated circulating SH-compounds.

Loss of decorin from the surface zone of articular cartilage in a chick model of osteoarthritis.

The objective of this study was to immunolocalize decorin and to assess changes as a result of pyridoxine (PN) deficiency in chick articular cartilage from femoral condyles. After maintenance on a normal diet for the first two weeks after hatching, 15 broiler chickens were deprived of this vitamin for 6 weeks. It was previously shown that the ankle joints of PN-deficient animals are swollen with effusions. They also present an abnormal gait, enlarged bony margins, and fissuring of the articular cartilages. Milder changes (no fissures) were also shown in the knee joints. Data from a previous study were suggestive that sulfated glycosaminoglycans are lost from the knee cartilage surface into synovial fluid. The current study was focused on the small proteoglycan, decorin, which coats the surface of collagen fibrils and may regulate their morphology. To examine decorin in normal and PN-deficient articular cartilage, a monoclonal antibody to an epitope on the protein core of decorin was used for immunohistochemical staining of tissue sections and for Western Blot analysis of cartilage extracts. Reduction of staining with the antibody was demonstrated in the tangential surface zone of PN-deficient cartilage, and Western Blot analysis showed reduced intensity of decorin bands compared to normal controls. These data suggest that a lack of decorin may play a role in the enlargement of collagen bundles in the tangential zone of PN-deficient articular cartilage as observed in a previous electron microscopic study.

Pyridoxine deficiency affects biomechanical properties of chick tibial bone.

The mechanical integrity of bone is dependent on the bone matrix, which is believed to account for the plastic deformation of the tissue, and the mineral, which is believed to account for the elastic deformation. The validity of this model is shown in this study based on analysis of the bones of vitamin B6-deficient and vitamin B6-replete chick bones. In this model, when B6-deficient and control animals are compared, vitamin B6 deficiency has no effect on the mineral content or composition of cortical bone as measured by ash weight (63 +/- 6 vs. 58 +/- 3); mineral to matrix ratio of the FTIR spectra (4.2 +/- 0.6 vs. 4.5 +/- 0.2), line-broadening analyses of the X-ray diffraction 002 peak (beta 002 = 0.50 +/- 0.1 vs. 0.49 +/- 0.01), or other features of the infrared spectra. In contrast, collagen was significantly more extractable from vitamin B6-deficient chick bones (20 +/- 2% of total hydroxyproline extracted vs. 10 +/- 3% p < or = 0.001). The B6-deficient bones also contained an increased amount of the reducible cross-links DHLNL, dehydro-dihydroxylysinonorleucine, (1.03 +/- 0.07 vs. 0.84 +/- 0.13 p < or = 0.001); and a nonsignificant increase in HLNL, dehydro-hydroxylysinonorleucine, (0.51 +/- 0.03 vs. 0.43 +/- 0.03, p < or = 0.10). There were no significant changes in bone length, bone diameter, or area moment of inertia. In four-point bending, no significant changes in elastic modulus, stiffness, offset yield deflection, or fracture deflection were detected. However, fracture load in the B6-deficient animals was decreased from 203 +/- 35 MPa to 151 +/- 23 MPa, p < or = 0.01, and offset yield load was decreased from 165 +/- 9 MPa to 125 +/- 14 MPa, p < or = 0.05. Since earlier histomorphometric studies had demonstrated that the B6-deficient bones were osteopenic, these data suggest that although proper cortical bone mineralization occurred, the alterations of the collagen resulted in changes to bone mechanical performance.

Connective tissue integrity is lost in vitamin B-6-deficient chicks.

The objective of the present investigation was to characterize further the connective tissue disorder produced by pyridoxine (vitamin B-6) deficiency, as previously evidenced by electron microscopy. Following the second post-natal week, fast growing male chicks were deprived of pyridoxine for a 1-mo period. Six weeks post-natally, blood concentrations in the experimental deficiency group had declined to deficiency levels as registered by low concentrations of pyridoxal phosphate (coenzyme form) in erythrocytes, but did not reach levels associated with neurological symptoms. Light microscopic study showed abnormalities in the extracellular matrix of the connective tissues. Collagen cross-links and the aldehyde contents were not significantly lower in cartilage and tendon collagens of vitamin B-6-deficient animals than in age-matched controls; also, their proteoglycan degrading protease and collagenase activities measured in articular cartilages were not greater. Thus, proteolysis was an unlikely alternative mechanism to account for the loss of connective tissue integrity. These results point to the need for further investigation into adhesive properties of collagen associated proteoglycans or other proteins in vitamin B-6-deficient connective tissue.

Effects of modifying dietary protein in the presence and absence of vitamin B6, on the regulation of plasma calcium and phosphorus levels--positive impact of yeast Saccharomyces cerevisiae.

Vitamin B6 status has been assessed according to the activation coefficient (AC) of plasma aspartic aminotransferase (AST) activity. Fast-growing male one-day-old broiler chicks, divided into two groups (supplemented with pyridoxine or not), were fed a soy protein isolate (Soyamin) or a purified amino acid diet containing or not Saccharomyces cerevisiae yeast (2%), primarily used to promote the growth of the B6-deficient animals. In one experiment, the protein level of the diet has been increased to augment the metabolic demand for PN. The B6-deficient Soyamin diet B containing yeast produced a mild deficiency (without incidence of morbidity and mortality) and the deficiency was severe (appearance of neurological symptoms after 10 days, AC 1.5) when yeast was deleted (diet A). The inclusion of yeast in both Soyamin and amino acid diets significantly increased plasma Ca and Pi levels (p < 0.001) whereas increasing the protein intake (diet C) had an inverse effect, reflecting an inhibitory effect on intestinal absorption of these minerals. Changes in plasma Ca and Pi levels due to dietary treatments were summarized in terms of their theoretical ion product. The amino acid diet D produced the lowest Ca x Pi ion product and the highest value was obtained with the yeast-containing diets B and E, regardless of the vitamin B6 intake and the dietary protein source. Plasma Ca and Pi levels were simultaneously elevated in severe vitamin B6 deficiency (diet A) as compared to control group (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Tubuloreticular structures in pyridoxine deficiency.

Electron microscopic studies on renal tissue obtained from animals subjected to pyridoxine deficiency have revealed the presence of round and/or tubular bodies in the cytoplasm of endothelial cells of the glomeruli. The bodies generally occur as aggregates in association with the endoplasmic reticulum. Along with the round forms other profiles are also observed. It is believed that they represent one of the many images of a system of undulating tubules. Since these bodies occur irrespective of the presence of virus particles in the tissue under study it is concluded that they are not viral in nature.

Electroencephalographic changes and periodontal status during short-term vitamin B-6 depletion of young, nonpregnant women.

As part of a larger investigation to determine the effect of animal vs. plant proteins on the vitamin B-6 requirement of young women, clinical changes during vitamin B-6 depletion were documented. Eight healthy young women were confined to a metabolic unit and fed a defined formula diet nearly devoid of vitamin B-6 (less than 0.05 mg/d). Serial electroencephalographic (EEG) tracings, peripheral nervous system tests, periodontal evaluations, and biochemical measures of vitamin B-6 status were conducted. Within 12 d on the depletion diet, two of the eight women exhibited abnormal EEG tracings. These changes were readily reversed by repletion of vitamin B-6 at the 0.5-mg/d level. Biochemical measures reflected lowered vitamin B-6 status but were not predictive of the onset of EEG changes. No detectable alterations in oral or periodontal status were found, nor did plaque flora change markedly. This study is the first report of EEG changes occurring in women undergoing vitamin B-6 depletion and the first report to document EEG changes in adults within 12 d on a vitamin B-6-depletion regimen.