The Promise of Niacin in Neurology.

Niacin (vitamin B3) is an essential nutrient that treats pellagra, and prior to the advent of statins, niacin was commonly used to counter dyslipidemia. Recent evidence has posited niacin as a promising therapeutic for several neurological disorders. In this review, we discuss the biochemistry of niacin, including its homeostatic roles in NAD+ supplementation and metabolism. Niacin also has roles outside of metabolism, largely through engaging hydroxycarboxylic acid receptor 2 (Hcar2). These receptor-mediated activities of niacin include regulation of immune responses, phagocytosis of myelin debris after demyelination or of amyloid beta in models of Alzheimer's disease, and cholesterol efflux from cells. We describe the neurological disorders in which niacin has been investigated or has been proposed as a candidate medication. These are multiple sclerosis, Alzheimer's disease, Parkinson's disease, glioblastoma and amyotrophic lateral sclerosis. Finally, we explore the proposed mechanisms through which niacin may ameliorate neuropathology. While several questions remain, the prospect of niacin as a therapeutic to alleviate neurological impairment is promising.

An Outbreak of Pellagra in the Kasese Catchment Area, Dowa, Malawi.

AbstractPellagra is a deficiency of niacin or its amino acid precursor, tryptophan, which presents with the classic four Ds: the characteristic dermatitis, diarrhea, dementia, and eventually death if left untreated. The incidence of pellagra is quite rare presently because of increased awareness and strategies such as vitamin fortification. However, the deficiency is still present in cultures that rely on maize as their primary source of sustenance. We report a recent outbreak in a catchment area in Kasese, Malawi, of 691 cases of pellagra which were successfully treated with niacin supplementation. We present this short report to highlight the importance of educating providers of at-risk populations about this diagnosis and to consider solutions for these populations to prevent further deficiencies.

Niacin metabolism and indoleamine 2,3-dioxygenase activation in malnourished patients with flaky paint dermatosis.

Flaky paint dermatosis, characterized by extensive, often bilateral areas of flaking and pigmentation, mostly in sun unexposed areas is considered a feature of kwashiorkor in both children and adults, and must be differentiated from other dermatosis, including chapped and xerotica skin, and pellagra. In this case series we provide evidence that malnourished patients with flaky paint dermatosis and infection/inflammation shown laboratory data suggestive of indoleamine 2,3-dioxygenase (IDO) activation, besides decreased urinary excretion of N1-methylnicotinamide (N1 MN), a marker of pellagra. We study nine adult patients showing flaky paint dermatosis and clinical features of infection or inflammation, and increased serum C-reactive protein, characteristic of the presence of acute phase response syndrome. As a group, they had low or deficient urinary N1 MN excretion (0.52 ± 0.39 mg/g creatinine) compatible with pellagra. They also showed low serum tryptophan levels (<29 µmol/L) and a serum kynurenine/tryptophan ratio higher than 0.04, suggesting increased IDO expression and increase in the tryptophan oxidation. Findings suggest that some patients with flaky paint dermatosis showed laboratory data suggestive of IDO activation, besides decreased N1 MN urinary excretion. Taken together, the data support the idea that flaky paint dermatosis could be a skin manifestation of niacin deficiency.

[Niacin deficiency and cutaneous immunity].

Niacin, also known as vitamin B3, is required for the synthesis of coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin binds with G protein-coupled receptor (GPR) 109A on cutaneous Langerhans cells and causes vasodilation with flushing in head and neck area. Niacin deficiency due to excessive alcohol consumption, certain drugs or inadequate uptake in diet causes pellagra, a photosensitivity dermatitis. Recently several studies have revealed the mechanism of photosensitivity in niacin deficiency, which may pave a way for new therapeutic approaches. The expression level of prostaglandin E synthase (PTGES) is up-regulated in the skin of both pellagra patients and niacin deficient pellagra mouse models. In addition, pellagra is mediated through prostaglandin E2-EP4 (PGE2-EP4) signaling via reactive oxygen species (ROS) production in keratinocytes. In this article, we have reviewed the role of niacin in immunity and the mechanism of niacin deficiency-induced photosensitivity.

Pellagra and alcoholism: a biochemical perspective.

Historical and clinical aspects of pellagra and its relationship to alcoholism are reviewed from a biochemical perspective. Pellagra is caused by deficiency of niacin (nicotinic acid) and/or its tryptophan (Trp) precursor and is compounded by B vitamin deficiencies. Existence on maize or sorghum diets and loss of or failure to isolate niacin from them led to pellagra incidence in India, South Africa, Southern Europe in the 18th century and the USA following the civil war. Pellagra is also induced by drugs inhibiting the conversion of Trp to niacin and by conditions of gastrointestinal dysfunction. Skin photosensitivity in pellagra may be due to decreased synthesis of the Trp metabolite picolinic acid → zinc deficiency → decreased skin levels of the histidine metabolite urocanic acid and possibly also increased levels of the haem precursor 5-aminolaevulinic acid (5-ALA) and photo-reactive porphyrins. Depression in pellagra may be due to a serotonin deficiency caused by decreased Trp availability to the brain. Anxiety and other neurological disturbances may be caused by 5-ALA and the Trp metabolite kynurenic acid. Pellagra symptoms are resolved by niacin, but aggravated mainly by vitamin B6. Alcohol dependence can induce or aggravate pellagra by inducing malnutrition, gastrointestinal disturbances and B vitamin deficiencies, inhibiting the conversion of Trp to niacin and promoting the accumulation of 5-ALA and porphyrins. Alcoholic pellagra encephalopathy should be managed with niacin, other B vitamins and adequate protein nutrition. Future studies should explore the potential role of 5-ALA and also KA in the skin and neurological disturbances in pellagra.

Rapidly progressing bilateral cataracts in a patient with beta thalassemia and pellagra.

Soon after the diagnosis of pellagra in a 20-year-old patient with beta thalassemia, bilateral intumescent cataracts rapidly developed. We believe the patient's crystalline lenses were at an increased oxidative state due to iron overload from the thalassemia. Depletion of the lens epithelial cells of an important antioxidative agent (glutathione) as a result of niacin (vitamin B3) deficiency due to pellagra reduced the antioxidative capacity of the lenses. The oxidative damage led to rapid development of cataracts.

[Niacin in therapy]. / Zastosowanie niacyny w terapii.

Niacin (nicotinic acid and nicotinamide) is a vitamin used as a source of the NAD+ and NADP+ coenzymes required for many metabolic processes. Its low dietary levels induce the development of pellagra. Niacin has been used for decades in the treatment of patients with disturbed lipid and lipoprotein metabolism, this being the main cause of atherosclerotic changes in cardiovascular diseases. It is still the most efficacious drug in terms of its ability to increase HDL cholesterol content accompanied by a decrease in all atherogenic lipoproteins (VLDL, LDL, and L(a)) as well as fatty acids and triglycerides. Niacin also increases adiponectin level, which might result in additional atheroprotection. There are studies confirming the beneficial action of niacin against migraine and hyperphosphatemia associated with renal failure, ethanol-induced neurodegeneration, and loss of beta-cell function in type 1 diabetes. Moreover, it augments plasma tryptophan concentrations in HIV-infected patients and thyroid radiosensitivity to 131I. Inhibition of the invasion of hepatoma cells has also been proven. However, it is necessary to point out that the currently applied niacin preparations might exhibit such side effects as cutaneous flushing, gastrointestinal disturbances, and hepatotoxicity, particularly during treatment with sustained-release niacin preparations. The recent discovery of the G-protein-coupled receptor GPR109A, which mediates the antilipolytic effects induced by nicotinic acid in adipocytes as well as cutaneous vasodilation, allows the development of new agents interacting with this receptor. In view of these observations, niacin therapy must be accompanied by control of the choice of niacin preparation and its dose in order to eliminate or at least limit its side effects.

Increase in conversion of tryptophan to niacin in pregnant rats.

There is the report that the deaths by pellagra in women is approximately twofold excess that in men. In the present experiment, in order to clarify a factor in the etiology of pellagra in female and to get basic information how much niacin should be supplemented in pregnant state, we investigated the effects of pregnant on the metabolism of tryptophan to niacin in rats. The daily urine samples were collected from day -17 and day +6 (the delivery day was designated as day 0) and the intermediates of tryptophan to niacin were measured. The metabolites such as kynurenic acid, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide, N1-methyl-4-pyridone-3-carboxamide were increased with progress in pregnant and returned to normal levels after the delivery. The catabolism of tryptophan is accelerated during pregnancy, indicataing that pregnancy would not be an etiology of pellagra and no niacin supplement needs but tryptohan supplement would need.

Cutaneous manifestations of eating disorders.

BACKGROUND AND OBJECTIVE: No complete review of the cutaneous manifestations of eating disorders exists. We therefore, set out to review and systematically describe the clinical and histopathologic features of dermatologic conditions associated with anorexia nervosa, bulimia nervosa, and obesity. Differential diagnosis, pathophysiology, laboratory studies, and treatment are also reviewed. METHODS: Index Medicus review (1966 to present) using Ovid-MEDLINE. Search terms included eating disorders, anorexia nervosa, bulimia nervosa, eating disorders not otherwise specified (ED-NOS), and obesity, as well as the terms dermatology skin and cutaneous manifestations, with cross-referencing sources. These were combined with our own clinical experience. All relevant publications, including case reports, case series, cohort studies, and histopathologic studies giving at least Level II-3 evidence (evidence from comparisons between times or places with or without the intervention, including dramatic results in uncontrolled experiments), were selected. CONCLUSION: Forty dermatological signs have been reported in eating disorder patients. Eating disorders have many cutaneous manifestations and cutaneous signs may lead to the diagnosis of an occult eating disorder. The resolution of skin eruptions in eating disorder patients often depends on treatment of the underlying disorder.

Effects of sex hormones on the metabolism of tryptophan to niacin and to serotonin in male rats.

It is known that deaths attributable to pellagra, which is considered to be a disease caused by the disturbance of tryptophan metabolism, have been approximately two-fold higher in women than in men. We investigated the effects of the administration of female and male sex hormones on the contents of tryptophan and such metabolites as serotonin, nicotinamide, N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide, and N1-methyl-4-pyridone-3-carboxamide, and on the conversion ratio of tryptophan to niacin in male rats. Feeding a diet containing estrone or testosterone had no effect on the concentrations of tryptophan and serotonin in the blood and brain, or on the concentration of 5-hydroxyindole-3-acetic acid in the brain. On the contrary, feeding a diet containing estrone caused to a decrease in the urinary excretion of nicotinamide, N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide, and N1-methyl-4-pyridone-3-carboxamide, and of the conversion ratio of tryptophan to niacin when compared with the control rats. Feeding a diet containing testosterone had no effect on any parameter. We postulate from these findings that the cause of higher pellagra deaths in women than in men is attributable to the decrease in the formation of niacin from tryptophan, but not in the formation of serotonin by the female hormone. It seems likely that female sex hormones inhibit the synthesis of niacin from tryptophan, and that women, especially during pregnancy, will be more at risk to pellagra than are men.

Assessment of zinc nutritional status of pellagra patients.

The objective of the present study was to assess zinc nutritional status in alcoholic patients with pellagra using plasma, hair, urine and nail zinc levels, as well as the zinc tolerance test. The study was conducted on 81 patients, 73 males and eight females. Zinc parameters were compared with those of 84 individuals with no apparent disease aged 23-45 years. Plasma zinc levels were lower in patients with pellagra than in the controls (P < 0.01). The results of the zinc tolerance test showed that: (1) basal zinc levels were 69.7 +/- 16.8 micrograms/100 ml in pellagrins and 82.3 +/- 34.0 micrograms/100 ml in the controls (P < 0.01); (2) after 1 h the increase in plasma levels was similar in the pellagrin and control groups; (3) during the second hour the increase was more marked in the controls (P < 0.01), and the same was observed during the third and fourth hours (P < 0.05). Urinary zinc excretion (mg/24 h) was higher in pellagrins (P < 0.01). Zinc concentration in hair and toenails did not differ between pellagrins and controls. We conclude that pellagrins present zinc deficiency as demonstrated by plasma and urine zinc levels and by their abnormal response to the zinc tolerance test. We suggest that hair and nail zinc levels should not be used to assess zinc nutritional status in patients with pellagra.

Dietary niacin deficiency lowers tissue poly(ADP-ribose) and NAD+ concentrations in Fischer-344 rats.

Poly(ADP-ribose) is synthesized in response to DNA strand breaks, using NAD+ as substrate, and has been implicated in the process of DNA repair. Because NAD+ can be synthesized from niacin or tryptophan, both of these components must be manipulated to alter niacin status. Six dietary treatments were used, including niacin-deficient (ND) diets and niacin-replete (NR) diets consumed ad libitum and the NR diets pair-fed (PF) to the ND intake. The ND, NR and PF diets contained either 80 g casein + 50 g gelatin/kg diet (8-5 diets) or 70 g casein + 60 g gelatin/kg diet (7-6 diets) to control tryptophan content. The 8-5ND and 7-6ND diets induced mild and severe symptoms of niacin deficiency, respectively, over a 3-wk period in male weanling Fischer-344 rats. Food intake and weight gain were suppressed in both of the ND groups compared with their respective NR controls. Weight gain was not different between ND animals and their PF counterparts. At 3 wk, blood, liver, kidney, heart and lung NAD+ concentrations for both 8-5ND and 7-6ND animals were all significantly lower than those for their respective PF groups. In the groups fed the 8-5 diets, liver poly(ADP-ribose) was lower in the ND group (64% of PF), with no difference between the NR and PF groups. In rats fed the 7-6 diets, poly(ADP-ribose) levels were further decreased in the ND group (43% of PF), but food restriction also exerted an independent effect (PF levels were 46% of NR levels).(ABSTRACT TRUNCATED AT 250 WORDS)

[The functional characteristics of the inhibitory mediator systems in the brain synaptosomes of PP vitamin-deficient rats]. / Osobennosti funktsionirovaniia tormoznykh mediatornykh sistem sinaptosom golovnogo mozga u PP-gipovitaminoznykh krys.

A decrease of the NAD and serotonin level in the brain of rats with PP hypovitaminosis is shown. NAD in concentration of 10(-6) M in vitro exerts a less pronounced inhibiting influence on the neuronal uptake of [14C]serotonin and [14C]GABA by brain synaptosomes of rats with PP hypovitaminosis. GABA content under such conditions increases as compared with the control and correlates with changes in the [14C]GABA uptake system.

NADP+ biosynthesis by rats receiving a pellagragenic diet.

Rats showing signs of pellagra-like disease associated with gelatin ingestion were injected with [14C]-nicotinic acid into the portal vein and the incorporation of the label into hepatic NAD+ and NADP+ was determined. The quantity of NADP+ synthesized within 1 h after [14C]-nicotinic acid injection by the experimental group, supplemented or not with dietary niacin, was 75% lower than that synthesized by the control group fed a casein control diet (141 nmol h-1 g-1). The NAD+ and NADP+ contents of the liver of the experimental animals were 245 and 93 micrograms/g liver, respectively, i.e., significantly lower than those for the controls (597 and 210 micrograms/g, respectively). Dietary supplementation with niacin increased the NAD+ content to 317 micrograms/g liver but had no statistical effect on NADP+ content (75 micrograms/g liver) or NADP+ synthesis (46.5 in the free niacin group vs 37.0 nmol h-1 g-1 in the niacin-supplemented group). Therefore, NAD+ content did not seem to limit NADP+ synthesis. These results suggest that the lower availability of NADP+ is responsible, at least in part, for some metabolic derangements in pellagra-like disease, such as a decrease in the activity of NADP(+)-dependent enzymes observed in quail muscle.

Nadp+ biosynthesis by rats receiving a pellagragenic diet

Rats showing signs of pellagra-like disease associated with gelatin ingestion were injected with [14C}-nicotinic acid into the portal vein and the incorporation of the label into hepatic NAD+ and NADP+ was determined. The quantity of NADP+ synthesized within 1 h after [14C]-nicotine acid injection by the experimental group, supplemented or not with dietary niacin, was 75% lower than that synthesized by the control group fed a casein control diet (141nmol h-1 g-1). The NAD+ and NADP+ contents of the liverof the experimental animals were 245 and 93 *g/g liver, respectively, i. e., significantly lower than those for the controls (597 and 210 *g/g liver, respectively). Dietary supplementation with niacin increased the NAD+ content to 317 */g liver but had no statistical effect on NADP+ content (75 *g/g liver) or NADP+ synthesis (46.5 in the free niacin group vs 37.0 nmol h-1 g-1 in the niacin-supplemented group). Therefore, NAD+ content did not seem to limit NADP+ synthesis. These results that the lower availably of NADP+ is responsible, at least in part, for some metabolic derangements in pellagra-like disease, such as a decrease in the activity of NADP+-dependent enzymes observed in quail muscle

Fenilcetonúria clássica com manifestaçäo de dermatite pelagróide / Classic phenylketonuria with pellagra-like dermatitis manifestation

A fenilcetonúria clássica, erro inato do metabolismo transmitido de modo autossômico recessivo, caracteriza-se habitualmente por retardo mental, eczema, diluiçäo pigmentar, alteraçöes neurológicas e hiperfenilalaninemia. Apresenta-se um paciente fenilcetonúrico que mostra, além das manifestaçöes freqüentemente relatadas, episódios de dermatite pelagróide fotossensível acompanhada de deterioraçäo do comportamento, e que respondem a terapêutica com nicotinamida. A fotossensibilidade é atribuída a diluiçäo pigmentar secundária a produçäo deficiente de melanina e possivelmente a diminuiçäo da absorçäo intestinal do triptofano, que leva a níveis reduzidos de nicotinamida, ambas provocadas pela hiperfenilalaninemia. Para o dermatologista, é importante atentar para os distúrbios metabólicos ao se deparar com a associaçäo retardo mental-dermatite pelagróide

Interaction of niacin and zinc metabolism in patients with alcoholic pellagra.

The effect of zinc supplementation on the metabolism of tryptophan conversion to niacin was studied in 14 alcoholic patients with pellagra and in 7 male control subjects aged 21-45 y. The pellagrins received chemically defined diets based on crystalline amino acids through an enteral tube for 7 d. Patients were divided into two groups (A and B), both receiving a diet from which tryptophan, Zn, and niacin were excluded. Patients in group B, however, received 220 mg Zn sulfate orally. Upon admission the pellagra patients had low plasma Zn levels and low urinary excretion values of N'methylnicotinamide (N'MN) and N'methyl-2-pyridone-5-carboxamide (2-PYR) in relation to the control subjects (p less than 0.01). During the experimental period there was an increase in plasma Zn levels (p less than 0.005) and in urinary N'MN (p less than 0.05) and 2-PYR (p less than 0.05) excretion in the patients receiving Zn supplementation (group B). These results suggest that Zn interacts with niacin metabolism in alcoholic patients with pellagra through a probable mediation by vitamin B-6.