Pellagra in the USA: unusual manifestations of a rare entity.

The case involves a 62-year-old female native of the USA with a history of bipolar disorder and chronic obstructive pulmonary disease who presented with intractable diarrhoea. Prior to the index admission, she was admitted to the intensive care unit and required pericardiocentesis for an idiopathic pericardial effusion with tamponade physiology. Following discharge, she suffered intractable diarrhoea and represented for medical evaluation. She had a painful, swollen tongue as well as persistent hypoglycaemia and required glucose infusions. She had adrenal function testing which revealed adrenal insufficiency. Vitamin testing revealed normal B12 and folate levels but undetectable levels of thiamine, riboflavin and niacin. Her symptoms and signs resolved entirely with appropriate vitamin supplementation. Niacin (vitamin B3) is essential for multiple metabolic pathways, and severe deficiency may cause clinical syndrome of pellagra which is most commonly associated with diarrhoea, delirium and dermatitis. Additional physiological derangements may include adrenal insufficiency, insulin hypersensitivity and pericarditis.

[Skin Manifestations of Pellagra].

Pellagra is a type of dietary deficiency disease caused by an insufficiency of niacin or tryptophan. Symptoms of pellagra include diarrhea, dermatitis, and dementia. It is usually diagnosed based on a patient's dietary history and clinical symptoms. The diagnostic triad of pellagra includes symptoms of dermatitis, dementia, and diarrhea. Dermatitis is important for the diagnosis of this condition, because dementia and diarrhea show low specificity. In the modern era, pellagra rarely occurs in developed countries. However, pellagra should be considered in the differential diagnoses of dermatitis occurring on the sun-exposed areas of skin. Additionally, a hypoalimentation state with concomitant vitamin and/or zinc deficiency is observed in patients with pellagra. After checking the patient's overall nutritional status specifically with respect to pellagra, it is important to provide adequate food, supplemented with vitamins, zinc, and nicotinic acid to treat the patient's nutritional deficiencies.

Recognising the return of nutritional deficiencies: a modern pellagra puzzle.

A 34-year-old previously well woman presented with a 4-week history of diffuse erythema and crusting of skin affecting all four limbs. Examination revealed erythematous skin plaques associated with ulceration and fissuring affecting sun-exposed areas of all four limbs primarily on the dorsal surfaces, and a body mass index of 17 kg/m2 She was admitted under the infectious diseases unit, and an autoimmune and infective screen was performed which returned unremarkable. Dietetic consultation led to the diagnosis of severe protein-energy malnutrition, consequent to a severely restricted, primarily vegan, diet. Analysis of the patient's reported diet with nutritional software revealed grossly suboptimal caloric intake with risk of inadequacy for most micronutrients, vitamins and minerals, including niacin. Oral thiamine, multivitamin, iron supplementation and vitamin B complex were started, and a single intramuscular vitamin B12 dose was administered. Marked improvement was seen after 6 weeks, with near-complete resolution of skin changes. These findings supported a diagnosis of pellagra.

Adaptation of New Colombian Food-based Complementary Feeding Recommendations Using Linear Programming.

OBJECTIVE: The aim of the study was to use linear programming (LP) analyses to adapt New Complementary Feeding Guidelines (NCFg) designed for infants aged 6 to 12 months living in poor socioeconomic circumstances in Bogota to ensure dietary adequacy for young children aged 12 to 23 months. DESIGN: A secondary data analysis was performed using dietary and anthropometric data collected from 12-month-old infants (n = 72) participating in a randomized controlled trial. LP analyses were performed to identify nutrients whose requirements were difficult to achieve using local foods as consumed; and to test and compare the NCFg and alternative food-based recommendations (FBRs) on the basis of dietary adequacy, for 11 micronutrients, at the population level. RESULTS: Thiamine recommended nutrient intakes for these young children could not be achieved given local foods as consumed. NCFg focusing only on meat, fruits, vegetables, and breast milk ensured dietary adequacy at the population level for only 4 micronutrients, increasing to 8 of 11 modelled micronutrients when the FBRs promoted legumes, dairy, vitamin A-rich vegetables, and chicken giblets. None of the FBRs tested ensured population-level dietary adequacy for thiamine, niacin, and iron unless a fortified infant food was recommended. CONCLUSIONS: The present study demonstrated the value of using LP to adapt NCFg for a different age group than the one for which they were designed. Our analyses suggest that to ensure dietary adequacy for 12- to 23-month olds these adaptations should include legumes, dairy products, vitamin A-rich vegetables, organ meat, and a fortified food.

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.

Deficiency of dietary niacin impaired gill immunity and antioxidant capacity, and changes its tight junction proteins via regulating NF-κB, TOR, Nrf2 and MLCK signaling pathways in young grass carp (Ctenopharyngodon idella).

To investigate the effects of dietary niacin on gill immunity, tight junction proteins, antioxidant system and related signaling molecules mRNA expression, young grass carp (Ctenopharyngodon idella) were fed six diets containing graded levels of niacin (3.95-55.01 mg/kg diet) for 8 weeks. The study indicated that niacin deficiency decreased lysozyme and acid phosphatase activities, and complement 3 content, and caused oxidative damage that might be partly due to the decreased copper, zinc superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and glutathione-S-transferase activities and reduced glutathione content in fish gills (P < 0.05). Moreover, the relative mRNA levels of antimicrobial peptides (liver expressed antimicrobial peptide 2 and Hepcidin), anti-inflammatory cytokines (interleukin 10 and transforming growth factor ß1), tight junction proteins (Occludin, zonula occludens 1, Claudin-15 and -3), signaling molecules (inhibitor of κBα (IκBα), target of rapamycin (TOR), ribosomal protein S6 kinase 1 (S6K1) and NF-E2-related factor 2 (Nrf2)) and antioxidant enzymes were significantly decreased (P < 0.05) in niacin-deficient diet group. Conversely, the mRNA levels of pro-inflammatory cytokines (tumor necrosis factor α, interleukin 8, interferon γ2, and interleukin 1ß), signaling molecules (nuclear factor kappa B p65, IκB kinase α, IκB kinase ß, IκB kinase γ, Kelch-like-ECH-associated protein 1b, myosin light chain kinase and p38 mitogen-activated protein kinase (p38 MAPK) were significantly increased (P < 0.05) in fish gills fed niacin-deficient diet. Interestingly, the varying niacin levels of 3.95-55.01 mg/kg diet had no effect on the mRNA level of Kelch-like-ECH-associated protein 1a, Claudin-c and -12 in fish gills (P > 0.05). In conclusion, niacin deficiency decreased gill immunity, impaired gill antioxidant system, as well as regulated mRNA expression of gill tight junction proteins and related signaling molecules of fish.

Deficiency of dietary niacin impaired intestinal mucosal immune function via regulating intestinal NF-κB, Nrf2 and MLCK signaling pathways in young grass carp (Ctenopharyngodon idella).

This study investigated the effects of dietary niacin on intestinal mucosal immune and physical barrier, and relative mRNA levels of signaling molecules in the intestine of young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp (255.63 ± 0.41 g) were fed six diets containing graded levels of niacin (3.95, 14.92, 24.98, 35.03, 44.97 and 55.01 mg/kg diet) for 8 weeks. Results observed that niacin deficiency decreased lysozyme (LA) and acid phosphatase (ACP) activities, and complement 3 (C3) content in the intestine (P < 0.05), down-regulated mRNA levels of liver expressed antimicrobial peptide 2 (LEAP-2), hepcidin, interleukin 10, transforming growth factor ß1 and inhibitor of κBα (IκBα) (P < 0.05), up-regulated tumor necrosis factor α, interleukin 1ß, interferon γ2, interleukin 8, nuclear factor kappa B P65 (NF-κB P65), IκB kinase α (IKKα), IκB kinase ß (IKKß) and IκB kinase γ (IKKγ) in all intestinal segments of young grass carp (P < 0.05). In addition, niacin deficiency increased reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl (PC) contents, decreased glutathione content, and copper/zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferases (GST) and glutathione reductase (GR) activities in the intestine of young grass carp (P < 0.05). Additionally, niacin deficiency decreased mRNA levels of CuZnSOD, MnSOD, GPx, CAT, GST, GR, Claudin b, Claudin 3, Claudin c, Occludin, ZO-1, Claudin 15 and NF-E2-related factor 2 (Nrf2) (P < 0.05), and increased Claudin 12, Kelch-like ECH-associating protein 1a (Keap1a), myosin light-chain kinase (MLCK) and p38 mitogen-activated protein kinase (p38 MAPK) mRNA expression levels in the intestine of young grass carp (P < 0.05), while the mRNA level of Kelch-like ECH-associating protein 1b (Keap1b) did not change (P > 0.05). In conclusion, niacin deficiency decreased intestinal mucosal immune and intestinal physical function, as well as regulated mRNA levels of NF-κB P65, IκBα, IKKα, IKKß, IKKγ, Nrf2, Keap1a, p38 MAPK and MLCK in the intestine of young grass carp. Based on the broken-line model analysis of intestinal lysozyme activity, the requirement of niacin for young grass carp (255.63 ± 0.41 g) were estimated to be 39.80 mg/kg diet.

Effectiveness in improving knowledge, practices, and intakes of "key problem nutrients" of a complementary feeding intervention developed by using linear programming: experience in Lombok, Indonesia.

BACKGROUND: Complementary feeding recommendations (CFRs) with the use of locally available foods can be developed by using linear programming (LP). Although its potential has been shown for planning phases of food-based interventions, the effectiveness in the community setting has not been tested to our knowledge. OBJECTIVE: We aimed to assess effectiveness of promoting optimized CFRs for improving maternal knowledge, feeding practices, and child intakes of key problem nutrients (calcium, iron, niacin, and zinc). DESIGN: A community-intervention trial with a quasi-experimental design was conducted in East Lombok, West Nusa Tenggara Province, Indonesia, on children aged 9-16 mo at baseline. A CFR group (n = 240) was compared with a non-CFR group (n = 215). The CFRs, which were developed using LP, were promoted in an intervention that included monthly cooking sessions and weekly home visits. The mother's nutrition knowledge and her child's feeding practices and the child's nutrient intakes were measured before and after the 6-mo intervention by using a structured interview, 24-h recall, and 1-wk food-frequency questionnaire. RESULTS: The CFR intervention improved mothers' knowledge and children's feeding practices and improved children's intakes of calcium, iron, and zinc. At the end line, median (IQR) nutrient densities were significantly higher in the CFR group than in the non-CFR group for iron [i.e., 0.6 mg/100 kcal (0.4-0.8 mg/100 kcal) compared with 0.5 mg/100 kcal (0.4-0.7 mg/100 kcal)] and niacin [i.e., 0.8 mg/100 kcal (0.5-1.0 mg/100 kcal) compared with 0.6 mg/100 kcal (0.4-0.8 mg/100 kcal)]. However, median nutrient densities for calcium, iron, niacin, and zinc in the CFR group (23, 0.6, 0.7, and 0.5 mg/100 kcal, respectively) were still below desired densities (63, 1.0, 0.9, and 0.6 mg/100 kcal, respectively). CONCLUSIONS: The CFRs significantly increased intakes of calcium, iron, niacin, and zinc, but nutrient densities were still below desired nutrient densities. When the adoption of optimized CFRs is constrained by economic access for or acceptability of nutrient-dense foods, other strategies need to be incorporated into interventions to ensure adequate intakes of these nutrients.

Antidepressants may lead to a decrease in niacin and NAD in patients with poor dietary intake.

The term niacin is the generic name for the two compounds nicotinic acid and nicotinamide, the major dietary precursors for two important coenzymes, nicotinamide adenine dinucleotide (NAD) and its phosphorylated form, NADP. Niacin is important for the maintenance of cellular integrity and energy production and is involved in more than 500 intracellular reactions. Deficiencies of niacin may contribute to neuropsychiatric and neurodegenerative disorders. Patients who develop nutritional deficiencies as a result of poor dietary intake, especially inadequate intake of proteins and vitamins, could potentially suffer from niacin deficiency and NAD depletion. However, de novo synthesis of niacin and NAD in the kynurenine pathway of tryptophan metabolism may compensate for impaired dietary intake. The rate of synthesis of NAD and niacin from tryptophan oxidation depends on the induction of the enzyme indoleamine 2,3-dioxygenase (IDO) by pro-inflammatory cytokines such as interferon-gamma. Niacin synthesis is not limited by a decrease in tryptophan and excessive IDO activity may therefore lead to a decline in tryptophan levels. Antidepressants have an anti-inflammatory effect, including reduction of interferon-gamma and therefore inhibition of IDO, the rate-limiting enzyme of the kynurenine pathway. In theory, this could account for increased serotonin as more tryptophan becomes available for serotonin synthesis. However, the downside may be that less NAD and niacin are synthesised downstream, which could exacerbate common psychiatric problems. It is our hypothesis that patients with poor dietary intake, who are treated with antidepressants, are at risk of developing niacin/NAD deficiency with possible development of associated neuropsychiatric symptoms. We therefore propose that niacin supplementation be considered in patients with inadequate diets who are treated with antidepressants. We believe that if this does not happen, a subclinical niacin deficiency may result, which would be difficult to detect as it would cause the same symptoms of the original illness (e.g. depression). Niacin deficiency should be considered and ruled out in all patients with treatment-resistant depression, who have a poor response to antidepressants. This is potentially a cost-effective and easy intervention, which could be examined in a randomized controlled trial.

Dietary nicotinic acid supplementation ameliorates chronic alcohol-induced fatty liver in rats.

BACKGROUND: Alcohol abuse frequently causes niacin deficiency in association with the development of alcoholic liver disease. The objective of the present study was to determine whether dietary nicotinic acid (NA) deficiency exaggerates and whether dietary NA supplementation alleviates alcohol-induced fatty liver. METHODS: Male Sprague-Dawley rats were pair-fed with 4 isocaloric liquid diets: control, ethanol (EtOH), EtOH with dietary NA deficiency, and EtOH with dietary NA supplementation, respectively, for 8 weeks. The control and EtOH diets contained normal levels of NA (7.5 mg/l). Dietary NA deficiency (0 mg NA/l) was achieved by removing NA from the vitamin mix, while NA was added to the liquid diet at 750 mg/l for dietary NA supplementation. RESULTS: Chronic EtOH feeding induced significant lipid accumulation in the liver, which was not worsened by dietary NA deficiency, but was ameliorated by dietary NA supplementation. Liver total NAD, NAD(+) , and NADH levels were remarkably higher in the NA supplemented group than the NA deficient or EtOH alone groups. Dietary NA supplementation to EtOH-fed rats increased the protein levels of hepatic cytochrome P450 4A1 (CYP4A1) and acyl-coenzyme A oxidase 1 without affecting their mRNA levels. Interestingly, we found dietary NA supplementation reduced the ubiquitination level of CYP4A1. In addition, hepatic fatty acid synthase expression was reduced, while the serum ß-hydroxybutyrate and adiponectin concentrations were significantly elevated by dietary NA supplementation. Moreover, dietary NA supplementation modulated EtOH-perturbed liver and serum metabolite profiles. CONCLUSIONS: These results demonstrate that alcoholic fatty liver was not exaggerated by dietary NA deficiency, but was ameliorated by dietary NA supplementation. Increased hepatic fatty acid oxidation and decreased hepatic de novo lipogenesis contribute to the effects of dietary NA supplementation.

A case of pellagra associated with megaduodenum in a young woman.

Pellagra is a rare condition that has been known for many years to be related to niacin deficiency. Clinically known as the 4 "D" symptoms for dermatitis, diarrhea, dementia, and even death, skin changes remain one of the most important features of this pathology, leading frequently to the diagnosis. Pellagra is mostly seen in poor populations with a deficient diet; still, it is sporadically observed in developed countries, usually in association with digestive disorders. We report a new case of pellagra in a 29-year-old woman in whom the diagnosis of megaduodenum was made. Megaduodenum is a rare condition that can be idiopathic or secondary to visceral myopathy or neuropathy. Parenteral supplementation with niacin has resulted in a quick response of dermatological and psychiatric symptoms. To our knowledge, no case of pellagra due to megaduodenum has been reported in literature.

Several 'problem nutrients' are identified in complementary feeding of Guatemalan infants with continued breastfeeding using the concept of 'critical nutrient density'.

BACKGROUND/OBJECTIVES: The World Health Organization (WHO) recommends nutritionally adequate complementary feeding (CF) through the introduction of indigenous foodstuffs and local foods while breastfeeding for at least 2 years. To determine the adequacy of the contribution of CF to the diets of Guatemalan infants at the 7th-12th month of life receiving high-intensity continued breastfeeding. SUBJECTS/METHODS: Critical nutrient densities for CF were modelled using age- and sex-specific energy and protein requirements assuming children to be at the 50th weight percentile of local peers and 15th weight percentiles of the 2006 WHO standards. Nutrient requirements for the total diet were determined using the recommended nutrient intakes. Breast milk was assumed to provide 75% of total energy at the 7th-9th month and 50% at the 10th-12th month. Gaps between computed critical nutrient densities and the CF consumption of 128 Guatemalan infants based on data collected by means of three nonconsecutive 24-h quantitative intake recalls were examined. Locally consumed foods with nutrient densities above the modelled critical densities were identified. RESULTS: Observed non-breast milk complementation would result in total diets providing inadequate nutrient density for vitamin A, niacin and vitamin C in some age groups. Major gaps for calcium, iron and zinc were ubiquitous across all groups. Few foods commonly consumed among Guatemalan infants had adequate densities of 'problem nutrients'. CONCLUSIONS: The critical nutrient density concept is useful to evaluate the nutrient adequacy of the infant's diet. Fortified foods are essential sources of the main 'problem nutrients', namely calcium, iron and zinc, given that natural sources are scarce.

Niacin status and genomic instability in bone marrow cells; mechanisms favoring the progression of leukemogenesis.

Niacin deficiency causes dramatic genomic instability in bone marrow cells in an in vivo rat model. The end result is seen in the increased incidence of sister chromatid exchanges, micronuclei, chromosomal aberrations and the eventual development of nitrosourea-induced leukemias. From a mechanistic perspective, niacin deficiency delays excision repair and causes double strand break accumulation, which in turn favor chromosome breaks and translocations. Niacin deficiency also impairs cell cycle arrest and apoptosis in response to DNA damage, which combine to encourage the survival of cells with leukemogenic potential. Niacin deficiency also enhances the level of oxidant damage found in cellular proteins and DNA, but not through depression of GSH levels. Pharmacological supplementation of niacin decreases the development of nitrosourea-induced leukemias, while short term effects of high niacin intake include a large increase in cellular NAD+ and poly(ADP-ribose) content and enhanced apoptosis. These results are important to cancer patients, which tend to be niacin deficient, are exposed to large doses of genotoxic drugs, and suffer short-term bone marrow suppression and long-term development of secondary leukemias. The data from our rat model suggest that niacin supplementation of cancer patients may decrease the severity of short and long-term side effects, and may also improve tumor cell killing through activation of poly(ADP-ribose)-dependent apoptosis pathways.

Niacin requirements for genomic stability.

Through its involvement in over 400 NAD(P)-dependent reactions, niacin status has the potential to influence every area of metabolism. Niacin deficiency has been linked to genomic instability largely through impaired function of the poly ADP-ribose polymerase (PARP) family of enzymes. In various models, niacin deficiency has been found to cause impaired cell cycle arrest and apoptosis, delayed DNA excision repair, accumulation of single and double strand breaks, chromosomal breakage, telomere erosion and cancer development. Rat models suggest that most aspects of genomic instability are minimized by the recommended levels of niacin found in AIN-93 formulations; however, some beneficial responses do occur in the range from adequate up to pharmacological niacin intakes. Mouse models show a wide range of protection against UV-induced skin cancer well into pharmacological levels of niacin intake. It is currently a challenge to compare animal and human data to estimate the role of niacin status in the risk of genomic instability in human populations. It seems fairly certain that some portion of even affluent populations will benefit from niacin supplementation, and some subpopulations are likely well below an optimal intake of this vitamin. With exposure to stressors, like chemotherapy or excess sunlight, suraphysiological doses of niacin may be beneficial.

Dietary nicotinic acid supplementation improves hepatic zinc uptake and offers hepatoprotection against oxidative damage.

We examined the effect of dietary nicotinic acid (NA) variations before and after oxidative stress (OS) treatment on the antioxidant defence system, function and morphology of the liver along with Zn status in rats. OS was generated by three intraperitoneal injections of tert-butyl hydroperoxide in the first week for the pre-exposure group and in the third week for the post-exposure group, respectively. These groups were further divided into subgroups and fed on a diet with marginally deficient Zn (10 mg Zn/kg diet) and NA variations as NA deficient, normal and excess with 10, 30 and 1000 mg NA/kg diet, respectively. Aspartate aminotransferase and alanine aminotransferase levels were elevated in rats with OS coupled with the Zn- and NA-deficient diet, which decreased towards normal with excess dietary NA. Excess NA supplementation in the OS pre-exposure group resulted in nearly preserved hepatic architecture with normal hepatocytes, whereas maximum tissue destruction was evident in the post-exposure group with NA deficiency. Dose-dependent improvement in the antioxidant defence system, enhanced reduced glutathione levels, lowered lipid peroxidation and higher hepatic Zn levels were observed with NA supplementation. The effect was more prominent in the pre-exposure group. In conclusion, dietary NA supplementation improves hepatic Zn uptake and results in hepatoprotection against OS-induced damage in rats.

Niacin status and treatment-related leukemogenesis.

Chemotherapy often causes damage to hematopoietic tissues, leading to acute bone marrow suppression and the long term development of leukemias. Niacin deficiency, which is common in cancer patients, causes dramatic genomic instability in bone marrow cells in an in vivo rat model. From a mechanistic perspective, niacin deficiency delays excision repair and causes double strand break accumulation, which in turn favors chromosome breaks and translocations. Niacin deficiency also impairs cell cycle arrest and apoptosis in response to DNA damage, which combine to encourage the survival of cells with leukemogenic potential. Conversely, pharmacological supplementation of rats with niacin increases bone marrow poly(ADP-ribose) formation and apoptosis. Improvement of niacin status in rats significantly decreased nitrosourea-induced leukemia incidence. The data from our rat model suggest that niacin supplementation of cancer patients may decrease the severity of short- and long-term side effects of chemotherapy, and could improve tumor cell killing through activation of poly(ADP-ribose)-dependent apoptosis pathways.

Niacin status, NAD distribution and ADP-ribose metabolism.

Dietary niacin deficiency, and pharmacological excesses of nicotinic acid or nicotinamide, have dramatic effects on cellular NAD pools, ADP-ribose metabolism, tissue function and health. ADP-ribose metabolism is providing new targets for pharmacological intervention, and it is important to consider how the supply of vitamin B3 may directly influence ADP-ribosylation reactions, or create interactions with other drugs designed to influence these pathways. In addition to its redox roles, NAD+ is used as a substrate for mono-, poly- and cyclic ADP-ribose formation. During niacin deficiency, not all of these processes can be maintained, and dramatic changes in tissue function and clinical condition take place. Conversely, these reactions may be differentially enhanced by pharmacological intakes of vitamin B3, and potentially by changing expression of specific NAD generating enzymes. A wide range of metabolic changes can take place following pharmacological supplementation of nicotinic acid or nicotinamide. As niacin status decreases towards a deficient state, the function of other types of pharmaceutical agents may be modified, including those that target ADP-ribosylation reactions, apoptosis and inflammation. This article will explore what is known and yet to be learned about the response of tissues, cells and subcellular compartments to excessive and limiting supplies of niacin, and will discuss the etiology of the resulting pathologies.

The role of dietary niacin intake and the adenosine-5'-diphosphate-ribosyl cyclase enzyme CD38 in spatial learning ability: is cyclic adenosine diphosphate ribose the link between diet and behaviour?

The pyridine nucleotide NAD+ is derived from dietary niacin and serves as the substrate for the synthesis of cyclic ADP-ribose (cADPR), an intracellular Ca signalling molecule that plays an important role in synaptic plasticity in the hippocampus, a region of the brain involved in spatial learning. cADPR is formed in part via the activity of the ADP-ribosyl cyclase enzyme CD38, which is widespread throughout the brain. In the present review, current evidence of the relationship between dietary niacin and behaviour is presented following investigations of the effect of niacin deficiency, pharmacological nicotinamide supplementation and CD38 gene deletion on brain nucleotides and spatial learning ability in mice and rats. In young male rats, both niacin deficiency and nicotinamide supplementation significantly altered brain NAD+ and cADPR, both of which were inversely correlated with spatial learning ability. These results were consistent across three different models of niacin deficiency (pair feeding, partially restricted feeding and niacin recovery). Similar changes in spatial learning ability were observed in Cd38- / - mice, which also showed decreases in brain cADPR. These findings suggest an inverse relationship between spatial learning ability, dietary niacin intake and cADPR, although a direct link between cADPR and spatial learning ability is still missing. Dietary niacin may therefore play a role in the molecular events regulating learning performance, and further investigations of niacin intake, CD38 and cADPR may help identify potential molecular targets for clinical intervention to enhance learning and prevent or reverse cognitive decline.

Niacin deficiency alters p53 expression and impairs etoposide-induced cell cycle arrest and apoptosis in rat bone marrow cells.

One focus of chemoprevention research is the interaction of nutrients with specific molecular targets associated with the maintenance of genomic stability. This study tested the impact of dietary niacin status on bone marrow NAD+ and poly(ADP-ribose) (pADPr) levels, p53 expression, and etoposide (ETO)-induced apoptosis and cell cycle arrest. After 3 wk on niacin-deficient (ND), pair-fed niacin-replete (PF), or nicotinic acid-supplemented (4 g/kg diet) (NA) diets, Long-Evans rats were gavaged with ETO (25 mg/kg) or vehicle. ND and NA diets caused a 72% decrease and a 240% increase in bone marrow NAD+, respectively. Basal and ETO-induced pADPr levels differed dramatically among ND, PF, and NA diets (undetectable, 42 and 216 fmol/million cells, respectively; basal and undetectable, 119 and 484 fmol/million cells, respectively, following ETO). ND diet alone caused overexpression of two distinct isoforms of p53. Levels of p53 in PF and NA marrow increased in response to ETO treatment, but this did not occur in ND bone marrow. Quantitative polymerase chain reaction of regular and alternative spliced variants of p53 mRNA revealed that niacin deficiency actually decreased both forms of p53 message, implicating protein stability in the accumulation of p53 in ND marrow. ETO-induced apoptosis (TUNEL) was suppressed during niacin deficiency and enhanced by supplementation. G1 arrest was also impaired in ND bone marrow relative to PF and NA. Despite a poor G1 arrest, p21waf1 was overexpressed in the ND bone marrow and dramatically induced following ETO treatment. In conclusion, dietary niacin deficiency causes changes in NAD+ and pADPr metabolism, alters p53 expression, and impairs cellular responses to DNA damage.

The guinea-pig is a poor animal model for studies of niacin deficiency and presents challenges in any study using purified diets.

The guinea-pig was previously reported as being sensitive to a niacin-deficient (ND), high-protein diet, suggesting that it is a suitable model for the low tryptophan to NAD+ conversion observed in human subjects. However, these studies were based on growth rates and mortality. The objective of the present study was to determine whether guinea-pigs are suitable for ND studies based on measurements of blood and bone marrow NAD+. Using a 20 % casein diet, ND decreased blood NAD+ after 4 weeks, but this parameter returned to normal after 9 weeks of feeding, while bone marrow was decreased by 35 % at this time point. Using a 15 % casein diet, 7 weeks of ND caused 44 and 42 % decreases in blood and bone marrow NAD+. Using a 10 % casein diet, ND decreased NAD+ by 32 % in blood and 62 % in bone marrow at 7 weeks. Growth rates were directly related to the dietary tryptophan content, with the lowest growth rates seen with the 10 % casein diet. Changes in guinea-pig NAD+ are comparable with the rat model at similar levels of dietary tryptophan, while mortality rates were dramatically higher in the guinea-pig model. The present study concludes that mortality in ND guinea-pigs is not indicative of poor tryptophan conversion, but is due to environmental stresses in guinea-pigs that are not observed with rats. We conclude that guinea-pigs are not suitable for research on niacin deficiency and they present challenges for any study requiring purified diets and wire-bottomed cages.