Niacinamide Abstracts 4

©

From hematopoietic stem cells to platelets

         (Chang, Bluteau et al. 2007) Download

Megakaryocytopoiesis is the process that leads to the production of platelets. This process involves the commitment of multipotent hematopoietic stem cells toward megakaryocyte (MK) progenitors, the proliferation and differentiation of MK progenitors, the polyploidization of MK precursors and the maturation of MK. Mature MK produce platelets by cytoplasmic fragmentation occurring through a dynamic and regulated process, called proplatelet formation, and consisting of long pseudopodial elongations that break in the blood flow. Recent insights have demonstrated that the MK and erythroid lineages are tightly associated at both the cellular and molecular levels, especially in the transcription factors that regulate their differentiation programs. Megakaryocytopoiesis is regulated by two types of transcription factors, those regulating the differentiation process, such as GATA-1, and those regulating proplatelet formation, such as NF-E2. The humoral factor thrombopoietin (TPO) is the primary regulator of MK differentiation and platelet production through the stimulation of its receptor MPL. Numerous acquired or congenital pathologies of the MK lineage are now explained by molecular abnormalities in the activity of the transcription factors involved in megakaryocytopoiesis, in the Tpo or c-mpl genes, as well as in signaling molecules associated with MPL. The recent development of MPL agonists may provide efficient agents for the treatment of some thrombocytopenias.

Nicotinamide (vitamin B3) increases the polyploidisation and proplatelet formation of cultured primary human megakaryocytes

         (Giammona, Fuhrken et al. 2006) Download

Megakaryocytic (Mk) cell maturation involves polyploidisation, and the number of platelets produced increases with Mk DNA content. Ploidy levels in cultured human MK cells are much lower than those observed in vivo. This study demonstrated that adding the water-soluble vitamin nicotinamide (NIC) to mobilised peripheral blood CD34+ cells cultured with thrombopoietin (Tpo) more than doubled the percentage of high-ploidy (> or = 8N) MK cells. This was observed regardless of donor-dependent differences in Mk differentiation. Furthermore, MK cells in cultures with NIC were larger, had more highly lobated nuclei, reached a maximum DNA content of 64N (vs. 16N with Tpo alone), and exhibited more frequent and more elaborate cytoplasmic extensions. NIC also increased the ploidy of cultured primary murine MK cells and a cell line model (CHRF-288) of Mk differentiation. However, NIC did not alter Mk commitment, apoptosis, or the time at which endomitosis was initiated. Despite the dramatic phenotypic differences observed with NIC addition, gene expression microarray analysis revealed similar overall transcriptional patterns in primary human Mk cultures with or without NIC, indicating that NIC did not disrupt the normal Mk transcriptional program. Elucidating the mechanisms by which NIC increases Mk maturation could lead to advances in the treatment of Mk and platelet disorders.

Administration of nicotinamide does not increase platelet levels in mice

         (Konieczna, Panuganti et al. 2013) Download

Elucidating ways to enhance megakaryopoiesis in vivo would have therapeutic applications for thrombocytopenia and transfusion medicine. Nicotinamide has been shown to enhance endomitosis in megakaryocytes cultured in vitro, suggesting that it may be beneficial for the production of platelets in culture. We hypothesized that regular injections of nicotinamide in mice would also increase platelets in vivo. However, we found that platelet counts were reduced by about 25% with daily injections of nicotinamide. Altering the schedule, duration, or nicotinamide dose did not improve platelet production. Consistent with lower platelet levels, nicotinamide also tended to decrease megakaryocyte frequency in sternum and spleen sections, as well as colony formation in vitro by bone marrow progenitor cells. However, there was no effect on the fraction or ploidy of CD41(+) cells harvested from bone marrow. Together, our results suggest that, although nicotinamide increases polyploidization of megakaryocytes in culture, it does not have translatable effects in vivo.

Triple play: promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

         (Maiese 2008) Download

Oxidative stress is a principal pathway for the dysfunction and ultimate destruction of cells in the neuronal and vascular systems for several disease entities, not promoting the ravages of oxidative stress to any less of a degree than diabetes mellitus. Diabetes mellitus is increasing in incidence as a result of changes in human behavior that relate to diet and daily exercise and is predicted to affect almost 400 million individuals worldwide in another two decades. Furthermore, both type 1 and type 2 diabetes mellitus can lead to significant disability in the nervous and cardiovascular systems, such as cognitive loss and cardiac insufficiency. As a result, innovative strategies that directly target oxidative stress to preserve neuronal and vascular longevity could offer viable therapeutic options to diabetic patients in addition to more conventional treatments that are designed to control serum glucose levels. Here we discuss the novel application of nicotinamide, Wnt signaling, and erythropoietin that modulate cellular oxidative stress and offer significant promise for the prevention of diabetic complications in the nervous and vascular systems. Essential to this process is the precise focus upon diverse as well as common cellular pathways governed by nicotinamide, Wnt signaling, and erythropoietin to outline not only the potential benefits, but also the challenges and possible detriments of these therapies. In this way, new avenues of investigation can hopefully bypass toxic complications, or at the very least, avoid contraindications that may limit care and offer both safe and robust clinical treatment for patients.

Nicotinic acid and nicotinamide: a review of their use for hyperphosphatemia in dialysis patients

         (Rennick, Kalakeche et al. 2013) Download

Phosphate binders have traditionally been used to treat hyperphosphatemia, a common complication in patients with end stage renal disease (ESRD). New evidence suggests that nicotinic acid and its metabolites may effectively decrease phosphorus absorption in the gastrointestinal tract, thereby reducing serum phosphorus concentrations. We conducted a literature search to identify studies of patients with ESRD on dialysis that evaluated the role of niacin and related compounds in decreasing serum phosphorus levels. We searched PubMed using the search terms niacin, nicotinic acid, niacinamide, nicotinamide and hyperphosphatemia. Limits were set to include only those articles published since 2002, conducted in human subjects, and written in the English language. Review articles captured through this process were mined for references to other primary literature that may not have been returned through the initial search. All studies were included if they met the search criteria and were conducted in patients with ESRD who received either hemodialysis or peritoneal dialysis. To identify current, ongoing studies, another search was conducted through clinicaltrials.gov. Among the seven studies that met our exclusion criteria, three used nicotinic acid as the therapeutic intervention and four used nicotinamide. Both nicotinic acid and nicotinamide were effective in significantly reducing serum phosphorus concentrations in patients with ESRD on either hemodialysis or peritoneal dialysis. Additional, large-scale studies that assess the appropriate dose as well as long-term safety and efficacy are recommended before clinicians can confirm their place in therapy.

Neuronal nicotinic receptor agonists improve gait and balance in olivocerebellar ataxia

         (Wecker, Engberg et al. 2013) Download

Clinical studies have reported that the nicotinic receptor agonist varenicline improves balance and coordination in patients with several types of ataxia, but confirmation in an animal model has not been demonstrated. This study investigated whether varenicline and nicotine could attenuate the ataxia induced in rats following destruction of the olivocerebellar pathway by the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP (70 mg/kg followed by 300 mg niacinamide/kg; i.p.) led to an 85% loss of inferior olivary neurons within one week without evidence of recovery, and was accompanied by a 72% decrease in rotorod activity, a 3-fold increase in the time to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) for one week improved rotorod performance by 50% and normalized the increased hindpaw stride width, effects that were prevented by the daily preadministration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg). Varenicline (1 and 3 mg free base/kg daily) also improved rotorod performance by approximately 50% following one week of administration, and although it did not alter the time to traverse the beam, it did improve the ability to maintain balance on the beam. Neither varenicline nor nicotine, at doses that improved balance, affected impaired locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved.


References

Chang, Y., D. Bluteau, et al. (2007). "From hematopoietic stem cells to platelets." J Thromb Haemost 5 Suppl 1: 318-27. [PMID: 17635743]

Giammona, L. M., P. G. Fuhrken, et al. (2006). "Nicotinamide (vitamin B3) increases the polyploidisation and proplatelet formation of cultured primary human megakaryocytes." Br J Haematol 135(4): 554-66. [PMID: 17054670]

Konieczna, I. M., S. Panuganti, et al. (2013). "Administration of nicotinamide does not increase platelet levels in mice." Blood Cells Mol Dis 50(3): 171-6. [PMID: 23265740]

Maiese, K. (2008). "Triple play: promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus." Biomed Pharmacother 62(4): 218-32. [PMID: 18342481]

Rennick, A., R. Kalakeche, et al. (2013). "Nicotinic acid and nicotinamide: a review of their use for hyperphosphatemia in dialysis patients." Pharmacotherapy 33(6): 683-90. [PMID: 23526664]

Wecker, L., M. E. Engberg, et al. (2013). "Neuronal nicotinic receptor agonists improve gait and balance in olivocerebellar ataxia." Neuropharmacology 73: 75-86. [PMID: 23711550]