The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: Lessons learned from its deficiency

Scalabrino, Giuseppe

doi:10.1016/j.pneurobio.2009.04.004

Cited by 135 publications

(155 citation statements)

References 197 publications

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“…For neurite outgrowth, in addition to NGF, evidence points to the participation of the p75 NTR neurotrophin and Akt pathways. Earlier works suggest that NGF, TNF-␣ and their receptors may all be involved in regulating the proliferation and differentiation of B12-lacking cells (26,27). NGF can induce the synthesis of TNF-␣ through NF-B in neurons, and TNF-␣ can induce the expression of NGF in glia.…”

Section: Discussionmentioning

confidence: 99%

Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE

Battaglia-Hsu

Akchiche

Noel

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Vitamin B12 (cobalamin, Cbl) is indispensable for proper brain development and functioning, suggesting that it has neurotrophic effects beside its well-known importance in metabolism. The molecular basis of these effects remains hypothetical, one of the reasons being that no efficient cell model has been made available for investigating the consequences of B12 cellular deficiency in neuronal cells. Here, we designed an approach by stable transfection of NIE115 neuroblastoma cells to impose the anchorage of a chimeric B12-binding protein, transcobalamin-oleosin (TO) to the intracellular membrane. This model produced an intracellular sequestration of B12 evidenced by decreased methyl-Cbl and Sadenosylmethionine and increased homocysteine and methylmalonic acid concentrations. B12 deficiency affected the proliferation of NIE115 cells through an overall increase in catalytic protein phosphatase 2A (PP2A), despite its demethylation. It promoted cellular differentiation by improving initial outgrowth of neurites and, at the molecular level, by augmenting the levels of proNGF and p75 NTR . The up-regulation of PP2A and pro-nerve growth factor (NGF) triggered changes in ERK1/2 and Akt, two signaling pathways that influence the balance between proliferation and neurite outgrowth. Compared with control cells, a 2-fold increase of p75 NTR -regulated intramembraneous proteolysis (RIP) was observed in proliferating TO cells (P < 0.0001) that was associated with an increased expression of two tumor necrosis factor (TNF)-␣ converting enzyme (TACE) secretase enzymes, Adam 10 and Adam 17. In conclusion, our data show that B12 cellular deficiency produces a slower proliferation and a speedier differentiation of neuroblastoma cells through interacting signaling pathways that are related with increased expression of PP2A, proNGF, and TACE.homocysteine ͉ neurotrophin V itamin B12 (B12, also named cobalamin, Cbl) deficiency has long been associated with pernicious anaemia (1) and neurological disorders that range from minor behavior changes to severe neurodegenerative disorders (2). Molecular mechanisms are still lacking to explain how the deficiency can bring about all of the symptoms observed. Indeed, only two enzymes are B12-dependent in mammalian cells: the mitochondrial enzyme L-methylmalonyl-CoA mutase (EC 5.4.99.2) and the cytoplasmic homocysteine methyltransferase, also referred as methionine synthase (EC 2.1.1.13). Inferences are thus based on the two direct consequences of B12 deficiency: the accumulation of methylmalonic acid (MMA) and homocysteine (Hcy). Until now, the consequences of B12 deficiency in the brain have been difficult to evidence because of the experimental limitations of the classical cell models. Indeed, the minute amount of vitamin B12 needed by cells can be provided in vitro by B12 from the FCS, which can bind the ''autocrine'' B12 carrier protein, transcobalamin (TC) (3, 4).To delineate the role of B12 in neurological disorders, we designed a neuronal cell model made deficient in B12 through the stable ...

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Section: Discussionmentioning

confidence: 99%

Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE

Battaglia-Hsu

Akchiche

Noel

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Also evidence from animal studies substantiates the importance of DNA methylation in influencing the phenotype of a growing fetus [75]. More recently a body of research has evolved around the imbalance in neurotrophic and neurotoxic cytokine levels as a key point in the pathogenesis of B12-deficient neuropathy [76].…”

Section: Adverse Pregnancy Outcomesmentioning

confidence: 95%

Vitamin B12 Deficiency in Pregnancy and Lactation: Is there a Need for Pre and Post-natal Supplementation?

Siddiqua¹,

Allen²,

Raqib³

et al. 2014

J Nutr Disorders Ther

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This article reviews vitamin B12 (B12) status and deficiency during pregnancy and lactation, its effect on pregnancy, and the health of the offspring, with the aim to underscore the need for a sustainable strategy to improve maternal and infant vitamin B12 status of low and middle income countries. Vitamin B12 is a basic nutrient required for maintenance of normal erythropoiesis, cell reproduction, nucleoprotein and myelin synthesis. B12 deficiency is associated with adverse pregnancy outcomes and neurodevelopmental morbidity during infancy. Very few studies have indicated that B12 deficiency may contribute to altered immune responses in animals and humans. Additionally, no studies have shown modulation of infant motor development in response to maternal B12 supplementation. Despite the high global prevalence of B12 deficiency and its serious effects on pregnant women and offspring, there is still no consensus on the cut-off of biochemical markers (indicator of B12 deficiency) to correctly diagnose B12 deficiency in mother-infant dyad. Also, the optimum dose of B12 to normalize B12 status of mother-infant pairs in a deficient population is not known yet. In addition, markers of other functions such as neurodevelopment, immune response that may be affected by vitamin B12 deficiency should be measured to determine if they respond to supplementation. Thus, there is an urgent need to conduct more trials to find out the optimum dose, to investigate whether intervention with such pre-and post natal vitamin B12 supplementation would improve maternal, neonatal and child health outcomes in population at risk, giving emphasis on neurological processes, immune functions and epigenetic modifications. Other strategies including food based approach also require evidence based results which will help to understand effectiveness of a targeted and well-designed intervention among this population.

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“…The therapeutic effects of A-LA on transient cerebral ischemia, Alzheimer's disease and traumatic brain injury have been reported previously (8). Vitamin B12 also plays an important role in attenuating degenerative processes in the nervous system, and severe damage occurs in the spinal cord and central nervous system (CNS) in the presence of vitamin B12 deficiency (20). Vitamin B12 deficiency causes a wide range of hematological, gastrointestinal, psychiatric and neurological disorders, and neuropsychiatric symptoms may present as myelopathy, neuropathy, dementia and, less often, optic nerve atrophy (3).…”

Section: Experimental Groupsmentioning

confidence: 98%

Histomorphometric and ultrastructural evaluation of long term alpha lipoic acid and vitamin b12 use after experimental sciatic nerve injury in rats

Arıkan¹,

Toğral²,

Hastürk³

et al. 2015

Turkish Neurosurgery

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AIm: To analyze the therapeutic effects of long-term alpha lipoic acid (A-LA) and vitamin B12 use via histomorphometric methods and electron microscopy in the transected sciatic nerves of rats. mATERIAl and mEThODS: Forty rats were randomized into five groups (n=8/group). In group I, 1 cm segment of sciatic nerve was resected without any other intervention. In group II (sham), following right sciatic nerve transection, primary epineurial anastomosis was performed by placing the edges of the nerve end-to-end. In group III (saline), after right sciatic nerve transection, the ends of the nerves were brought together and closed after application of intraperitoneal physiologic saline. In group IV, 2 mg/kg of alpha lipoic acid and in group V, 2 mg/kg of vitamin B12 was administered intraperitoneally before surgical intervention. RESUlTS:Histomorphometric and electron microscopic analyses revealed that vitamin B12 did not prevent structural changes, abnormal myelination and g-ratio deviations regarding the functional aspects of the sciatic nerve. Alpha lipoic acid was more effective in restructuring the histomorphometric and structural aspects of the nerve with more myelinated fibers with optimal values (0.55-0.68) than vitamin B12 groups, in which the number of myelinated nerve fibers significantly decreased at optimal intervals (0.55-0.68).CONClUSION: A-LA administration following peripheral nerve transection injury is more effective in promoting nerve healing regarding the structural aspects of the sciatic nerve compared to vitamin B12 and also myelination of nerve fibers by increasing g-values.

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The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system: Lessons learned from its deficiency

Cited by 135 publications

References 197 publications

Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE

Vitamin B12 deficiency reduces proliferation and promotes differentiation of neuroblastoma cells and up-regulates PP2A, proNGF, and TACE

Vitamin B12 Deficiency in Pregnancy and Lactation: Is there a Need for Pre and Post-natal Supplementation?

Histomorphometric and ultrastructural evaluation of long term alpha lipoic acid and vitamin b12 use after experimental sciatic nerve injury in rats

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