102,016 research outputs found
Vitamin-regulated cytokines and growth factors in the CNS and elsewhere
No full textThere is a growing awareness that natural vitamins (with the only exception of pantothenic acid) positively or negatively modulate the synthesis of some cytokines and growth factors in the CNS, and various mammalian cells and organs. As natural vitamins are micronutrients in the human diet, studying their effects can be considered a part of nutritional genomics or nutrigenomics. A given vitamin selectively modifies the synthesis of only a few cytokines and/or growth factors, although the same cytokine and/or growth factor may be regulated by more than one vitamin. These effects seem to be independent of the effects of vitamins as coenzymes and/or reducing agents, and seem to occur mainly at genomic and/or epigenetic level, and/or by modulating NF-kappaB activity. Although most of the studies reviewed here have been based on cultured cell lines, but their findings have been confirmed by some key in vivo studies. The CNS seems to be particularly involved and is severely affected by most avitaminoses, especially in the case of vitamin B(12). However, the vitamin-induced changes in cytokine and growth factor synthesis may initiate a cascade of events that can affect the function, differentiation, and morphology of the cells and/or structures not only in the CNS, but also elsewhere because most natural vitamins, cytokines, and growth factors cross the blood-brain barrier. As cytokines are essential to CNS-immune and CNS-hormone system communications, natural vitamins also interact with these circuits. Further studies of such vitamin-mediated effects could lead to vitamins being used for the treatment of diseases which, although not true avitaminoses, involve an imbalance in cytokine and/or growth factor synthe
Methylmalonic acid as a marker for cobalamin deficiency: fact or fantasy? Elucidations from the cobalamin-deficient rat
No full textEpidermal Growth Factor in the CNS: A Beguiling Journey from Integrated Cell Biology to Multiple Sclerosis. An Extensive Translational Overview
No full textThis article reviews the wealth of papers dealing with the different effects of epidermal growth factor (EGF) on oligodendrocytes, astrocytes, neurons, and neural stem cells (NSCs). EGF induces the in vitro and in vivo proliferation of NSCs, their migration, and their differentiation towards the neuroglial cell line. It interacts with extracellular matrix components. NSCs are distributed in different CNS areas, serve as a reservoir of multipotent cells, and may be increased during CNS demyelinating diseases. EGF has pleiotropic differentiative and proliferative effects on the main CNS cell types, particularly oligodendrocytes and their precursors, and astrocytes. EGF mediates the in vivo myelinotrophic effect of cobalamin on the CNS, and modulates the synthesis and levels of CNS normal prions (PrPCs), both of which are indispensable for myelinogenesis and myelin maintenance. EGF levels are significantly lower in the cerebrospinal fluid and spinal cord of patients with multiple sclerosis (MS), which probably explains remyelination failure, also because of the EGF marginal role in immunology. When repeatedly administered, EGF protects mouse spinal cord from demyelination in various experimental models of autoimmune encephalomyelitis. It would be worth further investigating the role of EGF in the pathogenesis of MS because of its multifarious effects
The multi-faceted basis of vitamin B12 (cobalamin) neurotrophism in adult central nervous system : lessons learned from its deficiency
No full textGlial cells, myelin and the interstitium are the structures of the mammalian central nervous system (CNS) mainly affected by vitamin B(12) (cobalamin, Cbl) deficiency. Most of the response to the damage caused by Cbl deficiency seems to come from astrocytes and microglia, and is manifested as an increase in the number of cells positive for glial fibrillary acidic protein, the presence of ultrastructural signs of activation, and changes in cytokine and growth factor production and secretion. Myelin damage particularly affects the lamellae, which are disorganized by edema, as is the interstitium. Surprisingly, rat Schwann cells (myelin-forming cells of the peripheral nervous system) are fully activated but the few oligodendrocytes (myelin-forming cells of the CNS) are scarcely activated. The presence of intramyelin and interstitial edema raises questions about the integrity of the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier. The results obtained in the CNS of Cbl-deficient rats indicate that cytokine and growth factor imbalance is a key point in the pathogenesis of Cbl-deficient neuropathy. In the rat, Cbl deficiency increases the spinal cord (SC) synthesis and CSF levels of myelinotoxic cytokines (tumor necrosis factor (TNF)-alpha and soluble (s) CD40:sCD40 ligand dyad) and a myelinotoxic growth factor (nerve growth factor), but decreases SC synthesis and CSF levels of a myelinotrophic cytokine (interleukin-6) and a myelinotrophic growth factor (epidermal growth factor, EGF). The in vivo administration of IL-6 or EGF, or agents antagonizing the excess myelinotoxic agent, is as effective as Cbl in repairing or preventing Cbl-deficiency-induced CNS lesions. An imbalance in TNF-alpha and EGF levels has also been found in the CSF and serum of patients with severe Cbl deficiency
Normal prions as a new target of cobalamin deficiency in rat CNS
No full textIt is known that cobalamin (Cbl) deficiency damages myelin by increasing tumour necrosis factor(TNF)-α and decreasing epidermal growth factor(EGF) levels in rat central (CNS) and peripheral nervous system (PNS), and that TNF-α and EGF regulate normal prion protein (PrPC) expression. We investigated whether: a) the octapeptide repeat (OR)-region of PrPC (which is claimed to be myelinotrophic) is involved in the pathogenesis of rat Cbl-deficient (Cbl-D) neuropathy; and b) Cbl deficiency modifies PrPC levels of spinal cord (SC) and PNS in the rat. We intracerebroventricularly administered antibodies against the OR-region (OR-Abs) to Cbl-D rats to prevent SC and PNS myelin damage and maximum nerve conduction velocity (MNCV) abnormalities, and PrPCs to otherwise normal (ON) rats to reproduce Cbl-D-like lesions. The OR-Abs (but not when inactivated) normalized myelin ultrastructure and TNF-α levels in the SC and peripheral nerves, and MNCV values of Cbl-D rats. PrPC levels had increased in SC and peripheral nerves of Cbl-D rats by the time myelin lesions appeared. These increases were mediated by excess TNF-α. There were no changes in hepatic PrPC levels of Cbl-D rats. Cbl deficiency greatly reduced SC PrPC-mRNA levels, which were subsequently increased by Cbl and EGF, which proved to be effective in preventing the typical Cbl-D lesions. The SC and PNS of ON-, PrPC-treated rats showed typical Cbl-D lesions, significantly increased TNF-α levels, and significantly decreased MNCV values. Therefore: a) the number of OR regions in rat CNS and PNS seem to be “buffered” by Cbl; b) Cbl deficiency causes a vicious circle between TNF-α and PrPCs in rat CNS and PNS; and c) new PrPC synthesis is a common effect of different myelinotrophic agents in rat SC
Cobalamin (vitamin B12) in subacute combined degeneration and beyond : traditional interpretations and novel theories
No full textSubacute combined degeneration (SCD) is a neuropathy due to cobalamin (Cbl) (vitamin B12) deficiency acquired in adult age. Hitherto, the theories advanced to explain the pathogenesis of SCD have postulated a causal relationship between SCD lesions and the impairment of either or both of two Cbl-dependent reactions. We have identified a new experimental model, the totally gastrectomized rat, to reproduce the key morphological features of the disease [spongy vacuolation, intramyelinic and interstitial edema of the white matter of the central nervous system (CNS), and astrogliosis], and found new mechanisms responsible for the pathogenesis of SCD: the neuropathological lesions in TGX rats are not only due to mere vitamin withdrawal but also to the overproduction of the myelinolytic tumor necrosis factor (TNF)-α and the reduced synthesis of the two neurotrophic agents, epidermal growth factor (EGF) and interleukin-6. This deregulation of the balance between TNF-α and EGF synthesis induced by Cbl deficiency has been verified in the sera of patients with pernicious anemia (but not in those with iron-deficient anemia), and in the cerebrospinal fluid (CSF) of SCD patients. These new functions are not linked to the coenzyme functions of the vitamin, but it is still unknown whether they involve genetic or epigenetic mechanisms. Low Cbl levels have also been repeatedly observed in the sera and/or CSF of patients with Alzheimer's disease or multiple sclerosis, but whether Cbl deficit plays a role in the pathogenesis of these diseases is still unclear
Subacute combined degeneration one century later. The neurotrophic action of cobalamin (vitamin B12) revisited
No full textNormal prions as a new target of cobalamin (vitamin B 12) in rat central nervous system
No full textAbstract The pathogenesis of cobalamin (Cbl)-deficient (Cbl-D) neuropathy and the role of normal prions (PrPcs) in myelin maintenance are both subjects of debate. We have demonstrated that Cbl deficiency damages myelin by increasing tumor necrosis factor (TNF)-α, and decreasing epidermal growth factor (EGF) levels in the rat central nervous system (CNS). It is known that TNF-α and EGF regulate PrPc expression in vitro, and that myelin vacuolation, reactive astrocytosis and microglial activation are common to rat Cbl-D neuropathy and some prion diseases. We have shown that Cbl deficiency leads to high levels of PrPcs [particularly the octapeptide repeat (OR) domains] in the rat CNS thereby damaging the spinal cord (SC) myelin, and that chronic intra-cerebroventricular treatment with anti-OR antibodies normalizes SC myelin morphology. We have also found that PrPc levels are increased in the SC of Cbl-D rats by the time the myelin lesions appear, and that this increase is mediated by excess myelinotoxic TNF-α and prevented by EGF treatment, which has proved to be as effective as Cbl in preventing Cbl deficiency-induced lesions. Cbl stimulates PrPc mRNA-related synthesis in Cbl-D SC and duodenum, two rat tissues that are severely affected by Cbl deficiency. New PrPc synthesis is a common effect of various myelinotrophic agents, two of which (EGF and anti-TNF-α antibodies) also stimulate PrPc mRNA-related synthesis in the SC of Cbl-D rats
Myelin damage due to local quantitative abnormalities in normal prion levels: evidence from subacute combined degeneration and multiple sclerosis
No full textCobalamin (Cbl) deficiency causes an imbalance in some cytokines and growth factors in the central nervous system and peripheral nervous system (PNS) of the rat, and in the serum and cerebrospinal fluid (CSF) of adult Cbl-deficient (Cbl-D) patients. It is conceivable that this imbalance triggers subsequent cellular events. We hypothesized that an imbalance in normal prion (PrP C) levels and/or synthesis might be involved in the pathogenesis of Cbl-D neuropathy, and demonstrated that: (1) Cbl deficiency induces excess PrPC in rat spinal cord (SC) and PNS, concomitantly with myelin damage and PNS electrophysiological abnormalities; (2) the SC increase is mediated by a local Cbl deficiency-induced excess of tumor necrosis factor-α; (3) myelinotrophic Cbl and epidermal growth factor upregulate PrPC-mRNA levels in rat SC; (4) treatment with anti-PrPC octapeptide repeat region antibodies normalizes the ultrastructure of the Cbl-D rat SC and PNS myelins, and the PNS electrophysiological abnormalities, without modifying their Cbl-D status; (5) PrPC administration to otherwise normal rats causes SC and PNS myelin lesions and PNS electrophysiological abnormalities, similar to those of Cbl-D neuropathy; (6) CSF and serum PrP C concentrations in Cbl-D patients are significantly higher than in controls; and (7) these concentrations significantly correlate with their CSF and serum Cbl concentrations. CSF PrPC concentrations are significantly lower in patients with multiple sclerosis (MS) than neurological controls, but serum PrPC concentrations in patients with non-Cbl-D anemias and CSF PrPC concentrations in patients with non-myelin-damaging neurological diseases are normal
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