New clues about vitamin D functions in the nervous system (original) (raw)
Related papers
Vitamin D: is the brain a target?
Steroids
Results of some recent studies have suggested that the central nervous system (CNS) be added to the classic target tissues of vitamin D. These include the autoradiographic identification of vitamin D receptors within specific brain nuclei and the immunocytochemical and chemical demonstration of calcium binding protein in most neurons. In addition, a recent study suggests that the hormone may affect the activity of cholinergic enzymes within certain brain nuclei. In this review, these experiments will be discussed and evaluated. The possible function(s) of vitamin D action in the CNS will be discussed in relation to its classical role in calcium homeostasis and the possibility that central interactions of the hormone may also be involved in some aspects of neuroendocrine regulation. In addition, the characteristics and neurochemical actions of other steroid hormone systems that are known to act within the CNS will be briefly reviewed and compared with those of vitamin D. Finally, we will suggest some strategies for further evaluation of vitamin D action in the CNS, based on studies with other steroid hormones and on advances in molecular biology and pharmacology.
Current Pharmaceutical Design, 2020
Vitamin D is a steroid hormone implicated in the regulation of neuronal integrity and many brain functions. Its influence, as a nutrient and a hormone, on the physiopathology of the most common neurodegenerative diseases is continuously emphasized by new studies. This review addresses what is currently known about the action of vitamin D on the nervous system and neurodegenerative diseases such as Multiple Sclerosis, Alzheimer’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis. Further vitamin D research is necessary to understand how the action of this “neuroactive” steroid can help to optimize the prevention and treatment of several neurological diseases.
Endocrinology, 1997
Decreased nerve growth factor (NGF) synthesis in the hippocampus and reduced nerve growth factor receptor immunoreactivity in CH 1-4 basal forebrain areas have been implicated in neurodegeneration. Vitamin D receptors (VDR) have been located in brain areas affected by neurodegenerative diseases. 1,25-Dihydroxyvitamin D 3 [1,25-(OH) 2 D 3 ], the active form of vitamin D, has been shown to induce NGF in L929 mouse fibroblasts and rat hippocampus. In the present study we analyzed the VDR in L929 cells, which we used as a model system. We studied the regulation of VDR abundance and the ability of 1,25-(OH) 2 D 3 to induce NGF synthesis. Scatchard analysis of [ 3 H]1,25-(OH) 2 D 3 binding showed the VDR concentration to be 173 fmol/mg protein and the affinity to be 0.12 nM. VDR was localized to nuclei of L929 cells by immunocytochemistry. Treatment of cells with forskolin (FSK; 50 M), which activates the cAMP-protein kinase A pathway, resulted in an 8-to 10-fold up-regulation of VDR by 6 h, and VDR remained elevated at 24 h, as we have reported for other cells. NGF secretion was measured in serum-free conditioned medium us-ing a double sided enzyme-linked immunosorbent assay. 1,25-(OH) 2 D 3 treatment (0.1 pM to 10 nM) for 24 h increased the NGF concentration 2-to 3-fold, an effect that plateaued at 1 nM 1,25-(OH) 2 D 3 . VDR up-regulation by FSK pretreatment augmented the NGF response to 1,25-(OH) 2 D 3 2-fold compared to that in vehiclepretreated cells for a total 6-fold increase compared to basal NGF levels. The vitamin D analogs EB-1089 and 22-oxacalcitriol, which have been found to be less calcemic than 1,25-(OH) 2 D 3 , also induced NGF synthesis. The effects of these analogs were further enhanced by prior up-regulation of VDR with FSK. In conclusion, we have characterized the VDR in L929 cells and shown that 1,25-(OH) 2 D 3 and its less calcemic analogs induce NGF. Furthermore, up-regulation of VDR abundance enhanced NGF induction. These effects of 1,25-(OH) 2 D 3 and its analogs via VDR to regulate NGF synthesis may have significance for the eventual treatment of neurodegenerative diseases that are caused by decreased NGF production. (Endocrinology 138:
Molecular Brain Research, 1994
The effect of 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3) on nerve growth factor (NGF) synthesis was investigated in primary cultures of astrocytes prepared from brain of neonatal rats. 1,25-(OH) 2 D 3 elicited a dose-dependent increase of NGF mRNA with a maximal effect at 10 -7 M, which persisted for at least 48 h. Northern blot analysis revealed an expression of the vitamin D 3 receptor (VDR) gene in primary glial cells. Treatment of cells with 1,25-(OH) z D 3 led to an increase in the VDR mRNA levels. Similar results were obtained in C6 glioma cells. Exposure of primary glial cells to 10 -~ M 1,25-(OH) 2 D 3 caused only a 2-fold increase of the levels of cell-secreted NGF after 3 days of treatment. However, a 5-fold increase was observed three days after a second addition of vitamin D 3. Likewise, a pretreatment with lower doses of hormone such as 10 -w M or 10 -9 M enhanced the responsiveness of the cells to a 24 h treatment with 10 -8 M hormone. It appears, therefore, that the duration of the treatment influences the level of synthesis of NGF, possibly as a consequence of the increase of the VDR gene expression. The specificity of 1,25-(OH) 2 D 3 is supported by the fact that a concentration of 10 7 M of an another vitamin D 3 metabolite, 24,25-(OH) 2 D3, had no effect on NGF synthesis. Several lines of evidence indicate that astrocytes constitute the major cell type responsive to 1,25-(OH) 2 D 3 in primary cultures of glial cells. Firstly, the removal of microglial cells or oligodendrocytes did not modify the time-course and amplitude of the response to 1,25-(OH) 2 D 3. Secondly, 1,25-(OH) 2 D 3 had no effect on the synthesis of NGF in meninge-derived fibroblasts. Thirdly, an 1,25-(OH) 2 D3-dependent increase of NGF mRNA was also found in C6 glioma cells. In conclusion, the results suggest that 1,25-(OH) z D 3 may control the synthesis of NGF in the central nervous system, and strongly support the involvement of 1,25-(OH) 2 D 3 as a mediator of astrocytic plasticity.
Vitamin D and Neurological Diseases: An Endocrine View
International journal of molecular sciences, 2017
Vitamin D system comprises hormone precursors, active metabolites, carriers, enzymes, and receptors involved in genomic and non-genomic effects. In addition to classical bone-related effects, this system has also been shown to activate multiple molecular mediators and elicit many physiological functions. In vitro and in vivo studies have, in fact, increasingly focused on the "non-calcemic" actions of vitamin D, which are associated with the maintenance of glucose homeostasis, cardiovascular morbidity, autoimmunity, inflammation, and cancer. In parallel, growing evidence has recognized that a multimodal association links vitamin D system to brain development, functions and diseases. With vitamin D deficiency reaching epidemic proportions worldwide, there is now concern that optimal levels of vitamin D in the bloodstream are also necessary to preserve the neurological development and protect the adult brain. The aim of this review is to highlight the relationship between vit...
Mechanisms of Neuroprotective Action of Vitamin D 3
Biochemistry (Moscow), 2000
This review considers modern data on the mechanisms underlying the neuroprotective effect of the neurosteroid vitamin D 3 and its receptors in the nervous system. Special attention is paid to Ca 2+ regulation, stimulation of neurotrophin release, interaction with reactive oxygen and nitrogen species, and neuroimmunomodulatory effects of calcitriol, the main biologically active form of vitamin D 3 , in the nervous system.
Vitamin D and the central nervous system
Pharmacological Reports, 2013
Vitamin D is formed in human epithelial cells via photochemical synthesis and is also acquired from dietary sources. The so-called classical effect of this vitamin involves the regulation of calcium homeostasis and bone metabolism. Apart from this, non-classical effects of vitamin D have recently gained renewed attention. One important yet little known of the numerous functions of vitamin D is the regulation of nervous system development and function. The neuroprotective effect of vitamin D is associated with its influence on neurotrophin production and release, neuromediator synthesis, intracellular calcium homeostasis, and prevention of oxidative damage to nervous tissue. Clinical studies suggest that vitamin D deficiency may lead to an increased risk of disease of the central nervous system (CNS), particularly schizophrenia and multiple sclerosis. Adequate intake of vitamin D during pregnancy and the neonatal period seems to be crucial in terms of prevention of these diseases.
Effects of 1,25-dihydroxyvitamin D3 on growth of mouse neuroblastoma cells
Developmental Brain Research, 1997
Ž Ž . . Epitopes of the 1,25-dihydroxyvitamin D 1,25 OH D receptor have been shown in developing dorsal root ganglia in fetal mice, as 2 3 w well as in cells maintained in culture ,25-Dihydroxyvitamin D receptors 3 Ž . x Ž . in developing dorsal root ganglia of fetal rats, DeÕ. Brain Res., 92 1996 120-124 . To investigate a possible role for 1,25 OH D in 2 3 Ž . neural cell growth and development, a murine neuroblastoma cell line that expresses 1,25 OH D receptors, was treated with 2 3 Ž . Ž . 1,25 OH D . Treatment with 1,25 OH D resulted in a decrease in cell proliferation, a change in cell morphology, and the expression 2 3 2 3 of protein markers of mature neuronal cells. The decrease in cell proliferation was accompanied by an increase in the expression of nerve Ž . growth factor NGF . Anti-NGF monoclonal antibody added to the growth medium blocked the decrease in cell proliferation caused by Ž . Ž . 1,25 OH D treatment. Our results show that the sterol hormone 1,25 OH D , causes a decrease in the proliferation of mouse 2 3 2 3 neuroblastoma cells through alterations in the expression of NGF.
Vitamin D3 analogs inhibit growth and induce differentiation in LA-N-5 human neuroblastoma cells
Clinical & experimental metastasis, 1996
The physiologically active metabolite of vitamin D3, 1,25-dihydroxycholecalciferol (D3), plays an important role in embryonic development and cell differentiation. Previously, we have demonstrated that D3 significantly induces differentiation and inhibits growth of LA-N-5 human neuroblastoma cells at concentrations of 24 nm and higher. In this study, we compared two D3 analogs, 20-epi-22oxa-25a,26a,27a-tri-homo-1,25-D3 (KH 1060) and 1,25-dihydroxy-22,24-diene, 24,26,27-trihomo (EB 1089), with D3 with respect to their effects on differentiation and growth inhibition. We report an inhibition of growth by 45-55% in cells treated with 0.24 nm EB 1089 and 0.24 nM KH 1060, similar to that seen in cells treated with 24 nM D3. At these concentrations, both EB 1089 and KH 1060 stimulate the differentiation of LA-N-5 neuroblastoma cells as shown by increased neurite outgrowth, decreased N-myc expression and decreased invasiveness in vitro. An increase in acetylcholinesterase activity, a funct...
Cancer Letters, 1996
la,25-Dihydroxyvitamin D3 (lc~,25(OH)~D~) has recently been reported to exert a toxic effect on both rat and human glioma cell lines. However the potential clinical use of la,25(OH)*D3 in the treatment of glioma is impaired by its potent hypercalcemic effects. We have therefore investigated the effects on glioma cell growth of several vitamin D3 analogues which have previously been shown to be less calcemic in vivo than la,25(OH)zD3. The present study shows that several analogues are able to induce, in vitro, the death of rat glioma cells (C6.9). The compound KH 1060 appears to be the most effective in the induction of cell death, while MC 1288 and CB 1093 are as potent as la,25(OH)2D3. EB 1089 was somewhat less effective than la,25(OH)*D3 and MC 903, which is currently used in the treatment of psoriasis, has only a weak activity on C6.9 cells. The effective doses used are around 10m9 M for la,25(OH)*D3 and lo-lo M for KH 1060. Interestingly, the toxic effect exerted by la,25(OH)*D3 and its analogues is accompanied by several of the biochemical features of apoptosis, such as DNA fragmentation and induction of the c-myc protooncogene. These findings, together with the fact that the therapies currently available for glioma are only palliative, suggest that la,25(OH)2D3 analogues such as KH 1060, EB 1089 or CB 1093, alone or in combination with other therapeutic approaches, could be of potential interest in the treatment of brain glial tumors.