Trends in Endocrinology & Metabolism
ReviewNew clues about vitamin D functions in the nervous system
Section snippets
Brain 1,25-(OH)2D3 synthesis and degradation
Vitamin D3 can either be ingested, or synthesized in the skin from 7-dehydrocholesterol during exposure to sunlight in a reaction that is catalyzed by ultraviolet B radiation [1]. In both cases, vitamin D3 is biologically inert and requires a two-step enzymatic activation (Fig. 1). It was assumed that the brain 1,25-(OH)2D3 supply was dependent on the plasma concentration of 1,25-(OH)2D3 2., 3., 4.. However, recent data demonstrating the brain localization of vitamin D3 25-hydroxylase and
The vitamin D receptor (VDR)
The nuclear functions of 1,25-(OH)2D3 are mediated through the vitamin D receptor (VDR) 10., 11.. Since the initial reports of Stumpf and collaborators on the presence of vitamin D-specific nuclear binding in brain and spinal cord 12., 13., 14., evidence has accumulated to suggest that both mRNA encoding the VDR and the protein itself are present in the nervous system. Thus, VDR gene expression has been demonstrated in neuronal and glial cells 15., 16., 17., 18., 19., 20., 21., 22., 23.. VDR
Neuroprotective effects of 1,25-(OH)2D3
Since the regulation of nerve growth factor (NGF) synthesis by 1,25-(OH)2D3 was first reported [36], various studies have demonstrated that 1,25-(OH)2D3 can act on cells of the nervous system by modulating the production of neurotrophins (Fig. 2; Table 1). For instance, the synthesis of NGF 17., 20., 37., neurotrophin 3 (NT3) [38] and glial cell line-derived neurotrophic factor (GDNF) [39] was upregulated by 1,25-(OH)2D3, whereas neurotrophin 4 (NT4) was downregulated [38]. In several cases,
CNS tumors
The potential role of vitamin D in the treatment of cancer was first recognized in 1981 in myeloid leukemic cells [57]. It was then extended to several other malignancies, including breast, prostate and colon carcinoma. These antiproliferative properties have led to the development of numerous pharmacological analogs that inhibit cancer cell growth with reduced calcemic activity. In CNS tumors, 1,25-(OH)2D3 and several synthetic analogs are effective in inducing a cell death pathway in glioma
Concluding remarks
Currently available data strongly suggest a role for 1,25-(OH)2D3 in the nervous system. However, patients suffering from rickets show no obvious nervous dysfunction. In the same way, no gross abnormalities were identified in the brain of VDR- or 25-hydroxyvitamin D 1α-hydroxylase-deficient mice 74., 75., 76.. Even though the nervous systems of these knockout mice require more detailed study, this suggests that 1,25-(OH)2D3 functions might overlap with other signaling pathways. For instance, it
Acknowledgements
We are grateful to A. Goldsmith for helpful comments on the article. This review is dedicated to INSERM U298 (1986–1998).
References (81)
Porcine microsomal vitamin D3 25-hydroxylase (CYP2D25)
J. Biol. Chem.
(2000)1,25-Dihydroxyvitamin D3 regulates the synthesis of nerve growth factor in primary cultures of glial cells
Mol. Brain Res.
(1994)1,25-Dihydroxyvitamin D3 receptors in developing dorsal root ganglia of fetal rats
Dev. Brain Res.
(1996)1,25-Dihydroxyvitamin D3 receptors in the central nervous system of the rat embryo
Brain Res.
(1998)Distribution of 1,25-dihydroxyvitamin D3 receptor immunoreactivity in the rat brain and spinal cord
J. Chem. Neuroanat.
(1999)Evidence of functional vitamin D receptors in rat hippocampus
Neuroscience
(2001)RXR-β: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response element
Cell
(1991)Vitamin D receptor and nuclear receptor coactivators: crucial interactions in vitamin D-mediated transcription
Steroids
(2001)Rapid, nongenomic steroid actions: a new age?
Front. Neuroendocrinol.
(2000)Membrane receptors for steroid hormones: a case for specific cell surface binding sites for vitamin D metabolites and estrogens
Biochem. Biophys. Res. Commun.
(1998)
Immunochemical studies on the putative plasmalemmal receptor for 1,25-dihydroxyvitamin D3. II. Chick kidney and brain
Steroids
Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives
Trends Neurosci.
The effect of steroid hormones on electrical activity of excitable cells
Trends Neurosci.
Chronic 1,25-dihydroxyvitamin D3-mediated induction of nerve growth factor mRNA and protein in L929 fibroblasts and in adult rat brain
Brain Res.
Vitamin D3 attenuates cortical infarction induced by middle cerebral arterial ligation in rats
Neuropharmacology
Vitamin D3 attenuates 6-hydroxydopamine-induced neurotoxicity in rats
Brain Res.
1,25-Dihydroxyvitamin D3 inhibits the expression of inducible nitric oxide synthase in rat nervous system during experimental allergic encephalomyelitis
Mol. Brain Res.
Nitric oxide actions in neurochemistry
Neurochem. Int.
1,25-Dihydroxyvitamin D3 regulates γ-glutamyl transpeptidase activity in rat brain
Neurosci. Lett.
Chronic vitamin D deficiency in the weanling rat alters catecholamine metabolism in the cortex
Brain Res.
Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells
Mol. Brain Res.
Cytotoxic effects of 1α, 25-dihydroxyvitamin D3 and synthetic vitamin D3 analogues on a glioma cell line
Cancer Lett.
1,25-Dihydroxyvitamin D3 regulates the expression of the low-affinity neurotrophin receptor
Mol. Brain Res.
The p75 receptor: first insight into the transduction mechanisms leading to either cell death or survival
Trends Pharmacol. Sci.
Correlation of a unique 220-kDa protein with vitamin D sensitivity in glioma cells
Biochem. Pharmacol.
The steroid hormone of sunlight soltriol (vitamin D) as a seasonal regulator of biological activities and photoperiodic rhythms
J. Steroid Biochem. Mol. Biol.
Skin as the site of vitamin D synthesis and target tissue for 1,25-dihydroxyvitamin D3
Arch. Dermatol.
Apparent (3H)1,25-dihydroxyvitamin D3 uptake by canine and rodent brain
Am. J. Physiol.
25-Hydroxyvitamin D, 24,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D in human cerebrospinal fluid
Klin. Wochenschr.
Restricted transport of vitamin D and A derivatives through the rat blood–brain barrier
J. Neurochem.
Cloning of human 25-hydroxyvitamin D-1α-hydroxylase and mutations causing vitamin D-dependent rickets type 1
Mol. Endocrinol.
Extrarenal expression of 25-hydroxyvitamin D3-1α hydroxylase
J. Clin. Endocrinol. Metab.
Synthesis of 1,25-dihydroxyvitamin D3 by rat brain macrophages in vitro
J. Neurosci. Res.
Expression of 25(OH) vitamin D3 24-hydroxylase gene in glial cells
NeuroReport
Vitamin D
Am. J. Physiol.
Vitamin D and regulation of gene expression
Curr. Opin. Clin. Nutr. Metab. Care
Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid
Science
Brain target sites for 1,25-dihydroxyvitamin D3
Science
1,25(OH)2 vitamin D3 sites of action in spinal cord and sensory ganglion
Anat. Embryol.
Immunocytochemical localization of the 1,25-dihydroxyvitamin D3 receptor in target cells
Endocrinology
Cited by (744)
Impact of micronutrients and nutraceuticals on cognitive function and performance in Alzheimer's disease
2024, Ageing Research ReviewsCalcitriol protects against reductions in striatal serotonin in rats treated with neurotoxic doses of methamphetamine
2023, Neurochemistry InternationalVitamin D status and cognitive performance in community-dwelling adults: A dose-response meta-analysis of observational studies
2023, Frontiers in NeuroendocrinologyPostpartum depression: aetiology, pathogenesis and the role of nutrients and dietary supplements in prevention and management
2023, Saudi Pharmaceutical JournalDecreased vitamin D levels in obsessive-compulsive disorder patients
2023, CNS Spectrums