Review
New clues about vitamin D functions in the nervous system

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Abstract

Accumulating data have provided evidence that 1α,25 dihydroxyvitamin D3 [1,25-(OH)2D3] is involved in brain function. Thus, the nuclear receptor for 1,25-(OH)2D3 has been localized in neurons and glial cells. Genes encoding the enzymes involved in the metabolism of this hormone are also expressed in brain cells. The reported biological effects of 1,25-(OH)2D3 in the nervous system include the biosynthesis of neurotrophic factors and at least one enzyme involved in neurotransmitter synthesis. 1,25-(OH)2D3 can also inhibit the synthesis of inducible nitric oxide synthase and increase glutathione levels, suggesting a role for the hormone in brain detoxification pathways. Neuroprotective and immunomodulatory effects of this hormone have been described in several experimental models, indicating the potential value of 1,25-(OH)2D3 pharmacological analogs in neurodegenerative and neuroimmune diseases. In addition, 1,25-(OH)2D3 induces glioma cell death, making the hormone of potential interest in the management of brain tumors. These results reveal previously unsuspected roles for 1,25-(OH)2D3 in brain function and suggest possible areas of future research.

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).

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