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Vitamin D metabolism in the nervous system: potential effects of glucocorticoids
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Several studies have reported that neuronal function is influenced by vitamin D and it has been proposed that low serum 25-hydroxyvitamin D3 levels may be a risk factor for several brain disorders. However, little is known about the activation and metabolism as well as mechanisms of action of vitamin D in the neurons. In a previous study, we reported that the mouse motor neuron-like hybrid cell line NSC-34 expresses mRNA for CYP24A1 as well as the CYP24A1-mediated enzyme activity (Almokhtar et al., 2016). In contrast, the present results show that neither mRNA expression nor enzymatic activities of vitamin D3 metabolizing CYP enzymes could be detected in primary neuron-enriched cells from rat embryonic cortex. However, the levels of 25-hydroxyvitamin D3 incubated with cultured primary cells decreased substantially, indicating metabolism of this substrate. NSC-34 cells were found to produce, besides 24,25-dihydroxyvitamin D3, a major as yet unknown 25-hydroxyvitamin D3 metabolite in addition. The current results indicate drug-mediated regulation of vitamin D3 metabolism in cells of the nervous system. The results showing effects of prednisolone on expression of CYP24A1 mRNA, CYP24A1-mediated hydroxylase activity and 25-hydroxvitamin D3 consumption in NSC-34 cells are all consistent with an increased 25-hydroxyvitamin D3 metabolism. The results indicate that therapeutic treatment with glucocorticoids may lead to a potential decrease in active forms of vitamin D3 in brain cells. It might be speculated that administration of corticosteroids leading to reported CNS adverse effects may at least in part be due to effects of glucocorticoids on vitamin D3 metabolism.

National Category
Chemical Sciences Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-333917OAI: oai:DiVA.org:uu-333917DiVA, id: diva2:1158236
Available from: 2017-11-18 Created: 2017-11-18 Last updated: 2017-11-19
In thesis
1. Expression and regulation of steroid metabolizing enzymes in cells of the nervous and skeletal systems: Special focus on vitamin D metabolism
Open this publication in new window or tab >>Expression and regulation of steroid metabolizing enzymes in cells of the nervous and skeletal systems: Special focus on vitamin D metabolism
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Little is known about the mechanisms of vitamin D actions in the brain and bone. In this study, the metabolism of vitamin D and its regulation in various cell cultures of the nervous and skeletal systems were examined.

Human osteosarcoma Saos-2 cells, human primary osteoblasts (hOB) and murine motor neuron-like NSC-34 cells were found to express mRNA for all enzymes required in vitamin D3 metabolism as well as the vitamin D receptor (VDR) that mediates vitamin D actions. Also, production of 24,25-dihydroxyvitamin D3 was found in these cells. Studies on vitamin D metabolism in NSC-34 cells and in primary neuron-enriched cells from rat cerebral cortex indicate formation of a previously unknown major metabolite formed from 25-hydroxyvitamin D3. Evaluation of the NSC-34 cells suggests that this cell line could be a novel model for studies of neuronal vitamin D metabolism and its regulation by endogenous and exogenous compounds.

Treatment with glucocorticoids down regulated mRNA expression for the CYP24A1 gene in Saos-2 and hOB cells. Additionally, the glucocorticoid prednisolone showed suppression of CYP24A1-mediated metabolism and CYP24A1 promoter activity in Saos-2 cells. In NSC-34 cells, CYP24A1 mRNA levels were up-regulated by prednisolone, 1α,25-dihydroxyvitamin D3 and its synthetic analogues, EB1089 and tacalcitol. Formation of an endogenous glucocorticoid, 11-deoxycortisol, was observed in Saos-2 cells. Effects of glucocorticoids on the vitamin D system in bone cells may contribute to the adverse side effects in long-term treatment with glucocorticoids. Also, there may be a correlation between the administration of corticosteroids and adverse effects in the CNS.

Expression and effects of vitamin D on steroidogenic enzymes were studied in primary neuron-enriched rat cortex cells, primary rat astrocytes and human neuroblastoma SH-SY5Y cells. These different cell cultures all expressed CYP17A1, whereas only astrocytes expressed 3β-hydroxysteroid dehydrogenase (3β-HSD). 1α,25-Dihydroxyvitamin D3 suppressed mRNA levels and enzyme activity of CYP17A1 in SH-SY5Y cells and astrocytes. 1α,25-Dihydroxyvitamin D3 suppressed enzyme activity and mRNA levels of 3β-HSD in astrocytes. The results suggest that vitamin D-mediated regulation of CYP17A1 and 3β-HSD may play a role in the nervous system.

The results presented here contribute to our understanding of vitamin D metabolism and effects of glucocorticoids in the brain and bone.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 58
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 242
National Category
Chemical Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-333920 (URN)978-91-513-0154-9 (ISBN)
Public defence
2018-01-18, B7:101a, BMC, Husargatan 3, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2017-12-21 Created: 2017-11-19 Last updated: 2018-03-08

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