Abstract
Objective: Vitamin D in the brain has been suggested as a potential neuroprotective agent. For vitamin D to have the greatest effect, its receptor must be regulated or readily available. Vitamin D3 is a pleiotropic hormone but one common neuroprotective pathway studied in our laboratory is glutathione regulation. Our objective was to investigate the intrinsic response of the vitamin D receptor under stress conditions, in in vitro preparations, and determine whether the neuroprotective effect of vitamin D is linked to the cystine-glutamate exchanger System Xc-. Methods: In vitro, mouse cortical neural stem cells were cultured and exposed to glutamate, as a model of cellular stress, with or without vitamin D supplementation. Western Blot analysis and immunocytochemistry was used to demonstrate the protective effect of Vitamin D3. Main results: The vitamin D receptor was upregulated under stress conditions, and vitamin D supplementation was neuroprotective for neural stem cells. Vitamin D3-induced neuroprotection was attenuated by the addition of an inhibitor of System Xc-, a protein pivotal in glutathione biosynthesis. Conclusion: Vitamin D3 causes an increase in glutathione, suggesting that it has a major role in neuroprotection. Our results suggest that Vitamin D3-induced neuroprotection is regulated via System Xc- and glutathione biosynthesis.
Highlights
The relationship between vitamin D3 and calcium is understood, recent research suggests that 1,25-dihydroxyvitamin D3 plays a role in brain development [1]
Main results: The vitamin D receptor was upregulated under stress conditions, and vitamin D supplementation was neuroprotective for neural stem cells
Vitamin D3-induced neuroprotection was attenuated by the addition of an inhibitor of System Xc, a protein pivotal in glutathione biosynthesis
Summary
The relationship between vitamin D3 and calcium is understood, recent research suggests that 1,25-dihydroxyvitamin D3 plays a role in brain development [1]. The vitamin D3 receptor (VDR) has been identified in brain and spinal cord neurons of developing fetal rats [2,3,4], indicating that vitamin D3 must have some role in neurogenesis. Vitamin D3 was initially shown to increase NGF [6], but other trophic factors are affected by Vitamin D3, including glial cell linederived neurotrophic factor [7] and neurotrophin [8]. These increases in neurotrophic factors have been correlated with neuroprotection [9,10]. Other mechanisms imply that vitamin D3 has a role in neuroprotection by modulating glutathione, as shown by the inhibition of its synthesis with buthionine sulfoximine in dopaminergic neurons [12]
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