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Vitamin D3-induced Neuroprotection is Dependent on System Xc Activity

Aditi Jani, Stephanie Crockett, Melinda Clarke, Brittany Coleman and Brian Sims

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.