SVCT2-mediated ascorbic acid uptake buffers stress responses via DNA hydroxymethylation reprogramming of S100 calcium-binding protein A4 gene.
Redox Biol
; 58: 102543, 2022 12.
Article
in En
| MEDLINE
| ID: mdl-36436457
ABSTRACT
Vitamin C, a key antioxidant in the central nervous system, cycles between ascorbic acid and dehydroascorbic acid under pathophysiological conditions. Clinical evidence supports that the absence of vitamin C may be linked to depressive symptoms, but much less is known about the mechanism. Herein, we show that chronic stress disrupts the expression of ascorbic acid transporter, sodium-dependent vitamin C transport 2, and induces a deficiency in endogenous ascorbic acid in the medial prefrontal cortex, leading to depressive-like behaviors by disturbing redox-dependent DNA methylation reprogramming. Attractively, ascorbic acid (100 mg/kg-1000 mg/kg, intraperitoneal injection, as bioequivalent of an intravenous drip dose of 0.48 g-4.8 g ascorbic acid per day in humans) produces rapid-acting antidepressant effects via triggering DNA demethylation catalyzed by ten-eleven translocation dioxygenases. In particular, the mechanistic studies by both transcriptome sequencing and methylation sequencing have shown that S100 calcium binding protein A4, a potentially protective factor against oxidative stress and brain injury, mediates the antidepressant activity of ascorbic acid via activating erb-b2 receptor tyrosine kinase 4 (ErbB4)-brain derived neurotrophic factor (BDNF) signaling pathway. Overall, our findings reveal a novel nutritional mechanism that couples stress to aberrant DNA methylation underlying depressive-like behaviors. Therefore, application of vitamin C may be a potential strategy for the treatment of depression.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ascorbic Acid
/
Sodium-Coupled Vitamin C Transporters
Limits:
Humans
Language:
En
Journal:
Redox Biol
Year:
2022
Document type:
Article
Affiliation country: