Valproic acid regulates sodium‐dependent vitamin C transporter‐2 (SVCT‐2) functional expression in neuronal cells

Abstract

Neuronal uptake of ascorbic acid (AA) in humans occurs via the human sodium‐dependent vitamin C transporter‐2 (hSVCT2; the product of the SLC23A2gene). Studies have shown that a significantly lower level of vitamin C is present in the blood plasma of patients with chronic neurological conditions including epilepsy. Therefore, studies focused on determining the molecular mechanisms involved in regulating hSVCT2 functional expression are vital for identifying potential therapeutic strategies to optimize vitamin C body homeostasis. Currently, little is known about the role of valproic acid (VPA), a drug used to treat epilepsy that also acts as a class I histone deacetylase inhibitor (HDACi), on AA uptake in neuronal systems. Thus, this study aims to investigate the effect of VPA on SVCT2 functional expression using human neuroblastoma SH‐SY5Y cells (in vitro) and mouse (in vivo) models. VPA (1mM) treatment up‐regulated the AA uptake and this increased uptake was accompanied by a marked increase in hSVCT2 protein and mRNA expression levels as well as SLC23A2 promoter activity in SH‐SY5Y cells. In addition, the protein and mRNA expression levels of specific protein‐1 (Sp1), a transcription factor that drives the basal activity of SLC23A2 promoter, were also markedly up‐regulated in VPA‐treated SH‐SY5Y cells. Further, knocking down the HDAC2, the predominant isoform in the neuronal system, significantly increased AA uptake and up‐regulated the hSVCT2 protein and mRNA expression levels in SH‐SY5Y cells. VPA administration (150 mg/kg body weight) to wild‐type (WT) mice displayed increased mouse (m)SVCT2 protein, mRNA and hnRNA expression in the brain. Together, our findings suggests that VPA up‐regulates the functional expression of SVCT2 and HDAC2 plays an essential role in neuronal AA uptake.