The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is one of the primary pathways responsible for the cellular defense system against oxidative stress. Oxidative stress-induced apoptosis is a causal event in diabetic
embryopathy. Thus, the Nrf2 pathway may play an important role in the induction of diabetic
embryopathy. In the present study, we investigated the potentially protective effect of the Nrf2 activator, vinylsulfone, on high
glucose-induced cellular stress, apoptosis, and
neural tube defects (NTDs). Embryonic day 8.5 (E8.5) whole mouse embryos were cultured in normal (5 mmol/L) or high (16.7 mmol/
L) glucose conditions, with or without vinylsulfone. At a concentration of 10 μmol/L, vinylsulfone had an inhibitory effect on high
glucose-induced NTD formation, but it was not significant. At a concentration of 20 μmol/L, vinylsulfone significantly reduced high
glucose-induced NTDs. In addition, 20 μmol/L vinylsulfone abrogated the high
glucose-induced oxidative stress markers
lipid hydroperoxide (LPO),
4-hydroxynonenal (4-HNE), and
nitrotyrosine-modified
proteins. The high
glucose-induced endoplasmic reticulum (ER) stress
biomarkers were also suppressed by 20 μmol/L vinylsulfone through the inhibition of phosphorylated
protein kinase RNA-like ER
kinase (PERK),
inositol requiring
protein 1α (IRE1a), eukaryotic
initiation factor 2α (eIF2a), upregulated
C/EBP-homologous protein (CHOP), binding
immunoglobulin protein (BiP), and
x-box binding protein 1 (XBP1)
messenger RNA splicing. Furthermore, 20 μmol/L vinylsulfone abolished
caspase 3 and
caspase 8 cleavage, markers of apoptosis, in embryos cultured under high
glucose conditions. The Nrf2 activator, vinylsulfone, is protective against high
glucose-induced cellular stress,
caspase activation, and subsequent NTD formation. Our data suggest that vinylsulfone supplementation is a potential
therapy for diabetes-associated neurodevelopmental defects.