Ischemic stroke remains one of the most common causes of death and disability worldwide. The stroke patients with an inadequate intake of folic acid tend to have increased brain injury and poorer prognosis. However, the precise mechanisms underlying the harmful effects of folic acid deficiency (FD) in ischemic stroke is still elusive. Here, we aimed to test the hypothesis that mitochondrial localized STAT3 (mitoSTAT3) expression may be involved in the process of neuronal damage induced by FD in in vivo and in vitro models of ischemic stroke. Our results exhibited that FD increased infarct size and aggravated the damage of mitochondrial ultrastructure in ischemic brains. Meanwhile, FD upregulated the phosphorylation levels of mitoSTAT3 at Tyr705 (Y705) and Ser727 (S727) sites in the rat middle cerebral artery occlusion/reperfusion (MCAO/R) model and oxygen-glucose deprivation followed by reperfusion (OGD/R) N2a cells. Furthermore, the inhibition of JAK2 by AG490 led to a significant decrease in FD-induced phosphorylation of Y705, while S727 phosphorylation was unaffected. Conversely, U0126 and LY294002, which respectively inhibited phosphorylation of ERK1/2 and Akt, partially prevented S727 phosphorylation, but had limited effects on the level of pY705, suggesting that phosphorylation of Y705 and S727 is regulated via independent mechanisms in FD-treated brains.
Keywords: Folic acid; Ischemic brain; Mitochondrial injury; N2a cells; STAT3 phosphorylation.
© 2020. Springer Science+Business Media, LLC, part of Springer Nature.