Bilateral transcranial direct-current stimulation confers neuroprotection through suppression of PKM2 after mouse cerebral ischemia injury

[Display omitted] •The level of PKM2 tetramers and the activity of PKM2 are increased after cerebral ischemia injury.•Ischemia-induced increase of PKM2 activity promotes neuronal death via the suppression of PPP-dependent antioxidant capacity.•We have established a newly direct-current stimulation approach, Bilateral transcranial direct-current stimulation (BtDCS).•BtDCS confers neuroprotection through regulating PKM2-mediated metabolic reprogramming. In its tetrameric form, pyruvate kinase M2 isoform (PKM2) catalyzes the last step of glycolysis and plays a key role in the metabolic reprogramming via regulating the signaling of pentose phosphate pathway (PPP). But the role of PKM2 in cerebral ischemia–reperfusion (I/R) injury remains unknown. Mice model of middle cerebral artery occlusion (MCAO) and model of oxygen-glucose deprivation (OGD) injury in cultured neurons were established. PKM2 activator or inhibitor were used to test the effects of PKM2 in wild-type and PKM2 (−/-) mice after I/R injury. Biochemical and molecular approach were used to detect the level of PKM2 tetramers and PPP metabolites. We showed for the first time that ischemia-induced increase of PKM2 activity promoted neuronal death via the suppression of PPP-dependent antioxidant capacity. To identify therapeutic approach that suppresses ischemia-induced increase of PKM2 activity, we tested the effect of bilateral transcranial direct-current stimulation (BtDCS), a newly established BtDCS approach by us, on PKM2 activity after mouse I/R. Our data demonstrated that BtDCS inhibited PKM2 activity in the ischemic neurons. BtDCS also reduced the cerebral infarct volume and the neurological deficits in stroke mice. We found that BtDCS-induced neuroprotection was mediated through the suppression of PKM2 activity after I/R. Together, this study provided novel evidence that supported PKM2 as a crucial regulator of neuronal metabolism after cerebral I/R injury, and revealed the molecular mechanism by which BtDCS protects against mouse cerebral I/R injury through regulating PKM2-mediated metabolic reprogramming.