Suppression Of PKM2 By TDCS Protects Against Mouse Cerebral Ischemia-reperfusion Injury Through Metabolic Reprogramming

Background: 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.Objectives: The purpose of this study is to investigate the role of PKM2-mediated metabolic reprogramming in mouse cerebral I/R injury and to determine whether transcranial direct-current stimulation(tDCS)exerts its neuroprotective effect through regulating PKM2 activity after I/R.Methods: The expression and activity of PKM2 are detected after mouse cerebral I/R injury.PPP-dependent antioxidative molecules are measured.The effects of tDCS on both PKM2 activity and neurological functional recovery are tested after I/R.Results: The level of PKM2 tetramers and the activity of PKM2 are increased in the injured ischemic penumbra after I/R.Ischemia-induced increase of PKM2 activity promotes neuronal death via the suppression of PPP-dependent antioxidant capacity.To identify therapeutic approach that suppresses ischemia-induced increase of PKM2 activity,we test the effect of tDCS on PKM2 activity after mouse I/R.Our data indicate that cathodal tDCS inhibits PKM2 activity in the ischemic penumbra.Cathodal tDCS also reduces the cerebral infarct size and the neurological deficits in stroke mice,and such neuroprotection is mediated through the suppression of PKM2 activity after I/R.Conclusions: This study identifies PKM2 as a crucial regulator of neuronal metabolism after mouse cerebral I/R injury.Our results indicate that tDCS protects against mouse cerebral I/R injury through regulating PKM2-mediated metabolic reprogramming.