Inhibition Of Glycolysis Abolishes Microglial Inflammatory Activation Via Suppression Of MTOR/NF-?B And NAD~+/SIRT1/p65 Acetylation

Microglial activation mediated neuroinflammation plays an important role in the progression of neurodegerative diseases.Inflammatory activation of microglial cells undergo aerobic glycolysis which positively regulates proinflammatory responses in peripheral inflammatory cells.However,the molecular mechanism underlying the role of glycolytic metabolism on microglial activation and progresses of neuroinflmamtory diseases have not yet been fully understood.In the present study,we demonstrated that inhibition of glycolysis by specific inhibitors or ?noc?down of glucose transporter or hexo?inase?abolished LPS-induced expression of proinflammatory genes in microglia cells.Mechanistic studies demonstrated that glycolytic inhibitors significantly inhibited IKK?phosphorylation,I?B phosphorylation,I?B degradation,nucler translocation of p65 and NF-?B luciferase activity by activation of AMPK/mTOR pathway.Furthermore,NAD~+/SIRT1 activation mediated inhibition of p65 subunit of NF-?B acetylation are also involved in the mechanisms underlying the suppression of proinflamamtory mediators production by glycolytic inhibitor.Co-culture study revealed that glycolytic inhibitor 2-DG(2-deoxyglucose)reduced the cytotoxicity of activated microglia toward HT-22 neuroblastoma cells with no direct protective effect on MES23.5 dopaminergic neuron cells.In vivo study demonstrated that 2-DG significantly ameliorated MPTP induced DA neuron loss and glial cell activation in mouse.Collectively,our results suggest that glycolysis is actively involved in the microglial activation and inhibition of glycolysis could ameliorate microglial activation related neuroinflamamtory diseases.