4.7 Article

Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice

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SCIENTIFIC REPORTS
卷 9, 期 -, 页码 -

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NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-019-48196-z

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资金

  1. MINECO [SAF2016-78114-R]
  2. CIBERFES [CB16/10/00282]
  3. H2020 European Commission (BatCure Grant) [666918]
  4. Ayudas Fundacion BBVA a Equipos de Investigacion Cientifica en Biomedicina 2017
  5. Fundacion Ramon Areces
  6. H2020 European Commission (PANA) [686009]
  7. Instituto de Salud Carlos III [PI15/00473, RD16/0019/0018]
  8. FEDER
  9. P.O. FEDER of Castilla y Leon 14-20 [CLU-2017-03)]
  10. Gero Discovery L.L.C.
  11. H2020 Societal Challenges Programme [666918] Funding Source: H2020 Societal Challenges Programme

向作者/读者索取更多资源

The glycolytic rate in neurons is low in order to allow glucose to be metabolized through the pentosephosphate pathway (PPP), which regenerates NADPH to preserve the glutathione redox status and survival. This is controlled by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), the pro-glycolytic enzyme that forms fructose-2,6-bisphosphate, a powerful allosteric activator of 6-phosphofructo-1-kinase. In neurons, PFKFB3 protein is physiologically inactive due to its proteasomal degradation. However, upon an excitotoxic stimuli, PFKFB3 becomes stabilized to activate glycolysis, thus hampering PPP mediated protection of redox status leading to neurodegeneration. Here, we show that selective inhibition of PFKFB3 activity by the small molecule AZ67 prevents the NADPH oxidation, redox stress and apoptotic cell death caused by the activation of glycolysis triggered upon excitotoxic and oxygen-glucose deprivation/reoxygenation models in mouse primary neurons. Furthermore, in vivo administration of AZ67 to mice significantly alleviated the motor discoordination and brain infarct injury in the middle carotid artery occlusion ischemia/reperfusion model. These results show that pharmacological inhibition of PFKFB3 is a suitable neuroprotective therapeutic strategy in excitotoxic-related disorders such as stroke.

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