Abstract
The glycolytic rate in neurons is low in order to allow glucose to be metabolized through the pentose-phosphate 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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A549 Cells
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Animals
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Brain Ischemia / drug therapy*
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Brain Ischemia / genetics
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Brain Ischemia / metabolism
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Brain Ischemia / pathology
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Cerebral Cortex / blood supply
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Cerebral Cortex / drug effects
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Cerebral Cortex / metabolism
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Cerebral Cortex / pathology
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Fructosediphosphates / metabolism
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Gene Expression Regulation
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Glutamic Acid / metabolism
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Glutamic Acid / pharmacology
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Glycolysis / drug effects
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Humans
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Male
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Mice
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Neurons / drug effects
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Neurons / metabolism
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Neurons / pathology
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Neuroprotective Agents / pharmacology*
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Pentose Phosphate Pathway / drug effects
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Phosphofructokinase-1 / genetics
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Phosphofructokinase-1 / metabolism
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Phosphofructokinase-2 / antagonists & inhibitors
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Phosphofructokinase-2 / genetics*
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Phosphofructokinase-2 / metabolism
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Primary Cell Culture
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Proteasome Endopeptidase Complex / drug effects
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Proteasome Endopeptidase Complex / metabolism
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Proteolysis / drug effects
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Psychomotor Performance / drug effects
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Pyridines / pharmacology*
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Pyrrolidines / pharmacology*
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Reperfusion Injury / genetics
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Reperfusion Injury / metabolism
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Reperfusion Injury / pathology
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Reperfusion Injury / prevention & control*
Substances
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3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one
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Enzyme Inhibitors
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Fructosediphosphates
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Neuroprotective Agents
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Pyridines
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Pyrrolidines
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Glutamic Acid
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fructose 2,6-diphosphate
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PFKFB3 protein, mouse
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Phosphofructokinase-2
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Phosphofructokinase-1
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Proteasome Endopeptidase Complex