Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice

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)...

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Autores principales:	Olga Burmistrova, Ana Olias-Arjona, Rebeca Lapresa, Daniel Jimenez-Blasco, Tatiana Eremeeva, Dmitry Shishov, Sergei Romanov, Kristina Zakurdaeva, Angeles Almeida, Peter O. Fedichev, Juan P. Bolaños
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/883ca8c766f94de9a52ed1902af7bd39
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spelling	oai:doaj.org-article:883ca8c766f94de9a52ed1902af7bd392021-12-02T15:09:13ZTargeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice10.1038/s41598-019-48196-z2045-2322https://doaj.org/article/883ca8c766f94de9a52ed1902af7bd392019-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-48196-zhttps://doaj.org/toc/2045-2322Abstract 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.Olga BurmistrovaAna Olias-ArjonaRebeca LapresaDaniel Jimenez-BlascoTatiana EremeevaDmitry ShishovSergei RomanovKristina ZakurdaevaAngeles AlmeidaPeter O. FedichevJuan P. BolañosNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-13 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Olga Burmistrova Ana Olias-Arjona Rebeca Lapresa Daniel Jimenez-Blasco Tatiana Eremeeva Dmitry Shishov Sergei Romanov Kristina Zakurdaeva Angeles Almeida Peter O. Fedichev Juan P. Bolaños Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice
description	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.
format	article
author	Olga Burmistrova Ana Olias-Arjona Rebeca Lapresa Daniel Jimenez-Blasco Tatiana Eremeeva Dmitry Shishov Sergei Romanov Kristina Zakurdaeva Angeles Almeida Peter O. Fedichev Juan P. Bolaños
author_facet	Olga Burmistrova Ana Olias-Arjona Rebeca Lapresa Daniel Jimenez-Blasco Tatiana Eremeeva Dmitry Shishov Sergei Romanov Kristina Zakurdaeva Angeles Almeida Peter O. Fedichev Juan P. Bolaños
author_sort	Olga Burmistrova
title	Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice
title_short	Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice
title_full	Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice
title_fullStr	Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice
title_full_unstemmed	Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice
title_sort	targeting pfkfb3 alleviates cerebral ischemia-reperfusion injury in mice
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/883ca8c766f94de9a52ed1902af7bd39
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Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice

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