Neuroprotective Effect of HIF Prolyl Hydroxylase Inhibition in an In Vitro Hypoxia Model

A novel potent analog of the branched tail oxyquinoline group of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, neuradapt, has been studied in two treatment regimes in an in vitro hypoxia model on murine primary hippocampal cultures. Neuradapt activates the expression of HIF1 and HIF2...

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Main Authors: Maria Savyuk, Mikhail Krivonosov, Tatiana Mishchenko, Irina Gazaryan, Mikhail Ivanchenko, Anna Khristichenko, Andrey Poloznikov, Dmitry Hushpulian, Sergey Nikulin, Evgeny Tonevitsky, Guzal Abuzarova, Elena Mitroshina, Maria Vedunova
Format: Article
Language:English
Published: MDPI AG 2020-07-01
Series:Antioxidants
Subjects:
Online Access:https://www.mdpi.com/2076-3921/9/8/662
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spelling doaj-190a771ad2484064962acf84212f51a62020-11-25T02:35:09ZengMDPI AGAntioxidants2076-39212020-07-01966266210.3390/antiox9080662Neuroprotective Effect of HIF Prolyl Hydroxylase Inhibition in an In Vitro Hypoxia ModelMaria Savyuk0Mikhail Krivonosov1Tatiana Mishchenko2Irina Gazaryan3Mikhail Ivanchenko4Anna Khristichenko5Andrey Poloznikov6Dmitry Hushpulian7Sergey Nikulin8Evgeny Tonevitsky9Guzal Abuzarova10Elena Mitroshina11Maria Vedunova12Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603950 Nizhny Novgorod, RussiaLobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603950 Nizhny Novgorod, RussiaLobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603950 Nizhny Novgorod, RussiaP. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 125284 Moscow, RussiaLobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603950 Nizhny Novgorod, RussiaP. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 125284 Moscow, RussiaP. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 125284 Moscow, RussiaP. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 125284 Moscow, RussiaFaculty of Biology and Biotechnologies, Higher School of Economics, 101000 Moscow, RussiaDevelopment Fund of the Innovation Science and Technology Center “Mendeleev Valley”, 125480 Moscow, RussiaP. A. Hertsen Moscow Oncology Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, 125284 Moscow, RussiaLobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603950 Nizhny Novgorod, RussiaLobachevsky State University of Nizhny Novgorod, 23 Gagarin Ave., 603950 Nizhny Novgorod, RussiaA novel potent analog of the branched tail oxyquinoline group of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, neuradapt, has been studied in two treatment regimes in an in vitro hypoxia model on murine primary hippocampal cultures. Neuradapt activates the expression of HIF1 and HIF2 target genes and shows no toxicity up to 20 μM, which is more than an order of magnitude higher than its biologically active concentration. Cell viability, functional activity, and network connectivity between the elements of neuronal networks have been studied using a pairwise correlation analysis of the intracellular calcium fluctuations in the individual cells. An immediate treatment with 1 μМ and 15 μМ neuradapt right at the onset of hypoxia not only protects from the death, but also maintains the spontaneous calcium activity in nervous cells at the level of the intact cultures. A similar neuroprotective effect in the post-treatment scenario is observed for 15 μМ, but not for 1 μМ neuradapt. Network connectivity is better preserved with immediate treatment using 1 μМ neuradapt than with 15 μМ, which is still beneficial. Post-treatment with neuradapt did not restore the network connectivity despite the observation that neuradapt significantly increased cell viability at 1 μМ and functional activity at 15 μМ. The preservation of cell viability and functional activity makes neuradapt promising for further studies in a post-treatment scenario, since it can be combined with other drugs and treatments restoring the network connectivity of functionally competent cells.https://www.mdpi.com/2076-3921/9/8/662hypoxia-inducible factor (HIF)HIF prolyl hydroxylaseprolyl hydroxylase (PHD)neuradaptprimary hippocampal culturesfunctional neural network activity
collection DOAJ
language English
format Article
sources DOAJ
author Maria Savyuk
Mikhail Krivonosov
Tatiana Mishchenko
Irina Gazaryan
Mikhail Ivanchenko
Anna Khristichenko
Andrey Poloznikov
Dmitry Hushpulian
Sergey Nikulin
Evgeny Tonevitsky
Guzal Abuzarova
Elena Mitroshina
Maria Vedunova
spellingShingle Maria Savyuk
Mikhail Krivonosov
Tatiana Mishchenko
Irina Gazaryan
Mikhail Ivanchenko
Anna Khristichenko
Andrey Poloznikov
Dmitry Hushpulian
Sergey Nikulin
Evgeny Tonevitsky
Guzal Abuzarova
Elena Mitroshina
Maria Vedunova
Neuroprotective Effect of HIF Prolyl Hydroxylase Inhibition in an In Vitro Hypoxia Model
Antioxidants
hypoxia-inducible factor (HIF)
HIF prolyl hydroxylase
prolyl hydroxylase (PHD)
neuradapt
primary hippocampal cultures
functional neural network activity
author_facet Maria Savyuk
Mikhail Krivonosov
Tatiana Mishchenko
Irina Gazaryan
Mikhail Ivanchenko
Anna Khristichenko
Andrey Poloznikov
Dmitry Hushpulian
Sergey Nikulin
Evgeny Tonevitsky
Guzal Abuzarova
Elena Mitroshina
Maria Vedunova
author_sort Maria Savyuk
title Neuroprotective Effect of HIF Prolyl Hydroxylase Inhibition in an In Vitro Hypoxia Model
title_short Neuroprotective Effect of HIF Prolyl Hydroxylase Inhibition in an In Vitro Hypoxia Model
title_full Neuroprotective Effect of HIF Prolyl Hydroxylase Inhibition in an In Vitro Hypoxia Model
title_fullStr Neuroprotective Effect of HIF Prolyl Hydroxylase Inhibition in an In Vitro Hypoxia Model
title_full_unstemmed Neuroprotective Effect of HIF Prolyl Hydroxylase Inhibition in an In Vitro Hypoxia Model
title_sort neuroprotective effect of hif prolyl hydroxylase inhibition in an in vitro hypoxia model
publisher MDPI AG
series Antioxidants
issn 2076-3921
publishDate 2020-07-01
description A novel potent analog of the branched tail oxyquinoline group of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, neuradapt, has been studied in two treatment regimes in an in vitro hypoxia model on murine primary hippocampal cultures. Neuradapt activates the expression of HIF1 and HIF2 target genes and shows no toxicity up to 20 μM, which is more than an order of magnitude higher than its biologically active concentration. Cell viability, functional activity, and network connectivity between the elements of neuronal networks have been studied using a pairwise correlation analysis of the intracellular calcium fluctuations in the individual cells. An immediate treatment with 1 μМ and 15 μМ neuradapt right at the onset of hypoxia not only protects from the death, but also maintains the spontaneous calcium activity in nervous cells at the level of the intact cultures. A similar neuroprotective effect in the post-treatment scenario is observed for 15 μМ, but not for 1 μМ neuradapt. Network connectivity is better preserved with immediate treatment using 1 μМ neuradapt than with 15 μМ, which is still beneficial. Post-treatment with neuradapt did not restore the network connectivity despite the observation that neuradapt significantly increased cell viability at 1 μМ and functional activity at 15 μМ. The preservation of cell viability and functional activity makes neuradapt promising for further studies in a post-treatment scenario, since it can be combined with other drugs and treatments restoring the network connectivity of functionally competent cells.
topic hypoxia-inducible factor (HIF)
HIF prolyl hydroxylase
prolyl hydroxylase (PHD)
neuradapt
primary hippocampal cultures
functional neural network activity
url https://www.mdpi.com/2076-3921/9/8/662
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