HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice
This study investigated the effects of 2-(1-chloro-4-hydroxyisoquinoline- 3-carboxamido) acetic acid (IOX3), a selective small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylases, on mouse brains subject to transient focal cerebral ischaemia. Male, 8- to 12-week-old C57/B6 mice...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Blackwell Publishing Ltd
2014
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| _version_ | 1797081339954987008 |
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| author | Chen, R Ogunshola, O Yeoh, K Jani, A Papadakis, M Nagel, S Schofield, C Buchan, A |
| author_facet | Chen, R Ogunshola, O Yeoh, K Jani, A Papadakis, M Nagel, S Schofield, C Buchan, A |
| author_sort | Chen, R |
| collection | OXFORD |
| description | This study investigated the effects of 2-(1-chloro-4-hydroxyisoquinoline- 3-carboxamido) acetic acid (IOX3), a selective small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylases, on mouse brains subject to transient focal cerebral ischaemia. Male, 8- to 12-week-old C57/B6 mice were subjected to 45 min of middle cerebral artery occlusion (MCAO) either immediately or 24 h after receiving IOX3. Mice receiving IOX3 at 20 mg/kg 24 h prior to the MCAO had better neuroscores and smaller blood brain barrier (BBB) disruption and infarct volumes than mice receiving the vehicle, whereas those having IOX3 at 60 mg/kg showed no significant changes. IOX3 treatment immediately before MCAO was not neuroprotective. IOX3 up-regulated HIF-1a, and increased EPO expression in mouse brains. In an in vitro BBB model (RBE4 cell line), IOX3 up-regulated HIF-1α and delocalized ZO-1. Pre-treating IOX3 on RBE4 cells 24 h before oxygen glucose deprivation had a protective effect on endothelial barrier preservation with ZO-1 being better localized, while immediate IOX3 treatment did not. Our study suggests that HIF stabilization with IOX3 before cerebral ischaemia is neuroprotective partially because of BBB protection, while immediate application could be detrimental. These results provide information for studies aimed at the therapeutic activation of HIF pathway for neurovascular protection from cerebral ischaemia. |
| first_indexed | 2024-03-07T01:13:06Z |
| format | Journal article |
| id | oxford-uuid:8db76837-4385-4dbe-b4ff-5ef12f200137 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:13:06Z |
| publishDate | 2014 |
| publisher | Blackwell Publishing Ltd |
| record_format | dspace |
| spelling | oxford-uuid:8db76837-4385-4dbe-b4ff-5ef12f2001372022-03-26T22:53:00ZHIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in miceJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8db76837-4385-4dbe-b4ff-5ef12f200137EnglishSymplectic Elements at OxfordBlackwell Publishing Ltd2014Chen, ROgunshola, OYeoh, KJani, APapadakis, MNagel, SSchofield, CBuchan, AThis study investigated the effects of 2-(1-chloro-4-hydroxyisoquinoline- 3-carboxamido) acetic acid (IOX3), a selective small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylases, on mouse brains subject to transient focal cerebral ischaemia. Male, 8- to 12-week-old C57/B6 mice were subjected to 45 min of middle cerebral artery occlusion (MCAO) either immediately or 24 h after receiving IOX3. Mice receiving IOX3 at 20 mg/kg 24 h prior to the MCAO had better neuroscores and smaller blood brain barrier (BBB) disruption and infarct volumes than mice receiving the vehicle, whereas those having IOX3 at 60 mg/kg showed no significant changes. IOX3 treatment immediately before MCAO was not neuroprotective. IOX3 up-regulated HIF-1a, and increased EPO expression in mouse brains. In an in vitro BBB model (RBE4 cell line), IOX3 up-regulated HIF-1α and delocalized ZO-1. Pre-treating IOX3 on RBE4 cells 24 h before oxygen glucose deprivation had a protective effect on endothelial barrier preservation with ZO-1 being better localized, while immediate IOX3 treatment did not. Our study suggests that HIF stabilization with IOX3 before cerebral ischaemia is neuroprotective partially because of BBB protection, while immediate application could be detrimental. These results provide information for studies aimed at the therapeutic activation of HIF pathway for neurovascular protection from cerebral ischaemia. |
| spellingShingle | Chen, R Ogunshola, O Yeoh, K Jani, A Papadakis, M Nagel, S Schofield, C Buchan, A HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice |
| title | HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice |
| title_full | HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice |
| title_fullStr | HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice |
| title_full_unstemmed | HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice |
| title_short | HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice |
| title_sort | hif prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice |
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