The slow-releasing and mitochondria-targeted hydrogen sulfide (H2s) delivery molecule ap39 induces brain tolerance to ischemia
dc.contributor.author | Pomierny, B | |
dc.contributor.author | Krzyżanowska, W | |
dc.contributor.author | Jurczyk, J | |
dc.contributor.author | Skórkowska, A | |
dc.contributor.author | Strach, B | |
dc.contributor.author | Szafarz, M | |
dc.contributor.author | Przejczowska-Pomierny, K | |
dc.contributor.author | Torregrossa, R | |
dc.contributor.author | Whiteman, M | |
dc.contributor.author | Marcinkowska, M | |
dc.contributor.author | Pera, J | |
dc.contributor.author | Budziszewska, B | |
dc.date.accessioned | 2021-08-06T12:35:14Z | |
dc.date.issued | 2021-07-22 | |
dc.description.abstract | Ischemic stroke is the third leading cause of death in the world, which accounts for almost 12% of the total deaths worldwide. Despite decades of research, the available and effective pharmacotherapy is limited. Some evidence underlines the beneficial properties of hydrogen sulfide (H2S) donors, such as NaSH, in an animal model of brain ischemia and in in vitro research; however, these data are ambiguous. This study was undertaken to verify the neuroprotective activity of AP39, a slow-releasing mitochondria-targeted H2S delivery molecule. We administered AP39 for 7 days prior to ischemia onset, and the potential to induce brain tolerance to ischemia was verified. To do this, we used the rat model of 90-min middle cerebral artery occlusion (MCAO) and used LC-MS/MS, RT-PCR, Luminex™ assays, Western blot and immunofluorescent double-staining to determine the absolute H2S levels, inflammatory markers, neurotrophic factor signaling pathways and apoptosis marker in the ipsilateral frontal cortex, hippocampus and in the dorsal striatum 24 h after ischemia onset. AP39 (50 nmol/kg) reduced the infarct volume, neurological deficit and reduced the microglia marker (Iba1) expression. AP39 also exerted prominent anti-inflammatory activity in reducing the release of Il-1β, Il-6 and TNFα in brain areas particularly affected by ischemia. Furthermore, AP39 enhanced the pro-survival pathways of neurotrophic factors BDNF-TrkB and NGF-TrkA and reduced the proapoptotic proNGF-p75NTR-sortilin pathway activity. These changes corresponded with reduced levels of cleaved caspase 3. Altogether, AP39 treatment induced adaptative changes within the brain and, by that, developed brain tolerance to ischemia. | en_GB |
dc.description.sponsorship | National Science Center, Poland | en_GB |
dc.description.sponsorship | Medical Research Council (MRC) | en_GB |
dc.identifier.citation | Vol. 22 (15), article 7816 | en_GB |
dc.identifier.doi | 10.3390/ijms22157816 | |
dc.identifier.grantnumber | 2016/21/D/NZ4/03302 | en_GB |
dc.identifier.grantnumber | MR/S002626/1 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/126692 | |
dc.language.iso | en | en_GB |
dc.publisher | MDPI | en_GB |
dc.rights | © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). | en_GB |
dc.subject | brain ischemia | en_GB |
dc.subject | hydrogen sulfide | en_GB |
dc.subject | AP39 | en_GB |
dc.subject | brain preconditioning | en_GB |
dc.subject | neuroinflammation | en_GB |
dc.subject | mitochondrial targeting | en_GB |
dc.title | The slow-releasing and mitochondria-targeted hydrogen sulfide (H2s) delivery molecule ap39 induces brain tolerance to ischemia | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2021-08-06T12:35:14Z | |
dc.identifier.issn | 1661-6596 | |
dc.description | This is the final version. Available on open access from MDPI via the DOI in this record | en_GB |
dc.identifier.journal | International Journal of Molecular Sciences | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2021-07-16 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2021-07-22 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2021-08-06T12:16:04Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2021-08-06T12:35:20Z | |
refterms.panel | A | en_GB |
Files in this item
This item appears in the following Collection(s)
Except where otherwise noted, this item's licence is described as © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).