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The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H(2)S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia
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 (H(2)S) donors, s...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346077/ https://www.ncbi.nlm.nih.gov/pubmed/34360581 http://dx.doi.org/10.3390/ijms22157816 |
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author | Pomierny, Bartosz Krzyżanowska, Weronika Jurczyk, Jakub Skórkowska, Alicja Strach, Beata Szafarz, Małgorzata Przejczowska-Pomierny, Katarzyna Torregrossa, Roberta Whiteman, Matthew Marcinkowska, Monika Pera, Joanna Budziszewska, Bogusława |
author_facet | Pomierny, Bartosz Krzyżanowska, Weronika Jurczyk, Jakub Skórkowska, Alicja Strach, Beata Szafarz, Małgorzata Przejczowska-Pomierny, Katarzyna Torregrossa, Roberta Whiteman, Matthew Marcinkowska, Monika Pera, Joanna Budziszewska, Bogusława |
author_sort | Pomierny, Bartosz |
collection | PubMed |
description | 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 (H(2)S) 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 H(2)S 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(TM) assays, Western blot and immunofluorescent double-staining to determine the absolute H(2)S 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-p75(NTR)-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. |
format | Online Article Text |
id | pubmed-8346077 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-83460772021-08-07 The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H(2)S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia Pomierny, Bartosz Krzyżanowska, Weronika Jurczyk, Jakub Skórkowska, Alicja Strach, Beata Szafarz, Małgorzata Przejczowska-Pomierny, Katarzyna Torregrossa, Roberta Whiteman, Matthew Marcinkowska, Monika Pera, Joanna Budziszewska, Bogusława Int J Mol Sci Article 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 (H(2)S) 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 H(2)S 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(TM) assays, Western blot and immunofluorescent double-staining to determine the absolute H(2)S 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-p75(NTR)-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. MDPI 2021-07-22 /pmc/articles/PMC8346077/ /pubmed/34360581 http://dx.doi.org/10.3390/ijms22157816 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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/). |
spellingShingle | Article Pomierny, Bartosz Krzyżanowska, Weronika Jurczyk, Jakub Skórkowska, Alicja Strach, Beata Szafarz, Małgorzata Przejczowska-Pomierny, Katarzyna Torregrossa, Roberta Whiteman, Matthew Marcinkowska, Monika Pera, Joanna Budziszewska, Bogusława The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H(2)S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia |
title | The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H(2)S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia |
title_full | The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H(2)S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia |
title_fullStr | The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H(2)S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia |
title_full_unstemmed | The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H(2)S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia |
title_short | The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H(2)S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia |
title_sort | slow-releasing and mitochondria-targeted hydrogen sulfide (h(2)s) delivery molecule ap39 induces brain tolerance to ischemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346077/ https://www.ncbi.nlm.nih.gov/pubmed/34360581 http://dx.doi.org/10.3390/ijms22157816 |
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