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The Slow-Releasing and Mitochondria-Targeted Hydrogen Sulfide (H 2 S) Delivery Molecule AP39 Induces Brain Tolerance to Ischemia.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 Jul 22; Vol. 22 (15). Date of Electronic Publication: 2021 Jul 22. - Publication Year :
- 2021
-
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 (H <subscript>2</subscript> 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 <subscript>2</subscript> 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 <superscript>TM</superscript> assays, Western blot and immunofluorescent double-staining to determine the absolute H <subscript>2</subscript> 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 <superscript>NTR</superscript> -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.
- Subjects :
- Animals
Brain Ischemia etiology
Brain Ischemia metabolism
Brain Ischemia pathology
Hydrogen Sulfide analysis
Male
Mitochondria drug effects
Organophosphorus Compounds administration & dosage
Protective Agents administration & dosage
Rats
Rats, Sprague-Dawley
Thiones administration & dosage
Brain Ischemia prevention & control
Hydrogen Sulfide metabolism
Infarction, Middle Cerebral Artery complications
Mitochondria metabolism
Organophosphorus Compounds pharmacology
Protective Agents pharmacology
Thiones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 34360581
- Full Text :
- https://doi.org/10.3390/ijms22157816