Celecoxib-Dependent Neuroprotection in a Rat Model of Transient Middle Cerebral Artery Occlusion (tMCAO) Involves Modifications in Unfolded Protein Response (UPR) and Proteasome
| Autor: | María, Santos-Galdiano, Paloma, González-Rodríguez, Enrique, Font-Belmonte, Irene F, Ugidos, Berta, Anuncibay-Soto, Diego, Pérez-Rodríguez, Arsenio, Fernández-López |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Proteasome Endopeptidase Complex Apoptosis Infarction Middle Cerebral Artery Protein Serine-Threonine Kinases Endoplasmic Reticulum Stress Neuroprotection Brain Ischemia Rats Sprague-Dawley Disease Models Animal Protein Subunits eIF-2 Kinase Celecoxib Multienzyme Complexes Endoribonucleases Proteolysis Autophagy Unfolded Protein Response Animals Polyubiquitin Endoplasmic Reticulum Chaperone BiP Biomarkers Heat-Shock Proteins |
| Zdroj: | Molecular neurobiology. 58(4) |
| ISSN: | 1559-1182 |
| Popis: | Stroke is one of the main causes of death and disability worldwide. Ischemic stroke results in unfolded/misfolded protein accumulation in endoplasmic reticulum (ER), a condition known as ER stress. We hypothesized that previously reported neuroprotection of celecoxib, a selective inhibitor of cyclooxygenase-2, in transient middle cerebral artery occlusion (tMCAO) model, relies on the ER stress decrease. To probe this hypothesis, Sprague-Dawley rats were subjected to 1 h of tMCAO and treated with celecoxib or vehicle 1 and 24 h after ischemia. Protein and mRNA levels of the main hallmarks of ER stress, unfolded protein response (UPR) activation, UPR-induced cell death, and ubiquitin proteasome system (UPS) and autophagy, the main protein degradation pathways, were measured at 12 and 48 h of reperfusion. Celecoxib treatment decreased polyubiquitinated protein load and ER stress marker expression such as glucose-related protein 78 (GRP78), C/EBP (CCAAT/enhancer-binding protein) homologous protein (CHOP), and caspase 12 after 48 h of reperfusion. Regarding the UPR activation, celecoxib promoted inositol-requiring enzyme 1 (IRE1) pathway instead of double-stranded RNA-activated protein kinase-like ER kinase (PERK) pathway. Furthermore, celecoxib treatment increased proteasome catalytic subunits transcript levels and decreased p62 protein levels, while the microtubule-associated protein 1 light chain 3 (LC3B) II/I ratio remained unchanged. Thus, the ability of celecoxib treatment on reducing the ER stress correlates with the enhancement of IRE1-UPR pathway and UPS degradation. These data support the ability of anti-inflammatory therapy in modulating ER stress and reveal the IRE1 pathway as a promising therapeutic target in stroke therapy.Graphical abstract. |
| Databáze: | OpenAIRE |
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