Celecoxib-Dependent Neuroprotection in a Rat Model of Transient Middle Cerebral Artery Occlusion (tMCAO) Involves Modifi
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Celecoxib-Dependent Neuroprotection in a Rat Model of Transient Middle Cerebral Artery Occlusion (tMCAO) Involves Modifications in Unfolded Protein Response (UPR) and Proteasome María Santos-Galdiano 1 & Paloma González-Rodríguez 1 & Enrique Font-Belmonte 1 Berta Anuncibay-Soto 1,3 & Diego Pérez-Rodríguez 1,4 & Arsenio Fernández-López 1
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Irene F. Ugidos 1,2
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Received: 7 July 2020 / Accepted: 3 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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.
Keywords Celecoxib . ER stress . Unfolded protein response . Proteasome . Neuroprotection . Middle cerebral artery occlusion (MCAO) Abbreviations Ab ATF4
Antibody Activating transcription factor 4
* Diego Pérez-Rodríguez [email protected] * Arsenio Fernández-López [email protected] 1
Área de Biología Celular, Instituto de Biomedicina, Campus de Vegazana s/n, Universidad de León, León, Spain
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Currently at AIV Institute, University of Eastern Finland, Kuopio, Finland
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Currently at Department of Life Sciences, Imperial College London (ICL), London, UK
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Currently at Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
ATF6 BAG BSA cH CHOP COX-2 DAPI eIF2α ER ERAD FrPaSS GAPDH GRP78 i.p I/R iH
Activating transcription factor
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