Journal
MOLECULAR NEUROBIOLOGY
Volume 58, Issue 4, Pages 1404-1417Publisher
SPRINGER
DOI: 10.1007/s12035-020-02202-y
Keywords
Celecoxib; ER stress; Unfolded protein response; Proteasome; Neuroprotection; Middle cerebral artery occlusion (MCAO)
Categories
Funding
- MINECO [RTC2015-4094-1]
- FEDER Funds [RTC2015-4094-1]
- Junta de Castilla y Leon [EDU/529/2017, EDU/310/2015, LE025P17]
- Neural Therapies S.L [NT-Dev-01]
- Universidad de Leon
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The study suggests that Celecoxib may exert neuroprotection by reducing ER stress, enhancing the IRE1-UPR pathway and UPS degradation, providing a potential new therapeutic target for stroke treatment.
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
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