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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

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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.

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Abbreviations

Ab:

Antibody

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

BAG:

B-cell lymphoma-2-associated athanogene

BSA:

Bovine serum albumin

cH:

Contralateral hemisphere

CHOP:

C/EBP (CCAAT/enhancer-binding protein) homologous protein

COX-2:

Cyclooxygenase-2

DAPI:

4,6-Diamidino-2-phenylindole

eIF2α:

Eukaryotic initiation factor 2 subunit α

ER:

Endoplasmic reticulum

ERAD:

ER-associated degradation

FrPaSS:

Frontoparietal cortex, somatosensory area

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GRP78:

Glucose-related protein 78

i.p:

Intraperitoneally

I/R:

Ischemia/reperfusion

iH:

Injured hemisphere

IRE1:

Inositol-requiring enzyme 1

LC3B:

Microtubule-associated protein 1 light chain 3

MCA:

Middle cerebral artery

ODs:

Optical densities

p62/SQSTM1:

Ubiquitin-binding protein p62/Sequestosome-1

PBS:

50-mm phosphate buffered saline pH 7.4

PERK:

Double-stranded RNA-activated protein kinase-like ER kinase

PFA:

Paraformaldehyde

polyUb:

Polyubiquitinated

Psmβ:

Proteasome β catalytic subunits

RRID:

Research resource identifiers

RT-qPCR:

Real-time quantitative PCR

SDS:

Sodium dodecyl sulfate

TBS-T:

Tris-buffered saline + 0.2% Tween-20

TFI:

Total fluorescence intensity

tMCAO:

Transient middle cerebral artery occlusion

UPR:

Unfolded protein response

UPS:

Ubiquitin proteasome system

XBP1s:

Spliced X-box binding protein 1

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Funding

This study was supported by MINECO and FEDER Funds (RTC2015-4094-1); by Junta de Castilla y León (LE025P17); and by Neural Therapies S.L (NT-Dev-01). Paloma Gonzalez-Rodriguez and Irene F Ugidos were granted from Junta de Castilla y Leon (EDU/529/2017 and EDU/310/2015 respectively). Enrique Font-Belmonte was supported by a grant from the Universidad de Leon. Neural Therapies SL also granted Marıa Santos-Galdiano and Berta Anuncibay-Soto.

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Authors and Affiliations

  1. Área de Biología Celular, Instituto de Biomedicina, Campus de Vegazana s/n, Universidad de León, León, Spain

    María Santos-Galdiano, Paloma González-Rodríguez, Enrique Font-Belmonte, Irene F. Ugidos, Berta Anuncibay-Soto, Diego Pérez-Rodríguez & Arsenio Fernández-López

  2. Currently at AIV Institute, University of Eastern Finland, Kuopio, Finland

    Irene F. Ugidos

  3. Currently at Department of Life Sciences, Imperial College London (ICL), London, UK

    Berta Anuncibay-Soto

  4. Currently at Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK

    Diego Pérez-Rodríguez

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  1. María Santos-Galdiano
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Correspondence to Diego Pérez-Rodríguez or Arsenio Fernández-López.

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Santos-Galdiano, M., González-Rodríguez, P., Font-Belmonte, E. et al. Celecoxib-Dependent Neuroprotection in a Rat Model of Transient Middle Cerebral Artery Occlusion (tMCAO) Involves Modifications in Unfolded Protein Response (UPR) and Proteasome. Mol Neurobiol 58, 1404–1417 (2021). https://doi.org/10.1007/s12035-020-02202-y

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