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Parecoxib Suppresses CHOP and Foxo1 Nuclear Translocation, but Increases GRP78 Levels in a Rat Model of Focal Ischemia

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Abstract

Parecoxib, a novel COX-2 inhibitor, functions as a neuroprotective agent and rescues neurons from cerebral ischemic reperfusion injury-induced apoptosis. However, the molecular mechanisms underlying parecoxib neuroprotection remain to be elucidated. There is growing evidence that endoplasmic reticulum (ER) stress plays an important role in neuronal death caused by brain ischemia. However, very little is known about the role of parecoxib in mediating pathophysiological reactions to ER stress induced by ischemic reperfusion injury. Therefore, in the present study, we investigated whether delayed administration of parecoxib attenuates brain damage via suppressing ER stress-induced cell death. Adult male Sprague–Dawley rats were administered parecoxib (10 or 30 mg kg−1, IP) or isotonic saline twice a day starting 24 h after middle cerebral artery occlusion (MCAO) for three consecutive days. The expressions of glucose-regulated protein 78 (GRP78) and oxygen-regulated protein 150 (ORP150) and C/EBP-homologous protein (CHOP) and forkhead box protein O 1 (Foxo1) in cytoplasmic and nuclear fraction were determined by Western blotting. The levels of caspase-12 expression were checked by immunohistochemistry analysis, served as a marker for ER stress-induced apoptosis. Parecoxib significantly suppressed cerebral ischemic injury-induced nuclear translocation of CHOP and Foxo1 and attenuated the immunoreactivity of caspase-12 in ischemic penumbra. Furthermore, the protective effect of delayed administration of parecoxib was accompanied by an increased GRP78 and ORP150 expression. Therefore, our study suggested that elevation of GRP78 and ORP150, and suppression of CHOP and Foxo1 nuclear translocation may contribute to parecoxib-mediated neuroprotection during ER stress responses.

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Abbreviations

ER:

Endoplasmic reticulum

MCAO:

Middle cerebral artery occlusion

GRP78:

Glucose-regulated protein 78

ORP150:

Oxygen-regulated protein 150

CHOP:

C/EBP-homologous protein

Foxo1:

Forkhead box protein O 1

ATF6:

Activating transcription factor 6

IREI:

Inositol-requiring enzyme-I

PERK:

Double-strand RNA-dependent protein kinase (PKR) ER-resident kinase

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Authors and Affiliations

  1. Department of Anesthesiology, The Affiliated Xiangya Hospital of Central South University, Changsha, 410078, Hunan Province, China

    Zhi Ye, Na Wang, Pingping Xia, E. Wang, Juan Liao & Qulian Guo

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  1. Zhi Ye
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  2. Na Wang
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  4. E. Wang
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  6. Qulian Guo
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Correspondence to Qulian Guo.

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Ye, Z., Wang, N., Xia, P. et al. Parecoxib Suppresses CHOP and Foxo1 Nuclear Translocation, but Increases GRP78 Levels in a Rat Model of Focal Ischemia. Neurochem Res 38, 686–693 (2013). https://doi.org/10.1007/s11064-012-0953-4

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  • DOI: https://doi.org/10.1007/s11064-012-0953-4

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