Salubrinal and robenacoxib treatment after global cerebral ischemia. Exploring the interactions between ER stress and inflammation

[Display omitted] Blood reperfusion of the ischemic tissue after stroke promotes increases in the inflammatory response as well as accumulation of unfolded/misfolded proteins in the cell, leading to endoplasmic reticulum (ER) stress. Both Inflammation and ER stress are critical processes in the dela...

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Bibliographic Details
Published in:Biochemical pharmacology 2018-05, Vol.151, p.26-37
Main Authors: Anuncibay-Soto, Berta, Pérez-Rodriguez, Diego, Santos-Galdiano, María, Font-Belmonte, Enrique, Ugidos, Irene F., Gonzalez-Rodriguez, Paloma, Regueiro-Purriños, Marta, Fernández-López, Arsenio
Format: Article
Language:English
Subjects:
Animals
Blood-Brain Barrier - metabolism
Blood–brain barrier
Brain Ischemia - diagnostic imaging
Brain Ischemia - drug therapy
Brain Ischemia - immunology
Cinnamates - administration & dosage
Cinnamates - therapeutic use
COX-2 inhibitor
Cyclooxygenase 2 Inhibitors - administration & dosage
Cyclooxygenase 2 Inhibitors - therapeutic use
Diphenylamine - administration & dosage
Diphenylamine - analogs & derivatives
Diphenylamine - therapeutic use
Drug Administration Schedule
Drug Therapy, Combination
Endoplasmic Reticulum Stress - drug effects
ER stress
Inflammation
Male
Microglia
Neuroprotective Agents - administration & dosage
Neuroprotective Agents - therapeutic use
Phenylacetates - administration & dosage
Phenylacetates - therapeutic use
Rats, Sprague-Dawley
Salubrinal
Thiourea - administration & dosage
Thiourea - analogs & derivatives
Thiourea - therapeutic use
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Summary:[Display omitted] Blood reperfusion of the ischemic tissue after stroke promotes increases in the inflammatory response as well as accumulation of unfolded/misfolded proteins in the cell, leading to endoplasmic reticulum (ER) stress. Both Inflammation and ER stress are critical processes in the delayed death of the cells damaged after ischemia. The aim of this study is to check the putative synergic neuroprotective effect by combining anti-inflammatory and anti-ER stress agents after ischemia. The study was performed on a two-vessel occlusion global cerebral ischemia model. Animals were treated with salubrinal one hour after ischemia and with robenacoxib at 8 h and 32 h after ischemia. Parameters related to the integrity of the blood–brain barrier (BBB), such as matrix metalloproteinase 9 and different cell adhesion molecules (CAMs), were analyzed by qPCR at 24 h and 48 h after ischemia. Microglia and cell components of the neurovascular unit, including neurons, endothelial cells and astrocytes, were analyzed by immunofluorescence after 48 h and seven days of reperfusion. Pharmacologic control of ER stress by salubrinal treatment after ischemia, revealed a neuroprotective effect over neurons that reduces the transcription of molecules involved in the impairment of the BBB. Robenacoxib treatment stepped neuronal demise forward, revealing a detrimental effect of this anti-inflammatory agent. Combined treatment with robenacoxib and salubrinal after ischemia prevented neuronal loss and changes in components of the neurovascular unit and microglia observed when animals were treated only with robenacoxib. Combined treatment with anti-ER stress and anti-inflammatory agents is able to provide enhanced neuroprotective effects reducing glial activation, which opens new avenues in therapies against stroke.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2018.02.029