Unfolded protein response to global ischemia following 48 h of reperfusion in the rat brain: the effect of age and meloxicam

Llorente, Irene L.; Burgin, Taiana C.; Pérez‐Rodríguez, Diego; Martínez-Villayandre, Beatriz; Pérez-García, Carlos César; Fernández‐López, Arsenio

doi:10.1111/jnc.12337

Cited by 25 publications

(19 citation statements)

References 68 publications

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“…This difference is consistent with differences observed in the expression of different neurotransmitter system genes (Montori et al 2010a, b, c) or markers of reticulum stress (Llorente et al 2013). Our results show that changes induced by age modify this structuredependent vulnerability.…”

Section: Gfapsupporting

confidence: 93%

Age-dependent modifications in vascular adhesion molecules and apoptosis after 48-h reperfusion in a rat global cerebral ischemia model

Anuncibay‐Soto

Pérez‐Rodríguez

Llorente

et al. 2014

AGE

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Stroke is one of the leading causes of death and permanent disability in the elderly. However, most of the experimental studies on stroke are based on young animals, and we hypothesised that age can substantially affect the stroke response. The two-vessel occlusion model of global ischemia by occluding the common carotid arteries for 15 min at 40 mmHg of blood pressure was carried out in 3-and 18-month-old male Sprague-Dawley rats. The adhesion molecules E-and P-selectin, cell adhesion molecules (CAMs), both intercellular (ICAM-1) and vascular (VCAM-1), as well as glial fibrillary acidic protein (GFAP), and cleaved caspase-3 were measured at 48 h after ischemia in the cerebral cortex and hippocampus using Western blot, qPCR and immunofluorescence techniques. Diametric expression of GFAP and a different morphological pattern of caspase-3 labelling, although no changes in the cell number, were observed in the neurons of young and old animals. Expression of E-selectin and CAMs was also modified in an age-and ischemia/reperfusiondependent manner. The hippocampus and cerebral cortex had similar response patterns for most of the markers studied. Our data suggest that old and young animals present different time-courses of neuroinflammation and apoptosis after ischemic damage. On the other hand, these results suggest that neuroinflammation is dependent on age rather than on the different vulnerability described for the hippocampus and cerebral cortex. These differences should be taken into account in searching for therapeutic targets.

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Section: Gfapsupporting

confidence: 93%

Age-dependent modifications in vascular adhesion molecules and apoptosis after 48-h reperfusion in a rat global cerebral ischemia model

Anuncibay‐Soto

Pérez‐Rodríguez

Llorente

et al. 2014

AGE

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“…Following Ischemia-Reperfusion injury, the PDI expression was enhanced in the cortex even if the statistical significance threshold was not reached (OD ratio: 2.18 ± 0.03). This elevation of PDI expression is reported to be lowered by anti-inflammatory treatment [40]. The hypolipidemic drug treatment before ischemia-reperfusion injury had a lowering effect on the ischemia-reperfusion injury induced PDI surged expression.…”

Section: Resultsmentioning

confidence: 99%

Recovery of brain biomarkers following peroxisome proliferator-activated receptor agonist neuroprotective treatment before ischemic stroke

et al. 2014

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BackgroundLipid lowering agent such as agonists of peroxisome proliferator-activated receptors (PPAR) are suggested as neuroprotective agents and may protect from the sequelae of brain ischemic stroke. Although the demonstration is not clearly established in human, the underlying molecular mechanism may be of interest for future therapeutic purposes. To this end, we have used our well established rodent model of ischemia-reperfusion pre-treated or not with fenofibrate or atorvastatin and performed a differential proteomics analyses of the brain and analysed the protein markers which levels returned to “normal” following pre-treatments with PPARα agonists.ResultsIn order to identify potential therapeutic targets positively modulated by pre-treatment with the PPARα agonists, two-dimensional gel electrophoresis proteome profiles between control, ischemia-reperfusion and pre-treated or not, were compared. The polypeptide which expression was altered following ischemia – reperfusion but whose levels remain unchanged after pre-treatment were characterized by mass spectrometry and further investigated by Western-blotting and immunohistochemistry. A series of 28 polypeptides were characterized among which the protein disulfide isomerase reduction – a protein instrumental to the unfolded protein response system - was shown to be reduced following PPARα agonists treatment while it was strongly increased in ischemia-reperfusion.ConclusionsPre-treatment with PPARα agonist or atorvastatin show potential neuroprotective effects by inhibiting the PDI overexpression in conjunction with the preservation of other neuronal markers, several of which are associated with the regulation of protein homeostasis, signal transduction and maintenance of synaptic plasticity. This proteomic study therefore suggests that neuroprotective effect of PPARα agonists supposes the preservation of the expression of several proteins essential for the maintenance of protein homeostasis not necessarily directly linked to PPARα known-regulated targets.

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“…We considered the unfolded protein response (UPR) as a promising target because UPR is activated to restore endoplasmic reticulum (ER) function that is impaired in a variety of stress conditions including stroke, 2–9 and because the ability to activate UPR declines with age. 10–12 …”

Section: Introductionmentioning

confidence: 99%

XBP1 (X-Box–Binding Protein-1)–Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G

Jiang

Zhang

et al. 2017

Stroke

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Background and Purpose Impaired protein homeostasis induced by endoplasmic reticulum (ER) dysfunction is a key feature of a variety of age-related brain diseases including stroke. To restore ER function impaired by stress, the unfolded protein response (UPR) is activated. A key UPR pro-survival pathway is controlled by the ER stress sensor inositol-requiring enzyme-1 (IRE1), downstream X-box binding protein-1 (XBP1), and O-linked b-N-acetylglucosamine (O-GlcNAc) modification of proteins (O-GlcNAcylation). Stroke impairs ER function, which activates UPR. The rationale of this study was to explore the potentials of the IRE1/XBP1/O-GlcNAc axis as a target for neuroprotection in ischemic stroke. Methods Mice with Xbp1 loss- and gain-of-function in neurons were generated. Stroke was induced by transient or permanent occlusion of the middle cerebral artery (MCAO) in young and aged mice. Thiamet-G was used to increase O-GlcNAcylation. Results Deletion of Xbp1 worsened outcome after transient and permanent MCAO. After stroke, O-GlcNAcylation was activated in neurons of the stroke penumbra in young mice, which was largely Xbp1-dependent. This activation of O-GlcNAcylation was impaired in aged mice. Pharmacologic increase of O-GlcNAcylation before or after stroke improved outcome in both young and aged mice. Conclusions Our study indicates a critical role for the IRE1/XBP1 UPR branch in stroke outcome. O-GlcNAcylation is a pro-survival pathway that is activated in the stroke penumbra in young mice but impaired in aged mice. Boosting pro-survival pathways to counterbalance the age-related decline in the brain’s self-healing capacity could be a promising strategy to improve ischemic stroke outcome in aged brains.

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Unfolded protein response to global ischemia following 48 h of reperfusion in the rat brain: the effect of age and meloxicam

Cited by 25 publications

References 68 publications

Age-dependent modifications in vascular adhesion molecules and apoptosis after 48-h reperfusion in a rat global cerebral ischemia model

Age-dependent modifications in vascular adhesion molecules and apoptosis after 48-h reperfusion in a rat global cerebral ischemia model

Recovery of brain biomarkers following peroxisome proliferator-activated receptor agonist neuroprotective treatment before ischemic stroke

XBP1 (X-Box–Binding Protein-1)–Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G

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