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

Anuncibay‐Soto, Berta; Pérez‐Rodríguez, Diego; Santos‐Galdiano, María; Font‐Belmonte, Enrique; Ugidos, Irene F; González‐Rodríguez, Paloma; Regueiro-Purriños, Marta; Fernández‐López, Arsenio

doi:10.1016/j.bcp.2018.02.029

Cited by 41 publications

(24 citation statements)

References 58 publications

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“…In this study we confirm the existence of neuronal demise after 7 days of reperfusion in the cerebral cortex by analyzing the area occupied by SNLs, where the large amount of small nuclei support a strong gliosis in this area (Santos‐Galdiano et al ). Our results support that an acute treatment of salubrinal (1 and 24 h after ischemia) maintains a neuroprotective effect up to 7 days after ischemia in accordance with a previous study reporting ischemic‐induced cell death in CA1 after 7 days and the neuroprotective effect of salubrinal in CA1 within this time frame (Anuncibay‐Soto et al ).…”

Section: Discussionsupporting

confidence: 93%

“…Our data provides additional evidence of necroptosis in CA1 based on the ischemic‐dependent increase in MLKL transcripts. Consistently, salubrinal, which has been reported to protect CA1 neurons against ischemia (Anuncibay‐Soto et al ,), is able to reduce MLKL transcription providing additional support for the existence of ischemia‐induced necroptosis in CA1. However, data regarding MLKL and RIPK3 phosphorylation does not provide conclusive results and thus some caution should be taken into account about necroptosis in CA1.…”

Section: Discussionsupporting

confidence: 52%

“…Previous studies allow us to estimate that we could detect changes at p ≤ 0.05 level with a statistical power of ≥ 80% with n ≥ 5 rats/ group (Llorerente et al ; Llorerente et al ; Anuncibay‐Soto et al ; Ugidos et al ; Anuncibay‐Soto et al ). Thus, prior to experimental procedure, the number of animals to be used in each group was established in five.…”

Section: Methodsmentioning

confidence: 92%

“…Salubrinal is a small chemical molecule which inhibits the dephosphorylation of the eukaryotic translation initiation factor 2 subunit α (eIF2α), thus inhibiting general protein translation and enhancing the UPR, therefore decreasing ER stress (Boyce et al ). The administration of salubrinal pre‐ischemically (Nakka et al ) and post‐ischemically (Anuncibay‐Soto et al ,) has been proved to have a neuroprotective role.…”

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confidence: 99%

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Post‐ischemic salubrinal administration reduces necroptosis in a rat model of global cerebral ischemia

Font‐Belmonte

Ugidos

Santos‐Galdiano

et al. 2019

Journal of Neurochemistry

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Ischemic stroke is one of the most important causes of death and disability worldwide. Subroutines underlying cell death after stroke are largely unknown despite their importance in the design of novel therapies for this pathology. Necroptosis, a recently described form of regulated cell death, has been related with inflammation and, in some models, with endoplasmic reticulum (ER) stress. We hypothesize that alleviation of ER stress following a salubrinal treatment will reduce the ischemic‐dependent necroptosis. To probe the hypothesis, we measured, at 48 and 72 h after transient global cerebral ischemia in rat, in cerebral cortex and cornu ammonis 1, the main hallmarks of necroptosis: mRNA levels and phosphorylation of mixed lineage kinase domain like pseudokinase as well as receptor interacting serine/threonine protein kinase 3, along the years 2017–2018. Selective neuronal loss after 7 days of the ischemic insult, and other markers related with the inflammatory response were also measured. This study shows that necroptosis in cerebral cortex can be detected after 72 h of the insult and seems to be elicited before 48 h of reperfusion. The type of necroptosis here observed seems to be tumor necrosis factor receptor 1 independent. Necroptotic response is less evident in the cornu ammonis 1 hippocampal area than in cerebral cortex. The treatment with salubrinal administered 1 and 24 h after the ischemia, decreased the necroptotic marker levels and reduced the areas of selective neuronal loss, supporting the presence of ischemic‐dependent necroptosis, and the notion that ER stress is involved in the necroptotic response. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 52%

Section: Methodsmentioning

confidence: 92%

mentioning

confidence: 99%

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Post‐ischemic salubrinal administration reduces necroptosis in a rat model of global cerebral ischemia

Font‐Belmonte

Ugidos

Santos‐Galdiano

et al. 2019

Journal of Neurochemistry

Self Cite

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“…Its expression may be enhanced by different cellular stresses, including ER stress, thereby attenuating EETs’ protective actions (Inceoglu et al, 2017; Inceoglu et al, 2015; Mak et al, 2017). Accumulating evidence has shown that salubrinal, an agent that limits ER stress by enhancing the unfolded protein response, has protective effects on the BBB in ischemic stroke by blocking the progression of the inflammatory response that is linked to microglial reactivity and production of MMP9 (Anuncibay-Soto et al, 2018). Besides attenuating neuronal death, the primary basis for the delayed microglial reactivity, salubrinal may also attenuate loss of EETs, although this possibility needs to be investigated.…”

Section: Recently Identified Molecular/cellular Targets and Approachesmentioning

confidence: 99%

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

Shekhar

Cunningham

Pabbidi

et al. 2018

European Journal of Pharmacology

100

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Ischemic stroke is a devastating and debilitating medical condition with limited therapeutic options. However, accumulating evidence indicates a central role of inflammation in all aspects of stroke including its initiation, the progression of injury, and recovery or wound healing. A central target of inflammation is disruption of the blood brain barrier or neurovascular unit. Here we discuss recent developments in identifying potential molecular targets and immunomodulatory approaches to preserve or protect barrier function and limit infarct damage and functional impairment. These include blocking harmful inflammatory signaling in endothelial cells, microglia/macrophages, or Th17/γδ T cells with biologics, third generation epoxyeicosatrienoic acid (EET) analogs with extended half-life, and miRNA antagomirs. Complementary beneficial pathways may be enhanced by miRNA mimetics or hyperbaric oxygenation. These immunomodulatory approaches could be used to greatly expand the therapeutic window for thrombolytic treatment with tissue plasminogen activator (t-PA). Moreover, nanoparticle technology allows for the selective targeting of endothelial cells for delivery of DNA/RNA oligonucleotides and neuroprotective drugs. In addition, although likely detrimental to the progression of ischemic stroke by inducing inflammation, oxidative stress, and neuronal cell death, 20-HETE may also reduce susceptibility of onset of ischemic stroke by maintaining autoregulation of cerebral blood flow. Although the interaction between inflammation and stroke is multifaceted, a better understanding of the mechanisms behind the pro-inflammatory state at all stages will hopefully help in developing novel immunomodulatory approaches to improve mortality and functional outcome of those inflicted with ischemic stroke.

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Mesenchymal stem cells (MSCs) and MSC‐derived exosomes in animal models of central nervous system diseases: Targeting the NLRP3 inflammasome

et al. 2023

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The NLRP3 (NOD‐, LRR‐, and pyrin domain‐containing protein 3) inflammasome is a multimeric protein complex that is engaged in the innate immune system and plays a vital role in inflammatory reactions. Activation of the NLRP3 inflammasome and subsequent release of proinflammatory cytokines can be triggered by microbial infection or cellular injury. The NLRP3 inflammasome has been implicated in the pathogenesis of many disorders affecting the central nervous system (CNS), ranging from stroke, traumatic brain injury, and spinal cord injury to Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, and depression. Furthermore, emerging evidence has suggested that mesenchymal stem cells (MSCs) and their exosomes may modulate NLRP3 inflammasome activation in a way that might be promising for the therapeutic management of CNS diseases. In the present review, particular focus is placed on highlighting and discussing recent scientific evidence regarding the regulatory effects of MSC‐based therapies on the NLRP3 inflammasome activation and their potential to counteract proinflammatory responses and pyroptotic cell death in the CNS, thereby achieving neuroprotective impacts and improvement in behavioral impairments.

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

Cited by 41 publications

References 58 publications

Post‐ischemic salubrinal administration reduces necroptosis in a rat model of global cerebral ischemia

Post‐ischemic salubrinal administration reduces necroptosis in a rat model of global cerebral ischemia

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

Mesenchymal stem cells (MSCs) and MSC‐derived exosomes in animal models of central nervous system diseases: Targeting the NLRP3 inflammasome

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