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The role of the endoplasmic reticulum stress response following cerebral ischemia

Hadley, G, Neuhaus, AA, Couch, Y, Beard, DJ, Adriaanse, BA, Vekrellis, K, DeLuca, GC, Papadakis, M, Sutherland, BA ORCID: 0000-0002-0791-0950 and Buchan, AM 2017 , 'The role of the endoplasmic reticulum stress response following cerebral ischemia' , International journal of stroke, vol. 13, no. 4 , 379–390 , doi: 10.1177/1747493017724584.

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Background: Cornu ammonis 3 (CA3) hippocampal neurons are resistant to global ischemia, whereas cornu ammonis(CA1) 1 neurons are vulnerable. Hamartin expression in CA3 neurons mediates this endogenous resistance via productiveautophagy. Neurons lacking hamartin demonstrate exacerbated endoplasmic reticulum stress and increased celldeath. We investigated endoplasmic reticulum stress responses in CA1 and CA3 regions following global cerebralischemia, and whether pharmacological modulation of endoplasmic reticulum stress or autophagy altered neuronalviability.Methods: In vivo: male Wistar rats underwent sham or 10 min of transient global cerebral ischemia. CA1 and CA3 areaswere microdissected and endoplasmic reticulum stress protein expression quantified at 3 h and 12 h of reperfusion.In vitro: primary neuronal cultures (E18 Wistar rat embryos) were exposed to 2 h of oxygen and glucose deprivation ornormoxia in the presence of an endoplasmic reticulum stress inducer (thapsigargin or tunicamycin), an endoplasmicreticulum stress inhibitor (salubrinal or 4-phenylbutyric acid), an autophagy inducer ([40-(N-diethylamino) butyl]-2-chlorophenoxazine (10-NCP)) or autophagy inhibitor (3-methyladenine).Results: In vivo, decreased endoplasmic reticulum stress protein expression (phospho-eIF2a and ATF4) was observed at3 h of reperfusion in CA3 neurons following ischemia, and increased in CA1 neurons at 12 h of reperfusion. In vitro,endoplasmic reticulum stress inducers and high doses of the endoplasmic reticulum stress inhibitors also increased celldeath. Both induction and inhibition of autophagy also increased cell death.Conclusion: Endoplasmic reticulum stress is associated with neuronal cell death following ischemia. Neither reductionof endoplasmic reticulum stress nor induction of autophagy demonstrated neuroprotection in vitro, highlighting theircomplex role in neuronal biology following ischemia.

Item Type: Article
Authors/Creators:Hadley, G and Neuhaus, AA and Couch, Y and Beard, DJ and Adriaanse, BA and Vekrellis, K and DeLuca, GC and Papadakis, M and Sutherland, BA and Buchan, AM
Keywords: Brain, stroke, ER stress, global ischaemia
Journal or Publication Title: International journal of stroke
Publisher: Blackwell Publishing Ltd
ISSN: 1747-4930
DOI / ID Number: 10.1177/1747493017724584
Copyright Information:

Copyright 2017 World Stroke Organization

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