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The role of the endoplasmic reticulum stress response following cerebral ischemia

Citation

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, The role of the endoplasmic reticulum stress response following cerebral ischemia, International journal of stroke ISSN 1747-4930 (2017) [Refereed Article]

Copyright Statement

Copyright 2017 World Stroke Organization

DOI: doi:10.1177/1747493017724584

Abstract

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 productive autophagy. Neurons lacking hamartin demonstrate exacerbated endoplasmic reticulum stress and increased cell death. We investigated endoplasmic reticulum stress responses in CA1 and CA3 regions following global cerebral ischemia, and whether pharmacological modulation of endoplasmic reticulum stress or autophagy altered neuronal viability.

Methods: In vivo: male Wistar rats underwent sham or 10 min of transient global cerebral ischemia. CA1 and CA3 areas were 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 or normoxia in the presence of an endoplasmic reticulum stress inducer (thapsigargin or tunicamycin), an endoplasmic reticulum 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 at 3 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 cell death. Both induction and inhibition of autophagy also increased cell death.

Conclusion: Endoplasmic reticulum stress is associated with neuronal cell death following ischemia. Neither reduction of endoplasmic reticulum stress nor induction of autophagy demonstrated neuroprotection in vitro, highlighting their complex role in neuronal biology following ischemia.

Item Details

Item Type:Refereed Article
Keywords:Brain, stroke, ER stress, global ischaemia
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Central Nervous System
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Medical and Health Sciences
Author:Sutherland, BA (Dr Brad Sutherland)
ID Code:120822
Year Published:2017
Deposited By:Medicine (Discipline)
Deposited On:2017-08-30
Last Modified:2018-01-12
Downloads:0

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