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, 13, (4) pp. 379-390. ISSN 1747-4930 (2018) [Refereed Article]
Copyright 2017 World Stroke Organization
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 Type:||Refereed Article|
|Keywords:||Brain, stroke, ER stress, global ischaemia|
|Research Division:||Medical and Health Sciences|
|Research Field:||Central Nervous System|
|Objective Division:||Expanding Knowledge|
|Objective Group:||Expanding Knowledge|
|Objective Field:||Expanding Knowledge in the Medical and Health Sciences|
|UTAS Author:||Sutherland, BA (Dr Brad Sutherland)|
|Year Published:||2018 (online first 2017)|
|Web of Science® Times Cited:||4|
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