University of Tasmania
Browse

File(s) under permanent embargo

The role of the endoplasmic reticulum stress response following cerebral ischemia

journal contribution
posted on 2023-05-19, 10:48 authored by Hadley, G, Neuhaus, AA, Couch, Y, Beard, DJ, Adriaanse, BA, Vekrellis, K, DeLuca, GC, Papadakis, M, Brad SutherlandBrad Sutherland, Buchan, AM

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.

History

Publication title

International journal of stroke

Volume

13

Issue

4

Pagination

379-390

ISSN

1747-4930

Department/School

Tasmanian School of Medicine

Publisher

Blackwell Publishing Ltd

Place of publication

United States

Rights statement

Copyright 2017 World Stroke Organization

Repository Status

  • Restricted

Socio-economic Objectives

Expanding knowledge in the health sciences

Usage metrics

    University Of Tasmania

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC