The role of the endoplasmic reticulum stress response following cerebral ischemia
2018
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.
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