期刊
INTERNATIONAL JOURNAL OF STROKE
卷 13, 期 4, 页码 379-390出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/1747493017724584
关键词
Autophagy; endogenous neuroprotection; endoplasmic reticulum stress; global ischemia; hamartin; mTOR; oxygen and glucose deprivation; TSC1
资金
- Oxford University Clinical Academic Graduate School
- Radcliffe Department of Medicine Scholarship
- Medical Research Council (UK)
- Engineering and Physical Sciences Research Council
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. MethodsInvivo: 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 3h and 12h of reperfusion. Invitro: primary neuronal cultures (E18 Wistar rat embryos) were exposed to 2h 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 ([4-(N-diethylamino) butyl]-2-chlorophenoxazine (10-NCP)) or autophagy inhibitor (3-methyladenine). ResultsInvivo, decreased endoplasmic reticulum stress protein expression (phospho-eIF2 and ATF4) was observed at 3h of reperfusion in CA3 neurons following ischemia, and increased in CA1 neurons at 12h of reperfusion. Invitro, 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 invitro, highlighting their complex role in neuronal biology following ischemia.
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