Melatonin protects brain against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress

Yu Wen Lin, Tsung Ying Chen, Chia Yang Hung, Shih-Huang Tai, Sheng Yang Huang, Che-Chao Chang, Hsin-Yi Hung, E-Jian Lee

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Endoplasmic reticulum (ER) stress plays a vital role in mediating ischemic reperfusion damage in brain. In this study, we evaluated whether melatonin inhibits ER stress in cultured neurons exposed to oxygen and glucose deprivation (OGD) and in rats subjected to transient focal cerebral ischemia. Sprague- Dawley rats were treated with melatonin (5 mg/kg) or control at reperfusion onset after transient occlusion of the right middle cerebral artery (MCA) for 90 min. Brain infarction and hemorrhage within infarcts were measured. The expression of ER stress proteins of phosphorylation of PRKR-like endoplasmic reticulum kinase (p-PERK), phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α), activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) were detected by western blotting and immunohistochemistry analysis. The terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) method, cleaved caspase-3 and cytochrome c were used to investigate cell apoptosis in OGD-induced cultured neurons. Our results demonstrated that animals treated with melatonin had significantly reduced infarction volumes and individual cortical lesion sizes as well as increased numbers of surviving neurons. Melatonin can significantly modulate protein levels by decreasing both p-PERK and p-eIF2α in the ischemic core and penumbra. Moreover, the expressions of ATF4 and CHOP were restrained in the ischemic core and penumbra, respectively. Furthermore, pretreatment with melatonin at 10-100 μM effectively reduced the levels of p-PERK and p-eIF2α in cultured neurons after OGD injury. Melatonin treatment also effectively decreased neuron apoptosis resulting from OGD-induced neuron injury. These results indicate that melatonin effectively attenuated post-ischemic ER stress after ischemic stroke.

Original languageEnglish
Pages (from-to)182-192
Number of pages11
JournalInternational journal of molecular medicine
Volume42
Issue number1
DOIs
Publication statusPublished - 2018 Jul 1

Fingerprint

Endoplasmic Reticulum Stress
Melatonin
Reperfusion Injury
Brain Ischemia
Eukaryotic Initiation Factor-2
Phosphorylation
Eukaryotic Initiation Factors
Neurons
Activating Transcription Factor 4
Transcription Factor CHOP
Endoplasmic Reticulum
Oxygen
Glucose
Phosphotransferases
Apoptosis
Brain Infarction
DNA Nucleotidylexotransferase
Intracranial Hemorrhages
Middle Cerebral Artery Infarction
Transient Ischemic Attack

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

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title = "Melatonin protects brain against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress",
abstract = "Endoplasmic reticulum (ER) stress plays a vital role in mediating ischemic reperfusion damage in brain. In this study, we evaluated whether melatonin inhibits ER stress in cultured neurons exposed to oxygen and glucose deprivation (OGD) and in rats subjected to transient focal cerebral ischemia. Sprague- Dawley rats were treated with melatonin (5 mg/kg) or control at reperfusion onset after transient occlusion of the right middle cerebral artery (MCA) for 90 min. Brain infarction and hemorrhage within infarcts were measured. The expression of ER stress proteins of phosphorylation of PRKR-like endoplasmic reticulum kinase (p-PERK), phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α), activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) were detected by western blotting and immunohistochemistry analysis. The terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) method, cleaved caspase-3 and cytochrome c were used to investigate cell apoptosis in OGD-induced cultured neurons. Our results demonstrated that animals treated with melatonin had significantly reduced infarction volumes and individual cortical lesion sizes as well as increased numbers of surviving neurons. Melatonin can significantly modulate protein levels by decreasing both p-PERK and p-eIF2α in the ischemic core and penumbra. Moreover, the expressions of ATF4 and CHOP were restrained in the ischemic core and penumbra, respectively. Furthermore, pretreatment with melatonin at 10-100 μM effectively reduced the levels of p-PERK and p-eIF2α in cultured neurons after OGD injury. Melatonin treatment also effectively decreased neuron apoptosis resulting from OGD-induced neuron injury. These results indicate that melatonin effectively attenuated post-ischemic ER stress after ischemic stroke.",
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Melatonin protects brain against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress. / Lin, Yu Wen; Chen, Tsung Ying; Hung, Chia Yang; Tai, Shih-Huang; Huang, Sheng Yang; Chang, Che-Chao; Hung, Hsin-Yi; Lee, E-Jian.

In: International journal of molecular medicine, Vol. 42, No. 1, 01.07.2018, p. 182-192.

Research output: Contribution to journalArticle

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