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

doi:10.3892/ijmm.2018.3607

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

Authors:
- Yu Wen Lin
- Tsung Ying Chen
- Chia Yang Hung
- Shih Huang Tai
- Sheng Yang Huang
- Che Chao Chang
- Hsin Yi Hung
- E Jian Lee
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Affiliations: Neurophysiology Laboratory, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan, R.O.C., Department of Anesthesiology, Buddhist Tzu-Chi University and Buddhist Tzu Chi General Hospital, Hualien 97004, Taiwan, R.O.C., School of Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan, R.O.C.
Published online on: March 30, 2018 https://doi.org/10.3892/ijmm.2018.3607
Pages: 182-192
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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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