Melatonin Protects Against Neuronal Apoptosis via Suppression of the ATF6/CHOP Pathway in a Rat Model of Intracerebral Hemorrhage
Neuronal apoptosis is an important factor accounting for the poor outcomes of intracerebral hemorrhage (ICH). This study first showed that inhibition of activating transcription factor 6 (ATF6) could alleviate secondary brain injury through anti-apoptosis after ICH in rats. Melatonin, ATF6 and CCAAT...
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Frontiers Media S.A.
2018-09-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2018.00638/full |
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| author | Weilin Xu Xiaoyang Lu Jingwei Zheng Tao Li Liansheng Gao Cameron Lenahan Anwen Shao Jianmin Zhang Jianmin Zhang Jianmin Zhang Jun Yu |
| author_facet | Weilin Xu Xiaoyang Lu Jingwei Zheng Tao Li Liansheng Gao Cameron Lenahan Anwen Shao Jianmin Zhang Jianmin Zhang Jianmin Zhang Jun Yu |
| author_sort | Weilin Xu |
| collection | DOAJ |
| description | Neuronal apoptosis is an important factor accounting for the poor outcomes of intracerebral hemorrhage (ICH). This study first showed that inhibition of activating transcription factor 6 (ATF6) could alleviate secondary brain injury through anti-apoptosis after ICH in rats. Melatonin, ATF6 and CCAAT/enhancer-binding protein homologous protein (CHOP) siRNAs were applied in this study. Brain edema, neurological functions, blood-brain barrier (BBB) integrity were evaluated at 24 h after ICH. Western blot analysis was used to evaluate the protein level of target proteins (ATF6, CHOP, Bip, Bcl-2, Bax, and cleaved caspase-3). Reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the mRNA level of ATF6, CHOP and cleaved caspase-3. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 immunofluorescence staining were applied to evaluate the neuronal cell death. The results suggested that the levels of ATF6 and its downstream protein, CHOP, were upregulated and reached the peak at 24 h after ICH. ATF6 was highly expressed in neurons. The administration of melatonin significantly decreased the mRNA and protein levels of ATF6, and its downstream targets, CHOP and cleaved caspase-3, but increased the Bcl-2/Bax ratio, which ameliorated the neurological functions. The CHOP siRNA significantly reversed the pro-apoptotic effect induced by the increased ATF6 level after ICH. Melatonin could protect against neuronal apoptosis via suppression of ATF6/CHOP arm of ER-stress-response pathway. |
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| language | English |
| last_indexed | 2024-12-22T13:46:03Z |
| publishDate | 2018-09-01 |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-46c7d79809df46c9aeacaa9c233d9df02022-12-21T18:23:48ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2018-09-011210.3389/fnins.2018.00638396573Melatonin Protects Against Neuronal Apoptosis via Suppression of the ATF6/CHOP Pathway in a Rat Model of Intracerebral HemorrhageWeilin Xu0Xiaoyang Lu1Jingwei Zheng2Tao Li3Liansheng Gao4Cameron Lenahan5Anwen Shao6Jianmin Zhang7Jianmin Zhang8Jianmin Zhang9Jun Yu10Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaDepartment of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaDepartment of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaDepartment of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaDepartment of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaBurrell College of Osteopathic Medicine, New Mexico State University, Las Cruces, NM, United StatesDepartment of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaDepartment of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaBrain Research Institute, Zhejiang University, Hangzhou, ChinaCollaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, ChinaDepartment of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaNeuronal apoptosis is an important factor accounting for the poor outcomes of intracerebral hemorrhage (ICH). This study first showed that inhibition of activating transcription factor 6 (ATF6) could alleviate secondary brain injury through anti-apoptosis after ICH in rats. Melatonin, ATF6 and CCAAT/enhancer-binding protein homologous protein (CHOP) siRNAs were applied in this study. Brain edema, neurological functions, blood-brain barrier (BBB) integrity were evaluated at 24 h after ICH. Western blot analysis was used to evaluate the protein level of target proteins (ATF6, CHOP, Bip, Bcl-2, Bax, and cleaved caspase-3). Reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the mRNA level of ATF6, CHOP and cleaved caspase-3. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 immunofluorescence staining were applied to evaluate the neuronal cell death. The results suggested that the levels of ATF6 and its downstream protein, CHOP, were upregulated and reached the peak at 24 h after ICH. ATF6 was highly expressed in neurons. The administration of melatonin significantly decreased the mRNA and protein levels of ATF6, and its downstream targets, CHOP and cleaved caspase-3, but increased the Bcl-2/Bax ratio, which ameliorated the neurological functions. The CHOP siRNA significantly reversed the pro-apoptotic effect induced by the increased ATF6 level after ICH. Melatonin could protect against neuronal apoptosis via suppression of ATF6/CHOP arm of ER-stress-response pathway.https://www.frontiersin.org/article/10.3389/fnins.2018.00638/fullintracerebral hemorrhagemesencephalic astrocyte-derived neurotrophic factor (ATF6)CCAAT/enhancer-binding protein homologous protein (CHOP)apoptosissecondary brain injury |
| spellingShingle | Weilin Xu Xiaoyang Lu Jingwei Zheng Tao Li Liansheng Gao Cameron Lenahan Anwen Shao Jianmin Zhang Jianmin Zhang Jianmin Zhang Jun Yu Melatonin Protects Against Neuronal Apoptosis via Suppression of the ATF6/CHOP Pathway in a Rat Model of Intracerebral Hemorrhage Frontiers in Neuroscience intracerebral hemorrhage mesencephalic astrocyte-derived neurotrophic factor (ATF6) CCAAT/enhancer-binding protein homologous protein (CHOP) apoptosis secondary brain injury |
| title | Melatonin Protects Against Neuronal Apoptosis via Suppression of the ATF6/CHOP Pathway in a Rat Model of Intracerebral Hemorrhage |
| title_full | Melatonin Protects Against Neuronal Apoptosis via Suppression of the ATF6/CHOP Pathway in a Rat Model of Intracerebral Hemorrhage |
| title_fullStr | Melatonin Protects Against Neuronal Apoptosis via Suppression of the ATF6/CHOP Pathway in a Rat Model of Intracerebral Hemorrhage |
| title_full_unstemmed | Melatonin Protects Against Neuronal Apoptosis via Suppression of the ATF6/CHOP Pathway in a Rat Model of Intracerebral Hemorrhage |
| title_short | Melatonin Protects Against Neuronal Apoptosis via Suppression of the ATF6/CHOP Pathway in a Rat Model of Intracerebral Hemorrhage |
| title_sort | melatonin protects against neuronal apoptosis via suppression of the atf6 chop pathway in a rat model of intracerebral hemorrhage |
| topic | intracerebral hemorrhage mesencephalic astrocyte-derived neurotrophic factor (ATF6) CCAAT/enhancer-binding protein homologous protein (CHOP) apoptosis secondary brain injury |
| url | https://www.frontiersin.org/article/10.3389/fnins.2018.00638/full |
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