Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats
Background: Neuroinflammation is a hallmark in intracerebral hemorrhage (ICH) that induces secondary brain injury, leading to neuronal cell death. ER stress-triggered apoptosis and proteostasis disruption caused neuroinflammation to play an important role in various neurological disorders. The conse...
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MDPI AG
2019-10-01
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| Online Access: | https://www.mdpi.com/2073-4409/8/11/1326 |
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| author | Hock-Kean Liew Wei-Fen Hu Peter Bor-Chian Lin Po-Kai Wang Andy Po-Yi Tsai Cheng-Yoong Pang Tsung-Ying Chen |
| author_facet | Hock-Kean Liew Wei-Fen Hu Peter Bor-Chian Lin Po-Kai Wang Andy Po-Yi Tsai Cheng-Yoong Pang Tsung-Ying Chen |
| author_sort | Hock-Kean Liew |
| collection | DOAJ |
| description | Background: Neuroinflammation is a hallmark in intracerebral hemorrhage (ICH) that induces secondary brain injury, leading to neuronal cell death. ER stress-triggered apoptosis and proteostasis disruption caused neuroinflammation to play an important role in various neurological disorders. The consequences of ER stress and proteostasis disruption have rarely been studied during the course of ICH development. Methods: ICH was induced by collagenase VII-S intrastriatal infusion. Animals were sacrificed at 0, 3, 6, 24, and 72 h post-ICH. Rats were determined for body weight changes, hematoma volume, and neurological deficits. Brain tissues were harvested for molecular signaling analysis either for ELISA, immunoblotting, immunoprecipitation, RT-qPCR, protein aggregation, or for histological examination. A non-selective proteasome inhibitor, MG132, was administered into the right striatum three hours prior to ICH induction. Results: ICH-induced acute proteasome over-activation caused the early degradation of the endoplasmic reticulum (ER) chaperone GRP78 and IκB protein. These exacerbations were accompanied by the elevation of pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP) and pro-inflammatory cytokines expression via nuclear factor-kappa B (NF-κB) signal activation. Pre-treatment with proteasome inhibitor MG132 significantly ameliorated the ICH-induced ER stress/proteostasis disruption, pro-inflammatory cytokines, neuronal cells apoptosis, and neurological deficits. Conclusions: ICH induced rapid proteasome over-activation, leading to an exaggeration of the ER stress/proteostasis disruption, and neuroinflammation might be a critical event in acute ICH pathology. |
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| spelling | doaj.art-78a9d6f645f14f8aab94f411eaac25752023-09-02T19:28:46ZengMDPI AGCells2073-44092019-10-01811132610.3390/cells8111326cells8111326Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in RatsHock-Kean Liew0Wei-Fen Hu1Peter Bor-Chian Lin2Po-Kai Wang3Andy Po-Yi Tsai4Cheng-Yoong Pang5Tsung-Ying Chen6Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, TaiwanDepartment of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, TaiwanIndiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Anesthesiology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, TaiwanIndiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, TaiwanDepartment of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, TaiwanBackground: Neuroinflammation is a hallmark in intracerebral hemorrhage (ICH) that induces secondary brain injury, leading to neuronal cell death. ER stress-triggered apoptosis and proteostasis disruption caused neuroinflammation to play an important role in various neurological disorders. The consequences of ER stress and proteostasis disruption have rarely been studied during the course of ICH development. Methods: ICH was induced by collagenase VII-S intrastriatal infusion. Animals were sacrificed at 0, 3, 6, 24, and 72 h post-ICH. Rats were determined for body weight changes, hematoma volume, and neurological deficits. Brain tissues were harvested for molecular signaling analysis either for ELISA, immunoblotting, immunoprecipitation, RT-qPCR, protein aggregation, or for histological examination. A non-selective proteasome inhibitor, MG132, was administered into the right striatum three hours prior to ICH induction. Results: ICH-induced acute proteasome over-activation caused the early degradation of the endoplasmic reticulum (ER) chaperone GRP78 and IκB protein. These exacerbations were accompanied by the elevation of pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP) and pro-inflammatory cytokines expression via nuclear factor-kappa B (NF-κB) signal activation. Pre-treatment with proteasome inhibitor MG132 significantly ameliorated the ICH-induced ER stress/proteostasis disruption, pro-inflammatory cytokines, neuronal cells apoptosis, and neurological deficits. Conclusions: ICH induced rapid proteasome over-activation, leading to an exaggeration of the ER stress/proteostasis disruption, and neuroinflammation might be a critical event in acute ICH pathology.https://www.mdpi.com/2073-4409/8/11/1326er stressgrp78intracerebral hemorrhagenfκboxidative stressproteasome activityproteostasis disturbanceprotein aggregationubiquitination |
| spellingShingle | Hock-Kean Liew Wei-Fen Hu Peter Bor-Chian Lin Po-Kai Wang Andy Po-Yi Tsai Cheng-Yoong Pang Tsung-Ying Chen Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats Cells er stress grp78 intracerebral hemorrhage nfκb oxidative stress proteasome activity proteostasis disturbance protein aggregation ubiquitination |
| title | Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats |
| title_full | Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats |
| title_fullStr | Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats |
| title_full_unstemmed | Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats |
| title_short | Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats |
| title_sort | over activated proteasome mediates neuroinflammation on acute intracerebral hemorrhage in rats |
| topic | er stress grp78 intracerebral hemorrhage nfκb oxidative stress proteasome activity proteostasis disturbance protein aggregation ubiquitination |
| url | https://www.mdpi.com/2073-4409/8/11/1326 |
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