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Open AccessArticle

Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats

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Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
2
Neuro-Medical Scientific Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
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Cardiovascular and Metabolomics Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
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PhD Program in Pharmacology and Toxicology, Tzu Chi University, Hualien 970, Taiwan
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Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Department of Anesthesiology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
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School of Medicine, Tzu Chi University, Hualien 970, Taiwan
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Department of Medical Education, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan
*
Authors to whom correspondence should be addressed.
Cells 2019, 8(11), 1326; https://doi.org/10.3390/cells8111326
Received: 17 September 2019 / Revised: 16 October 2019 / Accepted: 25 October 2019 / Published: 27 October 2019
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. View Full-Text
Keywords: ER stress; GRP78; intracerebral hemorrhage; NFκB; oxidative stress; proteasome activity; proteostasis disturbance; protein aggregation; ubiquitination ER stress; GRP78; intracerebral hemorrhage; NFκB; oxidative stress; proteasome activity; proteostasis disturbance; protein aggregation; ubiquitination
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Liew, H.-K.; Hu, W.-F.; Lin, P. .-C.; Wang, P.-K.; Tsai, A. .-Y.; Pang, C.-Y.; Chen, T.-Y. Over-Activated Proteasome Mediates Neuroinflammation on Acute Intracerebral Hemorrhage in Rats. Cells 2019, 8, 1326.

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