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A translocator protein 18 kDa agonist protects against cerebral ischemia/reperfusion injury

BACKGROUND: Cerebral ischemia is a leading cause of death and disability with limited treatment options. Although inflammatory and immune responses participate in ischemic brain injury, the molecular regulators of neuroinflammation after ischemia remain to be defined. Translocator protein 18 kDa (TS...

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Autores principales: Li, Han-Dong, Li, Minshu, Shi, Elaine, Jin, Wei-Na, Wood, Kristofer, Gonzales, Rayna, Liu, Qiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534039/
https://www.ncbi.nlm.nih.gov/pubmed/28754131
http://dx.doi.org/10.1186/s12974-017-0921-7
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author Li, Han-Dong
Li, Minshu
Shi, Elaine
Jin, Wei-Na
Wood, Kristofer
Gonzales, Rayna
Liu, Qiang
author_facet Li, Han-Dong
Li, Minshu
Shi, Elaine
Jin, Wei-Na
Wood, Kristofer
Gonzales, Rayna
Liu, Qiang
author_sort Li, Han-Dong
collection PubMed
description BACKGROUND: Cerebral ischemia is a leading cause of death and disability with limited treatment options. Although inflammatory and immune responses participate in ischemic brain injury, the molecular regulators of neuroinflammation after ischemia remain to be defined. Translocator protein 18 kDa (TSPO) mainly localized to the mitochondrial outer membrane is predominantly expressed in glia within the central nervous system during inflammatory conditions. This study investigated the effect of a TSPO agonist, etifoxine, on neuroinflammation and brain injury after ischemia/reperfusion. METHODS: We used a mouse model of middle cerebral artery occlusion (MCAO) to examine the therapeutic potential and mechanisms of neuroprotection by etifoxine. RESULTS: TSPO was upregulated in Iba1(+) or CD11b(+)CD45(int) cells from mice subjected to MCAO and reperfusion. Etifoxine significantly attenuated neurodeficits and infarct volume after MCAO and reperfusion. The attenuation was pronounced in mice subjected to 30, 60, or 90 min MCAO. Etifoxine reduced production of pro-inflammatory factors in the ischemic brain. In addition, etifoxine treatment led to decreased expression of interleukin-1β, interleukin-6, tumor necrosis factor-α, and inducible nitric oxide synthase by microglia. Notably, the benefit of etifoxine against brain infarction was ablated in mice depleted of microglia using a colony-stimulating factor 1 receptor inhibitor. CONCLUSIONS: These findings indicate that the TSPO agonist, etifoxine, reduces neuroinflammation and brain injury after ischemia/reperfusion. The therapeutic potential of targeting TSPO requires further investigations in ischemic stroke.
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spelling pubmed-55340392017-08-03 A translocator protein 18 kDa agonist protects against cerebral ischemia/reperfusion injury Li, Han-Dong Li, Minshu Shi, Elaine Jin, Wei-Na Wood, Kristofer Gonzales, Rayna Liu, Qiang J Neuroinflammation Research BACKGROUND: Cerebral ischemia is a leading cause of death and disability with limited treatment options. Although inflammatory and immune responses participate in ischemic brain injury, the molecular regulators of neuroinflammation after ischemia remain to be defined. Translocator protein 18 kDa (TSPO) mainly localized to the mitochondrial outer membrane is predominantly expressed in glia within the central nervous system during inflammatory conditions. This study investigated the effect of a TSPO agonist, etifoxine, on neuroinflammation and brain injury after ischemia/reperfusion. METHODS: We used a mouse model of middle cerebral artery occlusion (MCAO) to examine the therapeutic potential and mechanisms of neuroprotection by etifoxine. RESULTS: TSPO was upregulated in Iba1(+) or CD11b(+)CD45(int) cells from mice subjected to MCAO and reperfusion. Etifoxine significantly attenuated neurodeficits and infarct volume after MCAO and reperfusion. The attenuation was pronounced in mice subjected to 30, 60, or 90 min MCAO. Etifoxine reduced production of pro-inflammatory factors in the ischemic brain. In addition, etifoxine treatment led to decreased expression of interleukin-1β, interleukin-6, tumor necrosis factor-α, and inducible nitric oxide synthase by microglia. Notably, the benefit of etifoxine against brain infarction was ablated in mice depleted of microglia using a colony-stimulating factor 1 receptor inhibitor. CONCLUSIONS: These findings indicate that the TSPO agonist, etifoxine, reduces neuroinflammation and brain injury after ischemia/reperfusion. The therapeutic potential of targeting TSPO requires further investigations in ischemic stroke. BioMed Central 2017-07-28 /pmc/articles/PMC5534039/ /pubmed/28754131 http://dx.doi.org/10.1186/s12974-017-0921-7 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Li, Han-Dong
Li, Minshu
Shi, Elaine
Jin, Wei-Na
Wood, Kristofer
Gonzales, Rayna
Liu, Qiang
A translocator protein 18 kDa agonist protects against cerebral ischemia/reperfusion injury
title A translocator protein 18 kDa agonist protects against cerebral ischemia/reperfusion injury
title_full A translocator protein 18 kDa agonist protects against cerebral ischemia/reperfusion injury
title_fullStr A translocator protein 18 kDa agonist protects against cerebral ischemia/reperfusion injury
title_full_unstemmed A translocator protein 18 kDa agonist protects against cerebral ischemia/reperfusion injury
title_short A translocator protein 18 kDa agonist protects against cerebral ischemia/reperfusion injury
title_sort translocator protein 18 kda agonist protects against cerebral ischemia/reperfusion injury
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534039/
https://www.ncbi.nlm.nih.gov/pubmed/28754131
http://dx.doi.org/10.1186/s12974-017-0921-7
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