Apolipoprotein E Exerts a Whole-Brain Protective Property by Promoting M1? Microglia Quiescence After Experimental Subar
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ORIGINAL ARTICLE
Apolipoprotein E Exerts a Whole-Brain Protective Property by Promoting M1? Microglia Quiescence After Experimental Subarachnoid Hemorrhage in Mice Jinwei Pang 1 & Jianhua Peng 1 & Nathanael Matei 2 & Ping Yang 1 & Li Kuai 1 & Yue Wu 3 & Ligang Chen 1 & Michael P. Vitek 4,5 & Fengqiao Li 5 & Xiaochuan Sun 3 & John H. Zhang 2 & Yong Jiang 1,6,7 Received: 10 July 2018 / Revised: 30 August 2018 / Accepted: 6 September 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract Subarachnoid hemorrhage (SAH) is a neurologically destructive stroke in which early brain injury (EBI) plays a pivotal role in poor patient outcomes. Expanding upon our previous work, multiple techniques and methods were used in this preclinical study to further elucidate the mechanisms underlying the beneficial effects of apolipoprotein E (ApoE) against EBI after SAH in murine apolipoprotein E gene-knockout mice (Apoe−/−, KO) and wild-type mice (WT) on a C57BL/6J background. We reported that Apoe deficiency resulted in a more extensive EBI at 48 h after SAH in mice demonstrated by MRI scanning and immunohistochemical staining and exhibited more extensive white matter injury and neuronal apoptosis than WT mice. These changes were associated with an increase in NADPH oxidase 2 (NOX2) expression, an important regulator of both oxidative stress and inflammatory cytokines. Furthermore, immunohistochemical analysis revealed that NOX2 was abundantly expressed in activated M1 microglia. The JAK2/STAT3 signaling pathway, an upstream regulator of NOX2, was increased in WT mice and activated to an even greater extent in Apoe−/− mice; whereas, the JAK2-specific inhibitor, AG490, reduced NOX2 expression, oxidative stress, and inflammation in Apoe-deficient mice. Also, apoE-mimetic peptide COG1410 suppressed the JAK2/STAT3 signaling pathway and significantly reduced M1 microglia activation with subsequent attenuation of oxidative stress and inflammation after SAH. Taken together, apoE and apoE-mimetic peptide have whole-brain protective effects that may reduce EBI after SAH via M1 microglial quiescence through the attenuation of the JAK2/STAT3/NOX2 signaling pathway axis. Keywords Subarachnoid hemorrhage . Early brain injury . Apolipoprotein E . Oxidative stress . Neuroinflammation
Introduction * Yong Jiang [email protected] 1
Department of Neurosurgery, the Affiliated Hospital of Southwest Medical University, No 25 Taiping Street, Jiangyang District, Luzhou 646000, Sichuan Province, China
2
Loma Linda University School of Medicine, Loma Linda, CA 92354, USA
3
The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
4
Duke University Medical Center, Durham, North Carolina, USA
5
Cognosci Inc., Research Triangle Park, North Carolina, USA
6
Sichuan Province Neurosurgery Clinical Medical Research Center, Luzhou, China
7
Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
Subarachnoid hemorrhage (SAH) causes multiple secondary brain injuries th
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