NOX2 deficiency ameliorates cerebral injury through reduction of complexin II-mediated glutamate excitotoxicity in experimental stroke.

Abstract

Although NADPH oxidase (NOX)-mediated oxidative stress is considered one of the major mechanisms triggering the pathogenic actions of ischemic stroke and very recent studies have indicated that NADPH oxidase is a major source of reactive oxygen species (ROS) production controlling glutamate release, how neuronal NADPH oxidase activation is coupled to glutamate release is not well understood. Therefore, in this study, we used an in vivo transient middle cerebral artery occlusion model and in vitro primary cell cultures to test whether complexins, the regulators of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes necessary for vesicle fusion, are associated with NOX2-derived ROS and contribute to glutamate-mediated excitotoxicity in ischemic stroke. In this study, we first identified the upregulation of complexin II in the ischemic brain and evaluated its potential role in ischemic stroke showing that gene silencing of complexin II ameliorated cerebral injury as evidenced by reduced infarction volume, neurological deficit, and neuron necrosis accompanied by decreased glutamate levels, consistent with the results from NOX2(-/-) mice with ischemic stroke. We further demonstrated that complexin II expression was mediated by NOX2 in primary cultured neurons subjected to oxygen-glucose deprivation (OGD) and contributed to OGD-induced glutamate release and neuron necrosis via SNARE signaling. Taken together, these findings for the first time provide evidence that complexin II is a central target molecule that links NADPH oxidase-derived ROS to glutamate-mediated neuronal excitotoxicity in ischemic stroke.

• Authors: Ziying Wang, Xinbing Wei, Kang Liu, Xiumei Zhang, Fan Yang, Hongyu Zhang, Yeteng He, Tianfeng Zhu, Fengli Li, Weichen Shi, Yan Zhang, Huiyan Xu, Jiang Liu, Fan Yi
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 65 Pg. 942-951 (Dec 2013) ISSN: 1873-4596 [Electronic] United States
• PMID: 23982049 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Vesicular Transport
• Membrane Glycoproteins
• Nerve Tissue Proteins
• Reactive Oxygen Species
• complexin I
• complexin II
• Glutamic Acid
• Cybb protein, mouse
• NADPH Oxidase 2
• NADPH Oxidases

Topics

• Adaptor Proteins, Vesicular Transport (metabolism, physiology)
• Animals
• Astrocytes (enzymology)
• Cells, Cultured
• Glutamic Acid (physiology)
• Hippocampus (pathology)
• Infarction, Middle Cerebral Artery (enzymology, pathology)
• Male
• Membrane Glycoproteins (genetics, metabolism)
• Mice, Knockout
• NADPH Oxidase 2
• NADPH Oxidases (genetics, metabolism)
• Necrosis
• Nerve Tissue Proteins (metabolism, physiology)
• Oxidative Stress
• Reactive Oxygen Species (metabolism)