期刊
AIMS MOLECULAR SCIENCE
卷 2, 期 2, 页码 77-100出版社
AMER INST MATHEMATICAL SCIENCES-AIMS
DOI: 10.3934/molsci.2015.2.77
关键词
excitotoxicity; neuroinflammation; cytokines; toll-like receptors; endogenous TLR4 ligand; brain slice culture
资金
- National Institutes of Health, National Institute on Alcoholism and Alcohol Abuse [AA019767, AA11605, AA007573, AA021040]
- Neurobiology of Adolescent Drinking in Adulthood (NADIA) [AA020023, AA020024, AA020022]
- Bowles Center for Alcohol Studies
- Bowles Center for Alcohol Studies and Michael Hooker Microscopy Facility
- University of North Carolina at Chapel Hill, School of Medicine
Neurodegeneration in brain is linked to both excitotoxicity and neuroimmune gene induction, although the mechanisms are poorly understood. High-mobility group box 1 (HMGB1) is a cytokine like molecule released in brain by glutamate that has been found to enhance neuronal excitability through Toll-like receptor 4 (TLR4). To explore the role of HMGB1 in glutamate/NMDA excitotoxicity or neuroimmune-induced neurodegeneration we used an ex vivo model of organotypic hippocampal-entorhinal cortex (HEC) slice culture. Concentration response and time course studies find release of HMGB1 precedes neuronal death induced by glutamate, NMDA, TNFa and LPS. Blockade of glutamate receptors with antagonist MK-801 prevents glutamate/NMDA stimulation release of HMGB1 and neuronal death as well as blocking neuroimmune (LPS and TNFa) induced neuronal death. Similarly, HMGB1 neutralizing antibodies or inhibitor glycyrrhizin block glutamate/NMDA as well as neuroimmune (LPS and TNFa) induced neuronal death. Further, delayed neuronal cell death mediated by LPS and TNFa was rescued by NR2B inhibitor ifenprodil. Together, these findings suggest HMGB1 contributes a critical element of both glutamate/NMDA as well as neuroimmune induced neurodegeneration indicating HMGB1 may be a novel target crossing multiple neurodegeneration pathologies.
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