Glutamate/NMDA excitotoxicity and HMGB1/TLR4 neuroimmune toxicity converge as components of neurodegeneration

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, TNFα 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 TNFα) induced neuronal death. Similarly, HMGB1 neutralizing antibodies or inhibitor glycyrrhizin block glutamate/NMDA as well as neuroimmune (LPS and TNFα) induced neuronal death. Further, delayed neuronal cell death mediated by LPS and TNFα 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.