The Redox Biology of Excitotoxic Processes: The NMDA Receptor, TOPA Quinone, and the Oxidative Liberation of Intracellular Zinc

This special issue of Frontiers in Neuroscience-Neurodegeneration celebrates the 50th anniversary of John Olney’s seminal work introducing the concept of excitotoxicity as a mechanism for neuronal cell death. Since that time, fundamental research on the pathophysiological activation of glutamate receptors has played a central role in our understanding of excitotoxic cellular signaling pathways, leading to the discovery of many potential therapeutic targets in the treatment of acute or chronic/progressive neurodegenerative disorders. Importantly, excitotoxic signaling processes have been found repeatedly to be closely intertwined with oxidative cellular cascades. With this in mind, this review looks back at long-standing collaborative efforts by the authors linking cellular redox status and glutamate neurotoxicity, focusing first on the discovery of the redox modulatory site of the NMDA receptor, followed by the study of the oxidative conversion of 3,4-dihydroxyphenylalanine (DOPA) to the non-NMDA receptor agonist and neurotoxin 2,4,5-trihydroxyphenylalanine (TOPA) quinone. Finally, we summarize our work linking oxidative injury to the liberation of zinc from intracellular metal binding proteins, leading to the uncovering of a signaling mechanism connecting excitotoxicity with zinc-activated cell death-signaling cascades.