Abstract
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 N-methyl-D-aspartate (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.
Highlights
Reduction and oxidation reactions lie at the heart of critical biochemical processes indispensable for life
In the second part of the review, we outline the studies we performed characterizing the oxidative conversion of the catecholamine precursor 3,4-dihydroxyphenylalanine (DOPA) to the kainatelike excitotoxin 2,4,5-trihydroxyphenylalanine (TOPA) quinone (Aizenman et al, 1990b; Rosenberg et al, 1991) culminating with the demonstration that TOPA quinone could be generated by catecholamine-containing cells, thereby introducing a novel mechanism of neurodegeneration in the study of endogenous neurotoxic processes in the brain (Newcomer et al, 1995b)
We found that the oxidized form of TOPA, which was spectrophotometrically distinct from dopachrome, was strongly excitotoxic to cultured rat cultured neurons via non-NMDA receptor activation (Rosenberg et al, 1991)
Summary
Reduction and oxidation reactions lie at the heart of critical biochemical processes indispensable for life. We transition to describe our work that first described the oxidative liberation of intracellular zinc in neurons (Aizenman et al, 2000). This process, which is closely associated with excitotoxic injury, results in a now-well characterized, complex signaling cascade that is an important component of neuronal cell death (Pal et al, 2004; Redman et al, 2009b; McCord and Aizenman, 2014; Shah and Aizenman, 2014). This review is intended as a retrospective of our own collaborative work rather than a comprehensive overview of the redox biology of excitotoxic phenomena. We sincerely apologize in advance to all of our colleagues who have made significant contributions to this research topic but whom we have failed to cite
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