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Increase in external glutamate and NMDA receptor activation contribute to H2O2-induced neuronal apoptosis
Abstract:
The present study aims to investigate the role of extracellular glutamate and NMDA receptor stimulation in the neuronal death induced by a transient exposure to H2O2 of cultured neurons originating from mouse cerebral cortex. Most of the neuronal loss following a transient exposure to H2O2 of cortical neurons results from an apoptotic process involving a secondary stimulation of NMDA receptors, which occurs after H2O2 washout. Indeed, (a) the neurotoxic effect of H2O2 was strongly reduced by antagonists of NMDA receptors, (b) the neurotoxic effect of H2O2 was enhanced in the absence of Mg2+, (c) the protective effect of MK-801 progressively decayed when it was applied with increasing delay time after H2O2 exposure, and (d), finally, the extracellular concentration of glutamate was increased after H2O2 exposure. The major part of H2O2-induced neurotoxicity is mediated by the formation of hydroxyl radicals, which might be involved in (a) the delayed accumulation of extracellular glutamate and NMDA receptor activation and (b) the poly(ADP-ribose) polymerase activation and the related NAD content decrease. The combination of these two mechanisms could lead to both an increase in ATP consumption and a decrease of ATP synthesis. The resulting large decrease in ATP content might be finally responsible for the neuronal death.
Insights
Hydrogen peroxide (H2O2) causes neuronal death through a process involving glutamate and NMDA receptor activation. This neurotoxicity is linked to hydroxyl radical formation, impacting ATP levels and leading to apoptosis.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Hydrogen peroxide (H2O2) is a reactive oxygen species implicated in neuronal injury.
- Oxidative stress can trigger complex cellular signaling pathways leading to cell death.
Purpose of the Study:
- To investigate the role of extracellular glutamate and NMDA receptor stimulation in H2O2-induced neuronal death in mouse cortical neurons.
- To elucidate the mechanisms underlying H2O2 neurotoxicity.
Main Methods:
- Primary culture of mouse cerebral cortex neurons.
- Exposure to transient hydrogen peroxide (H2O2).
- Assessment of neuronal death using NMDA receptor antagonists and MK-801, and measurement of extracellular glutamate levels.
Main Results:
- H2O2-induced neurotoxicity was significantly reduced by NMDA receptor antagonists.
- Neurotoxicity was exacerbated in the absence of Mg2+ and MK-801's protective effect decayed with delayed application.
- Extracellular glutamate levels increased post-H2O2 exposure, suggesting a role in secondary NMDA receptor activation.
Conclusions:
- H2O2-induced neuronal death involves a secondary NMDA receptor stimulation pathway.
- Hydroxyl radical formation mediates delayed glutamate accumulation and NMDA receptor activation.
- This cascade, along with poly(ADP-ribose) polymerase activation and NAD+ depletion, leads to ATP depletion and subsequent apoptosis.