Pathophysiologically relevant levels of hydrogen peroxide induce glutamate-independent neurodegeneration that involves activation of transient receptor potential melastatin 7 channels.
Stroke/brain ischemia is a leading cause of death and long-term disabilities. Increased oxidative stress plays an important role in the pathology of brain ischemia. Hydrogen peroxide (H(2)O(2)) is a major oxidant known to cause neuronal injury; however, the detailed mechanism remains unclear. Previous studies have suggested that H(2)O(2)-induced injury is associated with increased intracellular Ca(2+), mediated by glutamate receptors or voltage-gated Ca(2+) channels. Here, we demonstrate that, at concentrations relevant to stroke, H(2)O(2) induces a Ca(2+)-dependent injury of mouse cortical neurons in the absence of activation of these receptors/channels. With the culture medium containing blockers of glutamate receptors and voltage-gated Ca(2+) channels, brief exposure of neurons to H(2)O(2) induced a dose-dependent injury. Reducing [Ca(2+)](e) inhibited whereas increasing [Ca(2+)](e) potentiated the H(2)O(2) injury. Fluorescent Ca(2+) imaging confirmed the increase of [Ca(2+)](i) by H(2)O(2) in the presence of the blockers of glutamate receptors and voltage-gated Ca(2+) channels. Addition of 2-aminoethoxydiphenyl borate, an inhibitor of transient receptor potential melastatin 7 (TRPM7) channels, or the use of TRPM7-small interference RNA, protected the neurons from H(2)O(2) injury. In contrast, overexpressing TRPM7 channels in human embryonic kidney 293 cells increased H(2)O(2) injury. Our findings indicate that H(2)O(2) can induce Ca(2+) toxicity independent of glutamate receptors and voltage-gated Ca(2+) channels. Activation of TRPM7 channels is involved in such toxicity.
Coombes
Emily
E
Robert S. Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon, USA.
Jiang
Jie
J
Chu
Xiang-Ping
XP
Inoue
Koichi
K
Seeds
Joshua
J
Branigan
Deborah
D
Simon
Roger P
RP
Xiong
Zhi-Gang
ZG
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018698:Glutamic Acid / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering; D017470:Receptors, Glutamate / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
D015220:Calcium Channels; D034741:RNA, Small Interfering; D017470:Receptors, Glutamate; D050053:TRPM Cation Channels; D018698:Glutamic Acid; D006861:Hydrogen Peroxide; C421903:Trpm7 protein, mouse
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