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The Journal of Neuroscience, 0000, 20:RC111:1-5
RAPID COMMUNICATION
Induction and Activation by Zinc of NADPH Oxidase in
Cultured Cortical Neurons and Astrocytes
Kyung-Min
Noh and
Jae-Young
Koh
National Creative Research Initiative Center for the Study
of CNS Zinc and Department of Neurology, University of Ulsan College of
Medicine, Seoul 138-736, Korea
Zinc overload may be a key mechanism of neuronal death in acute
brain injury. We have demonstrated previously that zinc overload neurotoxicity involves protein kinase C (PKC)-dependent rises in
intracellular levels of reactive oxygen species (ROS). However, the
cascade linking PKC activation to ROS generation in cultured cortical
neurons has been unknown. A recent study has demonstrated that
ROS-generating NADPH oxidase is present in sympathetic neurons and
contributes to NGF deprivation-induced cell death. Because NADPH
oxidase is activated by PKC, in the present study, we examined the
possibility that NADPH oxidase is the effector for oxidative stress in
zinc-overloaded cortical cells.
Reverse transcription-PCR and Western blot analyses revealed that naive
cultured cortical cells express subunits of NADPH oxidase at low
levels. Exposure to zinc substantially increased levels of NADPH
oxidase subunits in both neurons and astrocytes. In addition, zinc
exposure induced translocation of the p47PHOX and
p67PHOX subunits to the membrane, a signature event
for NADPH oxidase activation. Addition of a selective PKC inhibitor,
GF109203X, blocked both the induction and the membrane translocation of
NADPH oxidase by zinc. Supporting the role for NADPH oxidase in
zinc-triggered oxidative injury, NADPH oxidase inhibitors attenuated
ROS production and cortical neuronal death induced by zinc. In
addition, Cu/Zn-superoxide dismutase and catalase attenuated
zinc-induced cortical neuronal death.
Our results have demonstrated that zinc overload induces and activates
NADPH oxidase in cortical neurons and astrocytes in a PKC-dependent
manner. Thus, NADPH oxidase may be an enzyme contributing to ROS
generation in zinc-overloaded cortical neurons and astrocytes.
Key words:
oxidative stress; protein kinase C; superoxide; astrocyte; calcium; neuronal death
Copyright © 0000 Society for Neuroscience 0270-6474/00/$05.00/0
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