Abstract
Oxidative stress in the brain has been increasingly associated with the development of numerous human neurological diseases. Microglia, activated upon neuronal injury or inflammatory stimulation, are known to release superoxide anion (.O2-), hydrogen peroxide (H2O2), and nitric oxide (NO), thereby further contributing to oxidative neurotoxicity. The reaction of NO and .O2-, forming the toxic peroxynitrite (ONOO-), has been proposed to play a pathogenic role in neuronal injury. However, the interactions between H2O2 and NO during oxidative stress, which may promote or diminish cell death, is less clear. In this study, we explored oxidative neurotoxicity induced by H2O2 plus NO in primary cultures of rat cerebral cortex neurons. As the mechanisms may involve reactions between H2O2 and NO, we monitored the production of ONOO- and reactive oxygen species (ROS) throughout the experiments. Results indicated that the NO donor S-nitroso-N-acetyl-D, L-penicillamine (SNAP) and H2O2 by themselves elicited neuronal death in a concentration-and time-dependent manner. Sublytic concentrations of H2O2 plus SNAP were sufficient to induce neuronal apoptosis as determined by DNA laddering and fluorescent staining of apoptotic nuclei. Transient ONOO-increase was accompanied by rapid H2O2 decay and NO production, whereas ROS slowly decreased following treatment. Furthermore, p38 mitogen-activated protein kinase (MAPK) activation and the cleavage of caspase-3 were observed. Conversely, inhibition of p38 MAPK and caspase-3 significantly reduced apoptotic death induced by H2O2 plus SNAP. These data suggest that H2O2 and NO act synergistically to induce neuronal death through apoptosis in which activation of p38 MAPK and caspase-3 is involved.
| Original language | English |
|---|---|
| Pages (from-to) | 508-519 |
| Number of pages | 12 |
| Journal | Journal of Neuroscience Research |
| Volume | 72 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - May 15 2003 |
| Externally published | Yes |
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Keywords
- Apoptosis
- Caspase-3
- HO
- NO
- p38 MAPK
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
Oxidative neurotoxicity in rat cerebral cortex neurons : Synergistic effects of H2O2 and NO on apoptosis involving activation of p38 mitogen-activated protein kinase and caspase-3. / Wang, Jiz Yuh; Shum, Andrew Y C; Ho, Yi Jung; Wang, Jia Yi.
In: Journal of Neuroscience Research, Vol. 72, No. 4, 15.05.2003, p. 508-519.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Oxidative neurotoxicity in rat cerebral cortex neurons
T2 - Synergistic effects of H2O2 and NO on apoptosis involving activation of p38 mitogen-activated protein kinase and caspase-3
AU - Wang, Jiz Yuh
AU - Shum, Andrew Y C
AU - Ho, Yi Jung
AU - Wang, Jia Yi
PY - 2003/5/15
Y1 - 2003/5/15
N2 - Oxidative stress in the brain has been increasingly associated with the development of numerous human neurological diseases. Microglia, activated upon neuronal injury or inflammatory stimulation, are known to release superoxide anion (.O2-), hydrogen peroxide (H2O2), and nitric oxide (NO), thereby further contributing to oxidative neurotoxicity. The reaction of NO and .O2-, forming the toxic peroxynitrite (ONOO-), has been proposed to play a pathogenic role in neuronal injury. However, the interactions between H2O2 and NO during oxidative stress, which may promote or diminish cell death, is less clear. In this study, we explored oxidative neurotoxicity induced by H2O2 plus NO in primary cultures of rat cerebral cortex neurons. As the mechanisms may involve reactions between H2O2 and NO, we monitored the production of ONOO- and reactive oxygen species (ROS) throughout the experiments. Results indicated that the NO donor S-nitroso-N-acetyl-D, L-penicillamine (SNAP) and H2O2 by themselves elicited neuronal death in a concentration-and time-dependent manner. Sublytic concentrations of H2O2 plus SNAP were sufficient to induce neuronal apoptosis as determined by DNA laddering and fluorescent staining of apoptotic nuclei. Transient ONOO-increase was accompanied by rapid H2O2 decay and NO production, whereas ROS slowly decreased following treatment. Furthermore, p38 mitogen-activated protein kinase (MAPK) activation and the cleavage of caspase-3 were observed. Conversely, inhibition of p38 MAPK and caspase-3 significantly reduced apoptotic death induced by H2O2 plus SNAP. These data suggest that H2O2 and NO act synergistically to induce neuronal death through apoptosis in which activation of p38 MAPK and caspase-3 is involved.
AB - Oxidative stress in the brain has been increasingly associated with the development of numerous human neurological diseases. Microglia, activated upon neuronal injury or inflammatory stimulation, are known to release superoxide anion (.O2-), hydrogen peroxide (H2O2), and nitric oxide (NO), thereby further contributing to oxidative neurotoxicity. The reaction of NO and .O2-, forming the toxic peroxynitrite (ONOO-), has been proposed to play a pathogenic role in neuronal injury. However, the interactions between H2O2 and NO during oxidative stress, which may promote or diminish cell death, is less clear. In this study, we explored oxidative neurotoxicity induced by H2O2 plus NO in primary cultures of rat cerebral cortex neurons. As the mechanisms may involve reactions between H2O2 and NO, we monitored the production of ONOO- and reactive oxygen species (ROS) throughout the experiments. Results indicated that the NO donor S-nitroso-N-acetyl-D, L-penicillamine (SNAP) and H2O2 by themselves elicited neuronal death in a concentration-and time-dependent manner. Sublytic concentrations of H2O2 plus SNAP were sufficient to induce neuronal apoptosis as determined by DNA laddering and fluorescent staining of apoptotic nuclei. Transient ONOO-increase was accompanied by rapid H2O2 decay and NO production, whereas ROS slowly decreased following treatment. Furthermore, p38 mitogen-activated protein kinase (MAPK) activation and the cleavage of caspase-3 were observed. Conversely, inhibition of p38 MAPK and caspase-3 significantly reduced apoptotic death induced by H2O2 plus SNAP. These data suggest that H2O2 and NO act synergistically to induce neuronal death through apoptosis in which activation of p38 MAPK and caspase-3 is involved.
KW - Apoptosis
KW - Caspase-3
KW - HO
KW - NO
KW - p38 MAPK
UR - http://www.scopus.com/inward/record.url?scp=0242516020&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0242516020&partnerID=8YFLogxK
U2 - 10.1002/jnr.10597
DO - 10.1002/jnr.10597
M3 - Article
C2 - 12704812
AN - SCOPUS:0242516020
VL - 72
SP - 508
EP - 519
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 4
ER -