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

Autor: Jiz Yuh Wang, Andrew Yau-Chik Shum, Yi Jung Ho, Jia Yi Wang
Rok vydání: 2003
Předmět:
Programmed cell death
Blotting
Western
Apoptosis
DNA Fragmentation
S-Nitroso-N-Acetylpenicillamine
DNA laddering
Biology
Nitric Oxide
medicine.disease_cause
p38 Mitogen-Activated Protein Kinases
Nitric oxide
Rats
Sprague-Dawley
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Fetus
Peroxynitrous Acid
In Situ Nick-End Labeling
medicine
Animals
Nitric Oxide Donors
Enzyme Inhibitors
Cells
Cultured
Cerebral Cortex
Neurons
chemistry.chemical_classification
Reactive oxygen species
Dose-Response Relationship
Drug
Caspase 3
Neurotoxicity
Drug Synergism
Hydrogen Peroxide
Oxidants
medicine.disease
Immunohistochemistry
Rats
Cell biology
Oxidative Stress
chemistry
Caspases
Mitogen-Activated Protein Kinases
S-Nitroso-N-acetylpenicillamine
Extracellular Space
Reactive Oxygen Species
Peroxynitrite
Oxidative stress
Zdroj: Journal of Neuroscience Research. 72:508-519
ISSN: 1097-4547
0360-4012
DOI: 10.1002/jnr.10597
Popis: 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 (*O(2) (-)), hydrogen peroxide (H(2)O(2)), and nitric oxide (NO), thereby further contributing to oxidative neurotoxicity. The reaction of NO and *O(2) (-), forming the toxic peroxynitrite (ONOO(-)), has been proposed to play a pathogenic role in neuronal injury. However, the interactions between H(2)O(2) and NO during oxidative stress, which may promote or diminish cell death, is less clear. In this study, we explored oxidative neurotoxicity induced by H(2)O(2) plus NO in primary cultures of rat cerebral cortex neurons. As the mechanisms may involve reactions between H(2)O(2) 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 H(2)O(2) by themselves elicited neuronal death in a concentration- and time-dependent manner. Sublytic concentrations of H(2)O(2) 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 H(2)O(2) 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 H(2)O(2) plus SNAP. These data suggest that H(2)O(2) and NO act synergistically to induce neuronal death through apoptosis in which activation of p38 MAPK and caspase-3 is involved.
Databáze: OpenAIRE
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