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Methamphetamine-induced increase in striatal NF-kappaB DNA-binding activity is attenuated in superoxide dismutase
1Molecular Neuropsychiatry Section, NIH/ NIDA, Intramural Research Program, P.O. Box 5180, Baltimore, MD, USA.
Abstract:
Methamphetamine injection (x4 with 2-h interval) caused dose-dependent activation of striatal NF-kappaB activity. Striatal NF-kappaB binding increased significantly at 1-3 h after the last injection of methamphetamine (10 mg/kg, i.p. x4). This induction of striatal NF-kappaB activity was significantly attenuated in Cu, Zn-superoxide dismutase transgenic mice in a gene dosage-dependent fashion. The present results suggest that reactive oxygen species generated by methamphetamine injections can activate striatal NF-kappaB DNA-binding during this drug-induced toxic process.
Insights
Methamphetamine injections activate striatal nuclear factor-kappa B (NF-kappaB) activity, a process linked to reactive oxygen species. This activation was reduced in mice genetically engineered to combat oxidative stress.
Area of Science:
- Neuroscience
- Toxicology
- Molecular Biology
Background:
- Methamphetamine is a potent neurotoxin with significant abuse potential.
- Nuclear factor-kappa B (NF-kappaB) is a key transcription factor involved in inflammatory and cellular stress responses.
- Oxidative stress is implicated in the neurotoxicity of various drugs, including methamphetamine.
Purpose of the Study:
- To investigate the effect of methamphetamine injection on striatal NF-kappaB activity.
- To determine the role of reactive oxygen species in mediating methamphetamine-induced NF-kappaB activation.
- To examine the impact of antioxidant defense mechanisms on this process.
Main Methods:
- Administration of methamphetamine via intraperitoneal injection (10 mg/kg, 4 times with 2-h intervals) to rodents.
- Measurement of striatal NF-kappaB DNA-binding activity using electrophoretic mobility shift assays (EMSA).
- Utilized copper, zinc-superoxide dismutase (Cu, Zn-SOD) transgenic mice to assess the role of oxidative stress.
Main Results:
- Methamphetamine injection induced a dose-dependent increase in striatal NF-kappaB activity.
- Significant elevation in striatal NF-kappaB binding was observed 1-3 hours post-methamphetamine administration.
- This induction was significantly attenuated in Cu, Zn-SOD transgenic mice in a gene dosage-dependent manner.
Conclusions:
- Methamphetamine administration activates NF-kappaB DNA-binding in the striatum.
- Reactive oxygen species generated during methamphetamine exposure appear to mediate this NF-kappaB activation.
- Enhanced antioxidant defenses can mitigate methamphetamine-induced NF-kappaB activation, suggesting a role in neuroprotection.