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Relationship between methamphetamine exposure and matrix metalloproteinase 9 expression
Yun Liu1, Sheketta Brown, Jamaluddin Shaikh
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Abstract:
The involvement of matrix metalloproteinase (MMP) 9 in methamphetamine-induced neurotoxicity was evaluated. Injection of mice with stimulant or toxic doses of methamphetamine upregulated MMP9 gene expression in the brain within 5 min. By 24 h, MMP9 gene expression returned to control levels in the stimulant-treated mice, but remained elevated in animals exposed to toxic doses of methamphetamine. Reductions in striatal dopamine levels, a marker of methamphetamine neurotoxicity, developed 1-7 days after methamphetamine exposure, but were not accompanied by concomitant changes in MMP9 gene expression. In MMP9 knockout mice, methamphetamine retained its ability to elicit neurotoxicity. The data suggest that MMP9 expression does not contribute to methamphetamine-induced neurotoxicity, and may instead be involved in remodeling of the nervous system.
Insights
Matrix metalloproteinase (MMP) 9 is not involved in methamphetamine neurotoxicity. Studies show MMP9 gene expression changes do not correlate with dopamine loss, and knockout mice still experience neurotoxicity.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Methamphetamine (MA) abuse leads to significant neurotoxicity, particularly affecting dopamine pathways.
- Matrix metalloproteinase 9 (MMP9) is implicated in various neurological processes, including neuroinflammation and tissue remodeling.
Purpose of the Study:
- To investigate the role of MMP9 in the neurotoxic effects of methamphetamine.
- To determine if MMP9 contributes to methamphetamine-induced dopamine depletion.
Main Methods:
- Administered stimulant and toxic doses of methamphetamine to mice.
- Measured MMP9 gene expression in the brain at various time points.
- Assessed striatal dopamine levels as a marker of neurotoxicity.
- Utilized MMP9 knockout mice to evaluate MA neurotoxicity in the absence of MMP9.
Main Results:
- Methamphetamine rapidly upregulated MMP9 gene expression, with levels returning to baseline in stimulant-treated mice but remaining elevated in toxic dose groups.
- Striatal dopamine reductions, indicative of neurotoxicity, occurred 1-7 days post-exposure but were not associated with concurrent MMP9 expression changes.
- MMP9 knockout mice exhibited normal methamphetamine-induced neurotoxicity, indicating MMP9 is not essential for this process.
Conclusions:
- MMP9 gene expression is upregulated by methamphetamine but does not appear to mediate methamphetamine-induced neurotoxicity.
- The findings suggest MMP9 may play a role in the nervous system's response to methamphetamine, potentially in tissue remodeling rather than direct toxicity.