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Methamphetamine induces apoptosis in an immortalized rat striatal cell line by activating the mitochondrial cell
Xiaolin Deng1, Ning-Sheng Cai, Michael T McCoy
1Molecular Neuropsychiatry Section, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Abstract:
Methamphetamine is a neurotoxic drug of abuse known to cause cell death both in vitro and in vivo. Nevertheless, the molecular and cellular mechanisms involved in this process remain to be clarified. Herein, we show that methamphetamine-induced apoptosis is associated with early (2 h) overexpression of bax, decreases of mitochondrial membrane potential and oxygen consumption as well as release of cytochrome c from mitochondria. In addition, activated caspase-9 was detected at 4 h post-METH exposure. Cell death was detectable by annexin V and propidium iodide staining after 8 h of methamphetamine exposure. At that time, the majority of the cells were stained by annexin V alone, with some cells being stained for both annexin V and propidium iodide. Moreover, cleavage of caspase-3, poly (ADP-ribose) polymerase and DNA fragmentation-related factor 45 was detected at 8 h post drug treatment. These results indicate that methamphetamine-induced apoptotic cell death results from early overexpression of bax, reduction of mitochondrial respiration and membrane potential and release of mitochondrial cytochrome c with subsequent activation of the caspase cascade.
Insights
Methamphetamine (METH) triggers apoptosis by upregulating BAX, disrupting mitochondrial function, and activating caspases. This leads to programmed cell death, clarifying METH
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Methamphetamine (METH) is a neurotoxic drug of abuse.
- The precise molecular mechanisms underlying METH-induced cell death are not fully understood.
Purpose of the Study:
- To elucidate the molecular and cellular pathways involved in methamphetamine-induced apoptosis.
Main Methods:
- Assessed BAX expression, mitochondrial membrane potential, and oxygen consumption.
- Measured cytochrome c release, caspase activation (caspase-9, caspase-3), and cell death markers (annexin V, propidium iodide).
- Analyzed cleavage of PARP and DFF45.
Main Results:
- METH exposure led to early BAX overexpression and decreased mitochondrial function (membrane potential, oxygen consumption).
- Cytochrome c was released from mitochondria, followed by caspase-9 activation within 4 hours.
- Significant cell death, characterized by annexin V staining, was observed after 8 hours, with subsequent caspase-3 activation and DNA fragmentation.
Conclusions:
- Methamphetamine-induced apoptosis involves early BAX upregulation and mitochondrial dysfunction.
- The intrinsic apoptotic pathway, mediated by cytochrome c release and caspase activation, is central to METH neurotoxicity.