| Summary: | 碩士 === 國立陽明大學 === 藥理學研究所 === 94 === Methamphetamine (METH) is a widely abused drug, which is originally used as a psychostimulant. It has been reported that METH can induce neurotoxicity and neurodegeneration in animal brain. Nevertheless, the molecular and cellular mechanisms by which METH induces neurotoxicity remain unclear.
In a previous study, it was found that 250 μg/mL of METH induced mitochondrial membrane potential loss, reactive oxygen species (ROS) production, mitochondrial mass increase, cell viability decrease in human neuroblastoma SH-SY5Y cells. In this study, I further demonstrated that METH induced the loss of mitochondrial membrane potential within 1 hr of exposure, and the increase in ROS production after a 8 hr-treatment as well as the increase in mitochondrial mass after a 24 hr-treatment, respectively. Moreover, I evaluated the mechanism through overexpression of Bcl-XL protein, and treatment with a specific NADPH oxidase inhibitor apocynin, NADPH oxidase and mitochondrial Complex I inhibitor DPI, a PKC-δ inhibitor rottlerin, a PI3K inhibitor LY294002, and a protein synthesis inhibitor cycloheximide. I found that respiratory enzyme Complex I was involved in the increase of ROS under METH treatment. The elevated oxidative stress could lead to the increase of mitochondrial mass. In addition, PI3K and its downstream PKC-δ were involved in the oxidative stress-induced increase of mitochondrial mass, and de novo protein synthesis in the extramitochondrial compartment was required for the increase of mitochondrial mass. Based on these results, I suggest that oxidative stress-induced increase in mitochondrial mass may play an important role in METH-induced neurotoxicity.
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