Specific gene expression and possible involvement of inflammation in methamphetamine-induced neurotoxicity.

To reveal specific gene expression in methamphetamine (METH) -induced dopamine neurotoxicity, temporal characteristics of METH-induced changes in gene expression in dopaminergic neuronal cells were examined using the cDNA array and the differential display method. A number of genes in the class of "trafficking & protein turnover," "metabolic pathways," "transmitters & receptors," and "growth factors, cytokines" were upregulated after the METH treatment in the cDNA array assay. Whereas, some genes related to trafficking & protein turnover and "modulators, effectors & intracellular transducers" were decreased by METH. Some proteins associated with synaptic vesicle transportation indeed up- or downregulated after the METH treatment. These data suggest that the protein trafficking and degradation system is involved in the dopaminergic cell death induced by METH. Furthermore, focusing on inflammatory reactions after METH injection, possible neuroprotective property of nonsteroidal anti-inflammatory drugs were examined against METH-induced neurotoxicity. Coadministration of NSAID with METH significantly attenuated striatal dopamine terminal degeneration and microgliosis induced by METH, suggesting that the protective effects are based on their inhibitory activity on production of cytokines and nitric oxides or their suppressive action against microglia activation.