Regulation of matrix metalloproteinase-9 gene expression in MPP+- or 6-OHDA-treated human neuroblastoma SK-N-BE(2)C cells

The aberrant expression of matrix metalloproteinases (MMPs) is known to play an important role in various neurodegenerative diseases, such as Parkinson's disease. In the present study, we found that two well-known dopaminergic neurotoxins, 6-OHDA and MPP+, induced the expression of MMP-9 in SK-N-BE(2)C human neuroblastoma and Cath.a mouse dopaminergic cell lines. Treatment with MMP-9 inhibitors attenuated the neuronal cell death induced by either 6-OHDA or MPP+, suggesting that MMP-9 plays an important role in this neurotoxin-mediated cell death. Further mechanistic studies showed that 6-OHDA and MPP+ increased MMP-9 gene expression by inducing NF-κB and AP-1 binding to the MMP-9 promoter. Reactive oxygen species (ROS) appeared to be involved in MMP-9 expression because treatment with the free radical scavenger, N-acetylcysteine (NAC), suppressed both 6-OHDA- and MPP+-induced MMP-9 promoter activities. Treatment with several signaling pathway-specific inhibitors revealed that the PI3 kinase inhibitor, LY294002, suppressed 6-OHDA- and MPP+-induced MMP-9 promoter activities, whereas the p38 MAPK inhibitor, SB203580, inhibited 6-OHDA-, but not MPP+-induced promoter activity. These results collectively suggest that ROS, PI3 kinase, NF-κB, and AP-1 are commonly involved in 6-OHDA- and MPP+-induced MMP-9 gene expression, and that p38 MAPK is differentially involved. Therefore, controlling MMP-9 expression may have therapeutic potential in Parkinson's disease, which is caused by various neurotoxins, such as 6-OHDA and MPP+.