It has been widely reported that long-term exposure to copper increases the prevalence and mortality of Parkinson's disease . Our previous study showed that CuSO 4 exposure induced a significant increase in the expression of cleaved Caspase1 proteins and the loss of dopaminergic neurons in the SNpc of mice. In this study, the effects of copper(Ⅱ) on cAMP/PKA/CREB pathway and pyroptosis-related proteins in MN9D cells were investigated by setting up copper(Ⅱ) exposure groups with different concentration gradients, to provide possible molecular evidence for studying the mechanism of copper(Ⅱ)-induced degeneration of dopaminergic neurons. We found that after 48?h of copper(Ⅱ) exposure, the cu content in MN9D cells increased in a dose-dependent manner, and the proliferation activity decreased significantly. In addition, copper(Ⅱ) exposure caused up-regulation of PDE4D and down-regulation of D1R, cAMP, PKA and p-CREB/CREB. Simultaneously, we proved that copper(Ⅱ) exposure induced oxidative stress in MN9D cells, including decreased GSH-Px content, Keap1 expression and mitochondrial membrane potential, increased malondialdehyde content, ROS intensity, and Nrf2, NQO1 , HO-1, HSP-70 expression, further causing up-regulation of inflammasome and GSDMD protein. After pretreatment with Roflupram, the level of copper(Ⅱ)-induced oxidative damage decreased, the expression of inflammasome and GSDMD proteins were down-regulated. However, the protective effects of ROF were blocked by H-89. In summary, copper(Ⅱ) treatment induced oxidative stress and inflammasome-mediated pyroptosis in MN9D cells, which may be related to copper(Ⅱ)-induced postsynaptic cAMP, PKA, and CREB signal transduction disorders.
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