2. Academic Validation
  3. Upregulation of postsynaptic cAMP/PKA/CREB signaling alleviates copper(Ⅱ)-induced oxidative stress and pyroptosis in MN9D cells

Upregulation of postsynaptic cAMP/PKA/CREB signaling alleviates copper(Ⅱ)-induced oxidative stress and pyroptosis in MN9D cells

  • Toxicology. 2023 Jun 21;153582. doi: 10.1016/j.tox.2023.153582.
Qian Zhou 1,  Ying Zhang 2,  Lu Lu 3,  Wei Shi 4,  Hu Zhang 5,  Weizhuo Qin 6,  Yucheng Wang 7,  Yuepu Pu 8,  Lihong Yin 9
Affiliations

Affiliations

  • 1 Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
  • 2 Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
  • 3 Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
  • 4 Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
  • 5 Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
  • 6 Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
  • 7 Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
  • 8 Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
  • 9 Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China. Electronic address: [email protected].
PMID: 37353053 DOI: 10.1016/j.tox.2023.153582
Abstract

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 CuSO4 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 48hours 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.

Keywords

Copper(Ⅱ); MN9D cell; cAMP/PKA/CREB; oxidative stress; pyroptosis.

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