Aggravated behavioral and neurochemical deficits and redox imbalance in mice with enhanced neonatal iron intake: improvement by biochanin A and role of microglial p38 activation

ABSTRACT

Objectives: We aim to investigate the joint effect of iron (enhanced neonatal iron intake), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and biochanin A (BA, oral administration) and possible mechanisms for action on behavioral and neurochemical indicators in the mice.

Methods: Rotarod test, pole test and swim test were used to evaluate animal behavior. The neurochemical analysis was conducted by HPLC-ECD. Oxidative stress was determined in this study. Further mechanism was investigated through in vitro experiments.

Results: Iron and MPTP co-administration significantly induced behavioral deficits and decreased striatal dopamine content in the male and female mice. The co-administration of iron and MPTP also significantly induced redox imbalance in the substantia nigra (SN) of mice. Furthermore, BA significantly improved behavioral deficits and increased striatal dopamine content in the mice co-treated with iron and MPTP. BA also significantly improved redox imbalance in the SN of mice co-administered with iron and MPTP. Finally, we showed that iron and 1-Methyl-4-phenylpyridinium (MPP⁺) co-treatment significantly increased superoxide production in microglial cultures by inducing p38 mitogen-activated protein kinase (MAPK) activation. BA also significantly decreased superoxide production and p38 MAPK phosphorylation in the cultures co-treated with iron and MPP⁺.

Conclusion: Iron and MPTP co-treatment may result in worsened behavioral and neurochemical deficits and aggravated redox imbalance through inducing microglial p38 MAPK activation. BA may improve behavioral and neurochemical deficits and redox imbalance through repressing microglial p38 MAPK activation.

KEYWORDS:

• Neonatal iron intake
• biochanin A
• redox balance
• microglia
• p38 mitogen-activated protein kinase

Acknowledgements

Contributors: XJW conceived the research and designed the experiments. YHL, YL, YLX, HQC, ZQY, and XJW performed the experiments and collected the results. YHL, YL, YLX and XJW statistically analyzed the data. YHL, YL, YLX and XJW interpreted the results. YHL and XJW wrote the manuscript. All the authors critically reviewed the manuscript and approved the final submitted manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes on contributors

Yunhong Li is pursuing a master's degree at Shanghai Jiao Tong University School of Medicine, Shanghai, China. She is focused on studying the pathogenesis and therapy of Parkinson's disease.

Ying Liu is pursuing a master's degree at Shanghai Jiao Tong University School of Medicine, Shanghai, China. She is focused on studying the pathogenesis and therapy of Parkinson's disease.

Yaling Xu is pursuing a master's degree at Shanghai Jiao Tong University School of Medicine, Shanghai, China. She is focused on studying the pathogenesis and therapy of Parkinson's disease.

Hanqing Chen is a Professor of the School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei, China. He is focused on studying the pathogenesis and therapy of Parkinson's disease.

Zhiqiang Yan is an associate professor of Shanghai Laboratory Animal Center, Chinese Academy of Sciences, Shanghai, China. He is focused on studying the pathogenesis and therapy of Parkinson's disease.

Xijin Wang is a Professor of the Department of Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. He is focused on studying the pathogenesis and therapy of Parkinson's disease.

Ethics approval

This study was carried out according to the guidelines of the National Institutes of Health (publication No. 80-23), and all the animal protocols were approved by the Institutional Animal Care and Use Committee of Shanghai Jiao-Tong University School of Medicine (SJTUSM IACUC). All procedures in this study were approved by the Institutional Review Board of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine (Approval No. XHEC-F-2016-209, the date that the research proposal was approved: March 7th, 2016). All efforts were aimed to minimize animal suffering in the experiments.

Additional information

Funding

This work was supported by the Projects of the National Natural Science Foundation of China [grant number 81671273], [grant number 81171204], [grant number 30772280], [grant number 81400925], [grant number 81471148], [grant number 81771211], [grant number 81703852]; the Project of Shanghai Municipal Education Commission of China [grant number 14YZ046]; the Project of Shanghai Municipal Health and Family Planning Commission of China [grant number 20134049], the Project of Shanghai Jiao Tong University of China [grant number YG2013MS22]; the Project of National Eastern Tech-transfer Center [grant number 201713972877]; the Projects of Shanghai Committee of Science and Technology [grant number 17401901000]; National Key R&D Program of China [grant number 2017YFC1310300]; SHSMU-ION Research Center for Brain Disorders [grant number 2015NKX007].