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Soluble Epoxide Hydrolase Deficiency or Inhibition Attenuates MPTP-Induced Parkinsonism

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Abstract

Soluble epoxide hydrolase (sEH) inhibition has been demonstrated to have beneficial effects on various diseases, such as hypertension, diabetes, and brain ischemia. However, whether sEH inhibition has therapeutic potential in Parkinson’s disease is still unknown. In this paper, we found that sEH expression is increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-treated mice, and sEH deficiency and inhibition significantly attenuated tyrosine hydroxylase (TH)-positive cell loss and improved rotarod performance. The substrate of sEH, 14,15-epoxyeicosatrienoic acid (14,15-EET), protected TH-positive cells and alleviated the rotarod performance deficits of wild-type mice but not sEH-knockout mice. Moreover, the 14,15-EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) abolished the neuronal protective effects of sEH deficiency. In primary cultured cortical neurons, MPP+ induced significant Akt inactivation in neurons from sEH wild-type mice, and this effect was not observed in neurons from knockout mice. Our data indicate that sEH deficiency and inhibition increased 14,15-EET in MPTP-treated mice, which activated the Akt-mediated protection of TH-positive neurons and behavioral functioning. We also found that sEH deficiency attenuated TH-positive cell loss in a paraquat-induced mouse model of Parkinson’s. Our data suggest that sEH inhibition might be a powerful tool to protect dopaminergic neurons in Parkinson’s disease.

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Acknowledgments

We thank Dr. Bruce D. Hammock for kindly providing the sEH antibody. This work was supported by the National Natural Science Foundation of China (81071016), the Program for New Century Excellent Talents in University (NCET-12-0647), the Key Project of Guangdong Province (CXZD1018), and the Program for Changjiang Scholars and the Innovative Research Team in University (IRT1142). The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Neurobiology, Southern Medical University, Guangzhou, Guangdong Province, China

    Xiaocui Qin, Qiaoqi Wu, Lifang Lin, Shuhu Liu, Xiaowen Li, Xiong Cao, Tianming Gao, Xinhong Zhu & Xuemin Wang

  2. Department of Radiology, Southern Medical University, Guangzhou, Guangdong Province, China

    Aimin Sun

  3. Huangshi Central Hospital, Hubei Polytechnic University, Hubei Province, China

    Pengcheng Luo

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  1. Xiaocui Qin
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  2. Qiaoqi Wu
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  3. Lifang Lin
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  4. Aimin Sun
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  5. Shuhu Liu
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  9. Pengcheng Luo
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  11. Xuemin Wang
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Correspondence to Xuemin Wang.

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Xiaocui Qin and Qiaoqi Wu contributed equally to this work.

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Qin, X., Wu, Q., Lin, L. et al. Soluble Epoxide Hydrolase Deficiency or Inhibition Attenuates MPTP-Induced Parkinsonism. Mol Neurobiol 52, 187–195 (2015). https://doi.org/10.1007/s12035-014-8833-3

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  • DOI: https://doi.org/10.1007/s12035-014-8833-3

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