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Soluble Epoxide Hydrolase Inhibition Attenuates Excitotoxicity Involving 14,15-Epoxyeicosatrienoic Acid–Mediated Astrocytic Survival and Plasticity to Preserve Glutamate Homeostasis

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A Correction to this article was published on 18 July 2019

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Abstract

Astrocytes play pivotal roles in regulating glutamate homeostasis at tripartite synapses. Inhibition of soluble epoxide hydrolase (sEHi) provides neuroprotection by blocking the degradation of 14,15-epoxyeicosatrienoic acid (14,15-EET), a lipid mediator whose synthesis can be activated downstream from group 1 metabotropic glutamate receptor (mGluR) signaling in astrocytes. However, it is unclear how sEHi regulates glutamate excitotoxicity. Here, we used three primary rat cortical culture systems, neuron-enriched (NE), astrocyte-enriched glia-neuron mix (GN), and purified astrocytes, to delineate the underlying mechanism by which sEHi and 14,15-EET attenuate excitotoxicity. We found that sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) and 14,15-EET both attenuated N-methyl-D-aspartate (NMDA)-induced neurite damage and cell death in GN, not NE, cortical cultures. The anti-excitotoxic effects of 14,15-EET and AUDA were both blocked by the group 1 mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), as were their protective effects against NMDA-disrupted perineuronal astrocyte processes expressing glutamate transporter-1 (GLT-1) and subsequent glutamate uptake. Knockdown of sEH expression also attenuated NMDA neurotoxicity in mGluR5- and GLT-1-dependent manners. The 14,15-EET/AUDA-preserved astroglial integrity was confirmed in glutamate-stimulated primary astrocytes along with the reduction of the c-Jun N-terminal kinase 1 phosphorylation, in which the 14,15-EET effect is mGluR5-dependent. In vivo studies validated that sEHi and genetic deletion of sEH (Ephx2-KO) ameliorated excitotoxic kainic acid-induced seizure, memory impairment, and neuronal loss while preserving GLT-1-expressing perineuronal astrocytes in hippocampal CA3 subregions. These results suggest that 14,15-EET mediates mGluR5-dependent anti-excitotoxicity by protecting astrocytes to maintain glutamate homeostasis, which may account for the beneficial effect of sEH inhibition in excitotoxic brain injury and diseases.

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  • 18 July 2019

    The original version of this article unfortunately contained a mistake. The authors observed inadvertent error in Fig. 7d, in which the image of the GFAP/DAPI in the WT saline treated mice was rotated left 90-degree by mistake. The corrected representative image is given below.

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Acknowledgments

We thank Drs. Anya Maan-Yuh Lin, I-Hui Lee, Hui-Ching Lin, Pei-Chun Wu, and Yeh-Shiu Chu for critical comments and suggestions; Prof. Ming-Yen Cheng at Department of Mathematics, Hong Kong Baptist University for verifying the statistical analysis; Su-Pei Hsu and Wan-Ci Chen for technical assistance; and the technical services provided by Imaging Core Facility of Nanotechnology of the UST-YMU, Taiwan.

Funding

This work was supported by grants from the Anesthesiology Research and Development Foundation (ARDF10503), the Ministry of Science and Technology (MOST103-2321-B-010-011, 105-2320-B-400-001), and the Brain Research Center, National Yang-Ming University (107BRC-B405, 108BRC-B404) from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan.

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Authors and Affiliations

  1. Department and Institute of Physiology, National Yang-Ming University, 155 Sec. 2, Linong Street, Taipei, 11221, Taiwan

    Yi-Min Kuo, Pei-Chien Hsu, Chia-Chi Hung, Ya-Yu Hu, Yu-Jie Huang, Yu-Ling Gan & Yi-Hsuan Lee

  2. Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan

    Yi-Min Kuo, Wen-Kuei Chang & Mei-Yung Tsou

  3. Brain Research Center, National Yang-Ming University, Taipei, Taiwan

    Pei-Chien Hsu, Lung-Sen Kao & Yi-Hsuan Lee

  4. Department of Nursing, Kang-Ning University, Taipei, Taiwan

    Chun-Hua Lin

  5. Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan

    Feng-Shiun Shie

  6. Department of Life Sciences and Institute of Genomic Sciences, National Yang-Ming University, Taipei, Taiwan

    Lung-Sen Kao

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  1. Yi-Min Kuo
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Contributions

YMK, PCH, CCH, YYH, CHL, YJH, and YHL performed the experiments and analyzed the data; YMK, PCH, CCH, YYH, LSK, and YHL designed the experiments; YMK and YHL wrote the manuscript; FSS, WKC, MYT, and LSK commented on and proofread the manuscript.

Corresponding author

Correspondence to Yi-Hsuan Lee.

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Ethical Approval

All the procedures with animals were approved by the Experimental Animal Review Committee at National Yang-Ming University (Taipei, Taiwan). IACUC no.: 1060108. Animal care was performed in compliance and according to the guidelines of IACUC and the Guide for the Care and Use of Laboratory Animals of the National Institute of Health (USA) regarding the care and use of animals for experimental procedures.

Conflict of Interest

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Kuo, YM., Hsu, PC., Hung, CC. et al. Soluble Epoxide Hydrolase Inhibition Attenuates Excitotoxicity Involving 14,15-Epoxyeicosatrienoic Acid–Mediated Astrocytic Survival and Plasticity to Preserve Glutamate Homeostasis. Mol Neurobiol 56, 8451–8474 (2019). https://doi.org/10.1007/s12035-019-01669-8

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