Skip to main content
SpringerLink
Log in

Integrative analysis of non-targeted lipidomic data and brain structural imaging identifies phosphatidylethanolamine associated with epileptogenesis

  • Original Article
  • Published:
Metabolomics Aims and scope Submit manuscript

Abstract

Introduction

Epilepsy is a chronic disease, while epileptogenesis is a latent period where brain will be transformed into an epileptic one. Mechanisms of epileptogenesis remain unclear.

Objectives

We aim to provide information of hippocampal lipidomic changes related with epileptogenesis in two kindling models. Combining hippocampal structural imaging indices, our study also attempts to assess biochemical alterations as a function of epileptogenesis in a non-invasive way.

Methods

We constructed two kinds of chemical kindling models, which have long been used as models of epileptogenesis. Two kindling and one control groups were all subjected to structural imaging acquisition after successfully kindled. Voxel-based morphometry, a postprocessing method for brain imaging data, was used to segment and extract hippocampal gray matter volume for subsequent integrative analysis. LC–MS based lipidomic analysis was applied to identify distinct hippocampal lipidomic profiles between kindling and control groups. Further, we regress hippocampal structural indices on lipids to identify those associated with both epileptogenesis and brain structural changes.

Results

We report distinct lipidomic profiles between kindling groups and control. A total of 638 lipids were detected in all three groups. Among them were 98 individual lipids, showing significant alterations, in particular lipid class of phosphatidylethanolamine (PE), glucosylceramide and phosphatidylcholine. Hippocampal gray matter volumes were found significant different between groups (P = 0.0223). After combining brain imaging data, we demonstrate several individual PE, namely PE(O-18:1_22:3), PE(O-18:1_22:6) and PE(18:1_18:1), are associated with both epileptogenesis and hippocampal gray matter volume.

Conclusion

This study suggests metabolic pathway of PE might involve in epileptogenesis. Also, for the first time, we link level of PE with structural brain imaging indices, in an attempt to potentiate the futuristic application of noninvasive brain imaging techniques to identify epileptogenesis in its latent period.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

SM:

Sphinomyelin

GlcCer:

Glucosylceramides

PE:

Phosphatidylethanolamine

PI:

Phosphatidylinositol

PC:

Phosphatidylcholine

PG:

Phosphatidylglycerol

TG:

Triglyceride

PS:

Phosphatidylserine

DG:

Diglyceride

LPI:

Lysophosphatidylinositol

LPC:

Lysophosphatidylcholine

LdMePE:

Lysodi-methylphosphatidylethanolamine

GM1:

Ganglioside

PET:

Positron emission computed tomography

LCMS:

Liquid chromatography couple to mass spectrometry

References

  • Chang, C.-C., & Lin, C.-J. (2011). LIBSVM: A library for support vector machines. ACM Transactions on Intelligent Systems and Technology (TIST), 2, 27.

    Google Scholar 

  • de Freitas, R. M., do Nascimento, K. G., Ferreira, P. M., & Jordan, J. (2010). Neurochemical changes on oxidative stress in rat hippocampus during acute phase of pilocarpine-induced seizures. Pharmacology Biochemistry and Behavior, 94, 341–345.

    Article  Google Scholar 

  • Dhir, A. (2012). Pentylenetetrazol (PTZ) kindling model of epilepsy. Current Protocols in Neuroscience, Chapter 9, Unit9.37.

    PubMed  Google Scholar 

  • Duzel, E., Schiltz, K., Solbach, T., Peschel, T., Baldeweg, T., Kaufmann, J., et al. (2006). Hippocampal atrophy in temporal lobe epilepsy is correlated with limbic systems atrophy. Journal of Neurology, 253, 294–300.

    Article  PubMed  Google Scholar 

  • Goldberg, E. M., & Coulter, D. A. (2013). Mechanisms of epileptogenesis: A convergence on neural circuit dysfunction. Nature Reviews Neuroscience, 14, 337–349.

    Article  CAS  PubMed  Google Scholar 

  • Guan, X. L., He, X., Ong, W. Y., Yeo, W. K., Shui, G., & Wenk, M. R. (2006). Non-targeted profiling of lipids during kainate-induced neuronal injury. The FASEB Journal, 20, 1152–1161.

    Article  CAS  PubMed  Google Scholar 

  • Jenkinson, M., & Smith, S. (2001). A global optimisation method for robust affine registration of brain images. Medical Image Analysis, 5, 143–156.

    Article  CAS  PubMed  Google Scholar 

  • Keller, S. S., Mackay, C. E., Barrick, T. R., Wieshmann, U. C., Howard, M. A., & Roberts, N. (2002). Voxel-based morphometric comparison of hippocampal and extrahippocampal abnormalities in patients with left and right hippocampal atrophy. Neuroimage, 16, 23–31.

    Article  PubMed  Google Scholar 

  • Keller, S. S., Cresswell, P., Denby, C., Wieshmann, U., Eldridge, P., Baker, G., et al. (2007). Persistent seizures following left temporal lobe surgery are associated with posterior and bilateral structural and functional brain abnormalities. Epilepsy Research, 74, 131–139.

    Article  PubMed  Google Scholar 

  • Kliman, M., Vijayakrishnan, N., Wang, L., Tapp, J. T., Broadie, K., & McLean, J. A. (2010). Structural mass spectrometry analysis of lipid changes in a Drosophila epilepsy model brain. Molecular BioSystems, 6, 958–966.

    Article  CAS  PubMed  Google Scholar 

  • Nelson, D. L., & Cox, M. M. (2013). Lehninger principles of biochemistry (6th ed.). New York: W. H. Freeman and Company.

    Google Scholar 

  • Lerner, R., Post, J., Loch, S., Lutz, B., & Bindila, L. (2017). Targeting brain and peripheral plasticity of the lipidome in acute kainic acid-induced epileptic seizures in mice via quantitative mass spectrometry. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1862, 255–267.

    CAS  Google Scholar 

  • Martin, P., Winston, G. P., Bartlett, P., de Tisi, J., Duncan, J. S., & Focke, N. K. (2017). Voxel-based magnetic resonance image postprocessing in epilepsy. Epilepsia, 58, 1653–1664.

    Article  PubMed  Google Scholar 

  • Matyash, V., Liebisch, G., Kurzchalia, T. V., Shevchenko, A., & Schwudke, D. (2008). Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics. Journal of Lipid Research, 49, 1137–1146.

    Article  CAS  PubMed  Google Scholar 

  • Ngugi, A. K., Bottomley, C., Kleinschmidt, I., Sander, J. W., & Newton, C. R. (2010). Estimation of the burden of active and life-time epilepsy: A meta-analytic approach. Epilepsia, 51, 883–890.

    Article  PubMed  Google Scholar 

  • Pavlidis, P., Ramaswami, M., & Tanouye, M. A. (1994). The Drosophila easily shocked gene: A mutation in a phospholipid synthetic pathway causes seizure, neuronal failure, and paralysis. Cell, 79, 23–33.

    Article  CAS  PubMed  Google Scholar 

  • Pitkanen, A., & Lukasiuk, K. (2011). Mechanisms of epileptogenesis and potential treatment targets. The Lancet Neurology, 10, 173–186.

    Article  PubMed  Google Scholar 

  • Pitkanen, A., Lukasiuk, K., Dudek, F. E., & Staley, K. J. (2015). Epileptogenesis. Cold Spring Harbor Perspectives in Medicine, 5, a022822.

    Article  PubMed  Google Scholar 

  • Racine, R. J., Burnham, W. M., Gartner, J. G., & Levitan, D. (1973). Rates of motor seizure development in rats subjected to electrical brain stimulation: Strain and inter-stimulation interval effects. Electroencephalography and Clinical Neurophysiology, 35, 553–556.

    Article  CAS  PubMed  Google Scholar 

  • The, L. (2019). Epilepsy prevention: An urgent global unmet need. Lancet, 393, 2564.

    Google Scholar 

  • Valdes-Hernandez, P. A., Sumiyoshi, A., Nonaka, H., Haga, R., Aubert-Vasquez, E., Ogawa, T., et al. (2011). An in vivo MRI template set for morphometry, tissue segmentation, and fMRI localization in rats. Frontiers in Neuroinformatics, 5, 26.

    Article  PubMed  Google Scholar 

  • Wang, Y., Zhou, D., Wang, B., Li, H., Chai, H., Zhou, Q., et al. (2003). A kindling model of pharmacoresistant temporal lobe epilepsy in Sprague-Dawley rats induced by Coriaria lactone and its possible mechanism. Epilepsia, 44, 475–488.

    Article  PubMed  Google Scholar 

  • Yegin, A., Akbas, S. H., Ozben, T., & Korgun, D. K. (2002). Secretory phospholipase A2 and phospholipids in neural membranes in an experimental epilepsy model. Acta Neurologica Scandinavica, 106, 258–262.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, H., Ren, P., Huang, Y., Zeng, W., Zhong, K., Gao, H., et al. (2020). Untargeted lipidomic analysis of human hippocampus for temporal lobe epilepsy with hippocampal sclerosis. Epilepsy Research, 161, 106299.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We really appreciate Xiangzhe Qiu from School of Life Science and Technology, University of Electronic Science and Technology of China for his help in regression model construction and imaging data preprocess. This study was supported by the National Natural Science Foundation of China (Grant Number: 81871018) and Foundation from Health Commission of Sichuan Province (Grant Number: 18ZD010).

Author information

Authors and Affiliations

  1. Neurology Department, West China Hospital, Sichuan University, No. 37, Guoxue Road, Chengdu, 610041, Sichuan, China

    Xiangmiao Qiu, Wanlin Lai, Anjiao Peng, Wanling Li, Lin Zhang & Lei Chen

  2. West China-Washington Mitochondria and Metabolism Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Lu Zhang, Wen Zheng & Meng Gong

  3. Department of Neurology, National Hospital Organization, Utano National Hospital, Kyoto, Japan

    Masako Kinoshita

  4. Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Linghui Yang

Authors
  1. Xiangmiao Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masako Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wanlin Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anjiao Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wanling Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Linghui Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Meng Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Concept and study design: LC, XQ, MG; Data analyses: LZ, WZ, XQ, LZ; Drafting the initial versions of the manuscript: XQ; Data collection: XQ, LZ, WZ, WL, AP, WL; Supervision: MK, MG, LC, LY; Commenting on draft versions of the manuscript: LZ, MK, WL, WZ, AP, WL, LY, LZ, MG, LC; Final approval of the manuscript: XQ, LZ, MK, WL, WZ, AP, WL, LY, LZ, MG, LC.

Corresponding author

Correspondence to Lei Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests. The manuscript is approved by all authors for publication. The work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed in this study. This study was approved by Animal Ethics Committee of West China Hospital (Approval Code: 2018115A).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 25 kb)

Supplementary file2 (TXT 14963 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Qiu, X., Zhang, L., Kinoshita, M. et al. Integrative analysis of non-targeted lipidomic data and brain structural imaging identifies phosphatidylethanolamine associated with epileptogenesis. Metabolomics 16, 110 (2020). https://doi.org/10.1007/s11306-020-01731-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11306-020-01731-w

Keywords

Search

Navigation