Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model

  1. Satoru M Sato
  2. Catherine S Woolley  Is a corresponding author
  1. Northwestern University, United States

Abstract

Status epilepticus (SE) is a common neurological emergency for which new treatments are needed. In vitro studies suggest a novel approach to controlling seizures in SE: acute inhibition of estrogen synthesis in the brain. Here, we show in rats that systemic administration of an aromatase (estrogen synthase) inhibitor after seizure onset strongly suppresses both electrographic and behavioral seizures induced by kainic acid (KA). We found that KA-induced SE stimulates synthesis of estradiol (E2) in the hippocampus, a brain region commonly involved in seizures and where E2 is known to acutely promote neural activity. Hippocampal E2 levels were higher in rats experiencing more severe seizures. Consistent with a seizure-promoting effect of hippocampal estrogen synthesis, intra-hippocampal aromatase inhibition also suppressed seizures. These results reveal neurosteroid estrogen synthesis as a previously unknown factor in the escalation of seizures and suggest that acute administration of aromatase inhibitors may be an effective treatment for SE.

Article and author information

Author details

  1. Satoru M Sato

    Department of Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Catherine S Woolley

    Department of Neurobiology, Northwestern University, Evanston, United States
    For correspondence
    cwoolley@northwestern.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Gary L Westbrook, Vollum Institute, United States

Ethics

Animal experimentation: All animal procedures were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the Northwestern University Animal Care and Use Committee. Animal Study Protocol IS00000520 (expires 6/26/2017)Animal Welfare Assurance A3283-01

Version history

  1. Received: November 8, 2015
  2. Accepted: April 11, 2016
  3. Accepted Manuscript published: April 15, 2016 (version 1)
  4. Accepted Manuscript updated: April 18, 2016 (version 2)
  5. Version of Record published: May 10, 2016 (version 3)
  6. Version of Record updated: July 1, 2016 (version 4)

Copyright

© 2016, Sato & Woolley

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,350
    Page views
  • 622
    Downloads
  • 58
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Satoru M Sato
  2. Catherine S Woolley
(2016)
Acute inhibition of neurosteroid estrogen synthesis suppresses status epilepticus in an animal model
eLife 5:e12917.
https://doi.org/10.7554/eLife.12917

Share this article

https://doi.org/10.7554/eLife.12917

Further reading

    1. Neuroscience
    Daichi Sasaki, Ken Imai ... Ko Matsui
    Research Article

    The presence of global synchronization of vasomotion induced by oscillating visual stimuli was identified in the mouse brain. Endogenous autofluorescence was used and the vessel ‘shadow’ was quantified to evaluate the magnitude of the frequency-locked vasomotion. This method allows vasomotion to be easily quantified in non-transgenic wild-type mice using either the wide-field macro-zoom microscopy or the deep-brain fiber photometry methods. Vertical stripes horizontally oscillating at a low temporal frequency (0.25 Hz) were presented to the awake mouse, and oscillatory vasomotion locked to the temporal frequency of the visual stimulation was induced not only in the primary visual cortex but across a wide surface area of the cortex and the cerebellum. The visually induced vasomotion adapted to a wide range of stimulation parameters. Repeated trials of the visual stimulus presentations resulted in the plastic entrainment of vasomotion. Horizontally oscillating visual stimulus is known to induce horizontal optokinetic response (HOKR). The amplitude of the eye movement is known to increase with repeated training sessions, and the flocculus region of the cerebellum is known to be essential for this learning to occur. Here, we show a strong correlation between the average HOKR performance gain and the vasomotion entrainment magnitude in the cerebellar flocculus. Therefore, the plasticity of vasomotion and neuronal circuits appeared to occur in parallel. Efficient energy delivery by the entrained vasomotion may contribute to meeting the energy demand for increased coordinated neuronal activity and the subsequent neuronal circuit reorganization.