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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00351

Proenkephalin Derived Peptides are Involved in the Modulation of Mitochondrial Respiratory Control During Epileptogenesis

  • 1Innsbruck Medical University, Austria
  • 2Università degli Studi di Padova, Italy
  • 3Istituto Veneto di Medicina Molecolare (VIMM), Italy
  • 4Oroboros Instruments, Austria

Epilepsies are a group of common neurological diseases exerting a strong burden on patients and society, often lacking clear etiology and effective therapeutical strategies. Early intervention during the development of epilepsy (epileptogenesis) is of great medical interest, though hampered by poorly characterized epileptogenetic processes.
Using the intrahippocampal kainic acid mouse model of temporal lobe epilepsy, we investigated the functional role of the endogenous opioid enkephalin during epileptogenesis. We addressed 3 sequential questions: (1) How does enkephalin affect seizure threshold and how is it regulated during epileptogenesis? (2) Does enkephalin influence detrimental effects during epileptogenesis? (3) How is enkephalin linked to mitochondrial function during epileptogenesis?
In contrast to other neuropeptides, the expression of enkephalin is not regulated in a seizure dependent manner. The pattern of regulation, and enkephalin’s proconvulsive effects suggested it as a potential driving force in epileptogenesis. Surprisingly, enkephalin deficiency aggravated progressive granule cell dispersion in kainic acid induced epileptogenesis. Based on reported beneficial effects of enkephalin on mitochondrial function in hypoxic/ischemic states, we hypothesized that enkephalin may be involved in the adaptation of mitochondrial respiration during epileptogenesis. Using high-resolution respirometry, we observed dynamic improvement of hippocampal mitochondrial respiration after kainic acid-injections in wild-type, but not in enkephalin-deficient mice. Thus, wild-type mice displayed higher efficiency in the use of mitochondrial capacity as compared to enkephalin-deficient mice.
Our data demonstrate a Janus-headed role of enkephalin in epileptogenesis. In naive mice, enkephalin facilitates seizures, but in subsequent stages it contributes to neuronal survival through improved mitochondrial respiration.

Keywords: Mitochondria, High-resolution respirometry, enkephalin, delta opioid receptor, Granule cell dispersion

Received: 30 May 2018; Accepted: 07 Sep 2018.

Edited by:

Albert Quintana, Autonomous University of Barcelona, Spain

Reviewed by:

Nuno Raimundo, Universitätsmedizin Göttingen, Germany
Edward H. Beamer, Royal College of Surgeons in Ireland, Ireland  

Copyright: © 2018 Burtscher, Bean, Zangrandi, Kmiec, Agostinho, Scorrano, Gnaiger and Schwarzer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Christoph Schwarzer, Innsbruck Medical University, Innsbruck, Austria,