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Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: A putative mechanism of antiseizure action
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Department of Neuroscience, The Nobel Institute for Neurophysiology, Karolinska Institutet Karolinska Institutet, Stockholm.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0001-8493-0114
Department of Child Neurology, Astrid Lindgren Children¿s Hospital Karolinska Hospital, Stockholm.
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2008 (English)In: Epilepsy Research, ISSN 0920-1211, E-ISSN 1872-6844, Vol. 80, no 1, 57-66 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Many children with epilepsy do not satisfactorily respond to conventional pharmacological therapy, but to the ketogenic diet, a high-fat, low-carbohydrate diet. This diet increases the concentrations of ketone bodies and polyunsaturated fatty acids (PUFAs) in cerebrospinal fluid (CSF) and plasma. However, its anticonvulsant mechanism is not known. Methods: To investigate the mechanism by which the diet protects against seizures, we studied the effects of several PUFAs (docosahexaenoic acid, eicosapentaenoic acid, and linoleic acid), ketone bodies (β-hydroxybuturic acid and acetoacetic acid), and CSF from patients on the ketogenic diet on the voltage-gated Shaker K channel expressed in Xenopus oocytes. Results: We found that PUFAs at concentrations down to 21 μM clearly increased the K current by shifting the conductance versus voltage curve in negative direction along the voltage axis. CSF from patients on the ketogenic diet has similar but smaller effects. In contrast, high concentrations (1-5 mM) of ketone bodies did not affect the K current. Computer simulations showed that the observed shifts for clinically relevant concentrations of PUFAs, and CSF from patients could effectively impair repetitive firing. Conclusions: These data suggest that the ketogenic diet could prevent epileptic seizures by PUFA-induced openings of voltage-gated K channels. © 2008 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
2008. Vol. 80, no 1, 57-66 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-43176DOI: 10.1016/j.eplepsyres.2008.03.013Local ID: 72319OAI: diva2:264035
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2013-09-03Bibliographically approved
In thesis
1. Polyunsaturated Fatty Acids Modifying Ion Channel Voltage Gating
Open this publication in new window or tab >>Polyunsaturated Fatty Acids Modifying Ion Channel Voltage Gating
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Voltage-gated ion channels play fundamental roles in neuronal excitability and therefore dysfunctional channels can cause disease. Epilepsy is such a disease, affecting about 1% of the population and being characterized by synchronous electric activity of large groups of neurons leading to various types of seizures. In this thesis, polyunsaturated fatty acids (PUFAs) were used as key substances to study a new pharmacological mechanism for how to induce opening of voltage-gated potassium (Kv) channels, and how this possibly can protect against epileptic activity. All experiments were performed on cloned Shaker Kv channels expressed in Xenopus laevis oocytes. Channel activity was recorded with the electrophysiological two-electrode voltage clamp technique.

First we showed that both PUFAs and cerebrospinal fluid from children on the ketogenic diet open the Shaker Kv channel by shifting the channel voltage dependence towards more negative voltages, as we would expect for an antiepileptic effect. By testing fatty acids and related compounds with different properties and under different conditions we identified the critical structural components needed for the beneficial effect: a flexible cis-polyunsaturated lipid tail in combination with a negatively charged carboxyl head group. If substituting the negative charge for a positive amine group, channel opening was instead impeded. By mutating and modifying the channel at strategic positions the PUFA-action site was localized to a lipid-exposed surface close to the channel’s voltage sensor. We also showed that PUFAs induce channel opening by electrostatically facilitating a final voltage-sensor movement. The PUFA efficiency is dependent on the channel’s profile of charged residues in the outer end of the voltage sensor. This implies channel-specific effects. Finally, computer simulations demonstrated that small changes in channel voltage dependence can have dramatic effects on cellular excitability.

Both the identified PUFA-action site and the mechanism by which PUFAs induce channel opening are novel and could potentially be very useful in future drug design of compounds targeting neuronal and cardiac excitability. Our work also suggests that PUFA-induced Kv channel opening could be one important component in the ketogenic diet used as alternative epilepsy treatment.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 51 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1235
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-68084 (URN)978-91-7393-204-2 (ISBN)
Public defence
2011-05-06, Linden, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2011-05-10 Created: 2011-05-10 Last updated: 2013-09-03Bibliographically approved

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