Seizure control by ketogenic diet-associated medium chain fatty acids

Pishan Chang,Nicole Terbach,Nick Plant,Philip E Chen,Matthew C Walker,Robin S.B Williams

doi:10.1016/j.neuropharm.2012.11.004

Abstract

The medium chain triglyceride (MCT) ketogenic diet is used extensively for treating refractory childhood epilepsy. This diet increases the plasma levels of medium straight chain fatty acids. A role for these and related fatty acids in seizure control has not been established. We compared the potency of an established epilepsy treatment, Valproate (VPA), with a range of MCT diet-associated fatty acids (and related branched compounds), using in vitro seizure and in vivo epilepsy models, and assessed side effect potential in vitro for one aspect of teratogenicity, for liver toxicology and in vivo for sedation, and for a neuroprotective effect. We identify specific medium chain fatty acids (both prescribed in the MCT diet, and related compounds branched on the fourth carbon) that provide significantly enhanced in vitro seizure control compared to VPA. The activity of these compounds on seizure control is independent of histone deacetylase inhibitory activity (associated with the teratogenicity of VPA), and does not correlate with liver cell toxicity. In vivo, these compounds were more potent in epilepsy control (perforant pathway stimulation induced status epilepticus), showed less sedation and enhanced neuroprotection compared to VPA. Our data therefore implicates medium chain fatty acids in the mechanism of the MCT ketogenic diet, and highlights a related new family of compounds that are more potent than VPA in seizure control with a reduced potential for side effects.This article is part of the Special Issue entitled ‘New Targets and Approaches to the Treatment of Epilepsy’.

Highlights

The medium chain triglyceride (MCT) ketogenic diet has provided one of the most effective therapeutic approaches for children with drug resistant epilepsy (Kossoff et al, 2009; Liu, 2008; Neal et al, 2009; Rho and Stafstrom, 2012; Sills et al, 1986b; Vining et al, 1998)
Since octanoic acid and decanoic acid are elevated in plasma of patients undergoing the MCT ketogenic diet (Haidukewych et al, 1982; Sills et al, 1986a, 1986b), our data supports a possible role for decanoic acid and octanoic acid derivatives in the direct therapeutic mechanism of the diet in seizure control
As a potential mechanism for this, the medium chain triglycerides given in the diet are largely composed of two unbranched fatty acids, and these are found in elevated levels in the plasma of patients on the diet (Haidukewych et al, 1982; Sills et al, 1986a, 1986b)

Summary

Introduction

The medium chain triglyceride (MCT) ketogenic diet has provided one of the most effective therapeutic approaches for children with drug resistant epilepsy (Kossoff et al, 2009; Liu, 2008; Neal et al, 2009; Rho and Stafstrom, 2012; Sills et al, 1986b; Vining et al, 1998). The MCT diet causes a rise in ketone body formation, but this correlates poorly with seizure control (Likhodii et al, 2000; Thavendiranathan et al, 2000) It causes accumulation of medium chain fatty acids in blood plasma (in particular octanoic and decanoic acids, Fig. 1A) (Haidukewych et al, 1982; Newport et al, 1979; Sills et al, 1986a), the role of these fatty acids, if any, in seizure control remains unclear. Fatty acids with structures related to VPA have been associated with significant sedative properties, often preventing translation into clinical trials (Bojic et al, 1996; Keane et al, 1983; Palaty and Abbott, 1995)

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