AMPA Receptor Modulation Through Medium-Chain Triglycerides and Decanoic Acid Supports Nutritional Intervention in Pediatric Epilepsy

Abstract

Background: Developmental epileptic encephalopathies (DEEs) are often associated with variably severe cognitive and motor impairment and frequent refractory epilepsy, with many children not achieving adequate seizure control via standard antiepileptic medications. The classic ketogenic diet (KD) has proven effective in reducing seizure frequency and/or severity in a category of DEEs and in certain refractory epilepsies of infancy. However, its multifaceted mechanisms, e.g., epigenetic modulation, anti-inflammatory and antioxidative effects, and direct neuronal excitability changes, are balanced by a high burden and low long-term adherence. Medium-chain triglycerides (MCTs), particularly decanoic acid (C10:0), have gained attention in recent years for their potential direct inhibitory action on AMPA receptors, contributing to seizure reduction. Methods: A systematic review was conducted, including articles from January 2000 to January 2025, to explore the potential role of medium-chain triglyceride (MCT) add-on to classic KD and as MCT supplementation in free diets in the management of pediatric drug-resistant epilepsy (DRE). Results: Selected studies show how the action of MCTs, and decanoic acid in particular, is via negative modulation of AMPA receptors, with a positive impact on epileptic seizures. Conclusions: This review discusses the complexities of implementing and sustaining KD in children and presents recent pre-clinical and clinical evidence, including trials where MCTs (often enriched in decanoic acid) serve as an add-on therapy in both ketogenic and free/unrestricted diets. The summarized findings reinforce the therapeutic potential of MCTs, highlighting both the beneficial seizure outcomes and the hurdles that remain to be addressed through future research.

Keywords: AMPA; MCTs; drug-resistant epilepsy; ketogenic diet.

Figure 1

Flowchart of the search and study selection process.

Figure 2

Structural representation of the tetrameric AMPA receptor crystallized with four perampanel molecules (PDB: 5l1f). For clarity, only the protein backbone is shown. Two 4-BCCA molecules have been included by aligning PDB:511f with PDB:6xsr. Four putative binding sites of decanoic acid are highlighted (orange) on the AMPA backbone. Color code: Perampanel (magenta) and 4-BCCA (green) represented by spheres, one of the binding sites of decanoic acid represented as a surface (orange). In the figure, the M1, M2, M3, and M4 helices are highlighted.

Figure 3

Non-competitive modulation of AMPA receptor by decanoic acid.