Abstract
ObjectiveThe amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) is increasingly recognized as a therapeutic target in drug‐refractory pediatric epilepsy. Perampanel (PER) is a non‐competitive AMPAR antagonist, and pre‐clinical studies have shown the AMPAR‐mediated anticonvulsant effects of decanoic acid (DEC), a major medium‐chain fatty acid provided in the medium‐chain triglyceride ketogenic diet.MethodsUsing brain tissue resected from children with intractable epilepsy, we recorded the effects of PER and DEC in vitro. ResultsWe found resected pediatric epilepsy tissue exhibits spontaneous epileptic activity in vitro, and showed that DEC and PER inhibit this epileptiform activity in local field potential recordings as well as excitatory synaptic transmission.InterpretationThis study confirms AMPAR antagonists inhibit epileptiform discharges in brain tissue resected in a wide range of pediatric epilepsies.
Highlights
Molecular targets for pediatric epilepsy treatment have largely centered on voltage-gated sodium and calcium channels
Recent studies in epilepsy rodent models have demonstrated the anti-epileptic action of decanoic acid (DEC), a major medium-chain fatty acid provided in the medium-chain triglyceride (MCT) ketogenic diet (KD), is mediated through direct and selective inhibition of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR).[3,4]
This study confirms that AMPAR inhibition, either by DEC or PER, is effective in abolishing spontaneous epileptiform activity in human tissue from drug-resistant pediatric epilepsy patients through a direct reduction in excitatory neurotransmission
Summary
Molecular targets for pediatric epilepsy treatment have largely centered on voltage-gated sodium and calcium channels. The recent introduction of Perampanel (PER), a non-competitive amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist, has introduced the concept of AMPAR modulation as an effective anticonvulsant strategy.[1,2] recent studies in epilepsy rodent models have demonstrated the anti-epileptic action of decanoic acid (DEC), a major medium-chain fatty acid provided in the medium-chain triglyceride (MCT) ketogenic diet (KD), is mediated through direct and selective inhibition of AMPARs.[3,4]. Human tissue samples provide a valuable tool for preclinical drug screening and mechanism-of-action epilepsy studies.[5] This is useful in pediatrics, where few anticonvulsant drug trials include children and adult study results are often extrapolated to children with pediatricians prescribing “off-label”.6. We show that antagonism of AMPAR has a profound anticonvulsant effect in tissue derived from a spectrum of difficultto-treat seizure syndromes
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