perampanel and decanoic-acid

The 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.. Using brain tissue resected from children with intractable epilepsy, we recorded the effects of PER and DEC in vitro.. We 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.. This study confirms AMPAR antagonists inhibit epileptiform discharges in brain tissue resected in a wide range of pediatric epilepsies.

Topics: Adolescent; Anticonvulsants; Brain; Child; Child, Preschool; Decanoic Acids; Drug Resistant Epilepsy; Epilepsy; Female; Humans; Male; Nitriles; Patch-Clamp Techniques; Pyridones; Receptors, AMPA; Synaptic Potentials

Perampanel is an adjunctive treatment for epilepsy that works through the direct inhibition of AMPA receptors. The same molecular mechanism has recently been shown for a fatty acid, decanoic acid, prescribed in the medium chain triglyceride ketogenic diet for the treatment of patients with drug-resistant epilepsy. Because each compound has been proposed to act through a distinct AMPA receptor binding site, we predicted that perampanel and decanoic acid would act synergistically against AMPA receptors and, consequently, seizures. Here, we show a synergistic interaction between perampanel and decanoic acid in direct AMPA receptor inhibition, in an ex vivo model of seizure activity, and against seizure-induced activity in human brain slices. These data support a potential role for combination treatment using perampanel and dietary decanoic acid to provide enhanced seizure control.

Topics: Animals; Anticonvulsants; Brain; Decanoic Acids; Dopamine; Dose-Response Relationship, Drug; Drug Synergism; Evoked Potentials; Hippocampus; Humans; In Vitro Techniques; Nitriles; Oocytes; Pentylenetetrazole; Pyridones; Rats; Receptors, AMPA; Xenopus