Brain tumour-related epilepsy (BTRE) affects between 20-80% of patients with gliomas and is often resistant to typical anti-seizure medication (ASMs). Overactivity of glutamatergic signaling in the peritumoral region contributes to neuronal hyperexcitability and seizures in patients. Moreover, this activity further promotes the growth of tumours. AMPA receptors (AMPARs) mediate most of the excitatory synaptic transmission, and are regulated by Transmembrane AMPA Receptor Regulatory Proteins (TARPs). Among these, TARP γ8 is found in hippocampal and cortical networks that are frequently involved in glioma-related seizures. Recently, novel TARP-selective inhibitors such as JNJ55511118 and LY3130481 have demonstrated anti-seizure effects by selectively decreasing γ8-containing AMPA receptor activity, reducing excitatory activity without disrupting normal brain function. Furthermore, it has been demonstrated that the medium-chain fatty acid decanoic acid, which is a crucial part of the ketogenic diet, inhibits AMPA receptor-mediated currents and provides seizure protection without requiring ketosis. TARP inhibition and decanoic acid may therefore decrease seizures in patients with brain tumour-related epilepsy. The purpose of this project is to evaluate how well decanoic acid and TARP inhibitors (JNJ55511118 and LY3130481) work together to regulate epileptic activity in ex vivo human peritumoral brain slices.
