A selective small-molecule agonist of G protein-gated inwardly-rectifying potassium channels reduces epileptiform activity in mouse models of tumor-associated and provoked seizures

Tumor associated epilepsy is a common and debilitating co-morbidity of brain tumors, for which inadequate treatments are available. Additionally, animal models suggest a potential link between seizures and tumor progression. Our group has previously described a mouse model of diffusely infiltrating glioma and associated chronic epilepsy. G protein-gated inwardly rectifying potassium (GIRK) channels are important regulators of neuronal excitability, but their development as a target of antiseizure medications has been hampered by cross-reactivity with GIRK channels in the heart. Recently GiGA1, a novel GIRK agonist that is highly selective for brain tissue, was developed and shown to have antiseizure properties in an acute chemoconvulsant model. Here, we test GiGA1 ex vivo in our established mouse model of tumor associated epilepsy, demonstrating that a highly selective, small-molecule GIRK agonist can reduce seizure-like activity in the peritumoral region, where neurons and glioma cells interact and from which focal seizures arise.