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

Robert A Rifkin; Xiaoping Wu; Brianna Pereira; Brian Ja Gill; Edward M Merricks; Andrew J Michalak; Alexander R Goldberg; Nelson Humala; Athanassios Dovas; Ganesha Rai; Guy M McKhann; Paul A Slesinger; Peter Canoll; Catherine Schevon

doi:10.1016/j.neuropharm.2024.110259

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

Neuropharmacology. 2025 Mar 1:265:110259. doi: 10.1016/j.neuropharm.2024.110259. Epub 2024 Dec 9.

Authors

Affiliations

¹ Department of Neurology, Columbia University Irving Medical Center, 710 West 168th Street, New York, NY, 10032-3784, USA. Electronic address: [email protected].
² Department of Neurological Surgery, Columbia University Irving Medical Center, 710 West 168th Street, New York, NY, 10032-3784, USA. Electronic address: [email protected].
³ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 630 West 168th Street, Mailbox 23, New York, NY, 10032, USA. Electronic address: [email protected].
⁴ Department of Neurological Surgery, Columbia University Irving Medical Center, 710 West 168th Street, New York, NY, 10032-3784, USA. Electronic address: [email protected].
⁵ Department of Neurology, Columbia University Irving Medical Center, 710 West 168th Street, New York, NY, 10032-3784, USA. Electronic address: [email protected].
⁶ Department of Neurology, New York University Grossman School of Medicine, 222 East 41st Street, 14th Floor New York, NY, 10017, USA. Electronic address: [email protected].
⁷ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 630 West 168th Street, Mailbox 23, New York, NY, 10032, USA. Electronic address: [email protected].
⁸ Department of Neurological Surgery, Columbia University Irving Medical Center, 710 West 168th Street, New York, NY, 10032-3784, USA. Electronic address: [email protected].
⁹ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 630 West 168th Street, Mailbox 23, New York, NY, 10032, USA. Electronic address: [email protected].
¹⁰ National Center for Advancing Translational Sciences, National Institutes of Health, 9609 Medical Center Drive, Rockville, MD, 20850-9793, USA. Electronic address: [email protected].
¹¹ Department of Neurological Surgery, Columbia University Irving Medical Center, 710 West 168th Street, New York, NY, 10032-3784, USA. Electronic address: [email protected].
¹² Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029-5674, USA. Electronic address: [email protected].
¹³ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 630 West 168th Street, Mailbox 23, New York, NY, 10032, USA. Electronic address: [email protected].
¹⁴ Department of Neurology, Columbia University Irving Medical Center, 710 West 168th Street, New York, NY, 10032-3784, USA. Electronic address: [email protected].

PMID: 39662702
DOI: 10.1016/j.neuropharm.2024.110259

Abstract

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.

Keywords: Antiseizure medication; GABA(B) receptor; GIRK; GiGA1; Glioma.

MeSH terms

Animals
Anticonvulsants / pharmacology
Brain Neoplasms* / drug therapy
Brain Neoplasms* / metabolism
Disease Models, Animal
Epilepsy / drug therapy
G Protein-Coupled Inwardly-Rectifying Potassium Channels* / agonists
G Protein-Coupled Inwardly-Rectifying Potassium Channels* / metabolism
Glioma / drug therapy
Male
Mice
Mice, Inbred C57BL
Seizures* / drug therapy
Seizures* / physiopathology

Substances

G Protein-Coupled Inwardly-Rectifying Potassium Channels
Anticonvulsants