KRM-II-81 suppresses epileptifom activity across the neural network of cortical tissue from a patient with pharmacoresistant epilepsy

Jodi L Smith; Jeremy Wertz; Arnold Lippa; Xingjie Ping; Xiaoming Jin; James M Cook; Jeffrey M Witkin; Rok Cerne

doi:10.1016/j.heliyon.2023.e23752

KRM-II-81 suppresses epileptifom activity across the neural network of cortical tissue from a patient with pharmacoresistant epilepsy

Heliyon. 2023 Dec 16;10(1):e23752. doi: 10.1016/j.heliyon.2023.e23752. eCollection 2024 Jan 15.

Authors

Jodi L Smith¹, Jeremy Wertz², Arnold Lippa³, Xingjie Ping⁴, Xiaoming Jin⁴, James M Cook^{3

5}, Jeffrey M Witkin^{1

3

5}, Rok Cerne^{1

3

4

6}

Affiliations

¹ Laboratory of Antiepileptic Drug Discovery, Ascension St. Vincent, Indianapolis, IN, USA.
² Specialty Care, Indianapolis, IN, USA.
³ RespireRx Pharmaceuticals Inc, Glen Rock, NJ, USA.
⁴ Department of Anatomy and Cell Biology, Indiana University/Purdue University, Indianapolis, IN, USA.
⁵ Department of Chemistry & Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
⁶ Faculty of Medicine, University of Ljubljana, Zaloška cesta 4, Ljubljana, Slovenia.

Abstract

A clinical case of a 19-year-old male patient with pharmacoresistant seizures occurring following parieto-occipital tumor-resection at age 6 is described. Seizure surgery work-up included prolonged video EEG monitoring and head CT without contrast. Seizure focus was localized to the left temporal lobe, and we felt that the patient was an excellent candidate for seizure surgery. The patient underwent a left frontotemporal craniotomy for removal of the seizure focus with intraoperative electrocorticography (ECoG) conducted pre and post resection. ECoG recordings pre- and post-resection confirmed resolution of seizure generation. Imaging obtained immediately postoperatively showed complete resection of the residual tumor with no evidence of recurrence in follow-ups. A year after the surgery the patient is seizure-free but remains on seizure medication. With the patient's consent the excised epileptogenic tissue was used for ex-vivo research studies. The microelectrode recordings confirmed epileptiform activity in the excised tissue incubated in excitatory artificial cerebrospinal fluid. The epileptiform activity in the epileptogenic tissue was suppressed by addition of KRM-II-81, a novel α2/3 subtype preferring GABA_A receptor (GABAAR) potentiator with previously demonstrated antiepileptic efficacy in multiple animal models of epilepsy and with reduced potential for CNS side-effects compared to classical benzodiazepine GABAAR potentiators. These findings support the proposition that KRM-II-81 might reduce seizure burden in pharmacoresistant patients.

Keywords: GABA-PAM; GABAA receptor; Pharmacoresistant; Seizure; Subtype preferring.