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Future Pharmacology
Volume 5
Issue 2
10.3390/futurepharmacol5020025
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

KRM-II-81, a β3-Preferring GABAA Receptor Potentiator, Blocks Handling-Induced Seizures in Theiler’s Murine Encephalomyelitis Virus-Infected Mice

by
Dishary Sharmin
1,
Kamal P. Pandey
1,
Lalit K. Golani
1,2,
Sepideh Rezvanian
1,
Md Yeunus Mian
1,
Janet L. Fisher
3,
Arnold Lippa
4,
James M. Cook
1,4,
Daniel P. Radin
4,
Jodi L. Smith
5,
Jeffrey M. Witkin
1,4,5,
Hana Shafique
6 and
Rok Cerne
4,5,7,*
1
Department of Chemistry & Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA
2
Department of Chemistry and Chemical Biology, Neglected Diseases Laboratory Northeastern University, Boston, MA 02115, USA
3
Department of Pharmacology, Physiology & Neuroscience, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
4
RespireRx Pharmaceuticals Inc., Glen Rock, NJ 07452, USA
5
Laboratory of Antiepileptic Drug Discovery, Ascension St. Vincent, Indianapolis, IN 46260, USA
6
School of Medicine, Duke University, Durham, NC 27710, USA
7
Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
*
Author to whom correspondence should be addressed.
Future Pharmacol. 2025, 5(2), 25; https://doi.org/10.3390/futurepharmacol5020025
Submission received: 14 March 2025 / Revised: 16 May 2025 / Accepted: 23 May 2025 / Published: 30 May 2025
Versions Notes

Abstract

Background: The GABAA receptor (GABAAR) potentiator, KRM-II-81, is being developed as a novel antiseizure medication with reduced potential for sedation, tolerance development, and abuse liability. Although KRM-II-81 has been shown to provide antiseizure protection against a broad array of seizure induction paradigms, seizures induced by viral vectors have not been previously studied. GABAARs with specific α subunit compositions have been studied in relation to the reduced side-effect liability of KRM-II-81; however, the role of β subunit composition has yet to be determined. Methods: In the present study, KRM-II-81 was studied against handling-induced seizures in Theiler’s murine encephalomyelitis virus (TMEV)-infected mice. Results: An intracerebral infusion of TMEV on day 0 increased the cumulative seizure burden in mice when assessed for handling-induced seizures on days 3–7. KRM-II-81 (15 mg/kg, p.o., bid) nearly completely suppressed seizures in TMEV-infected mice over the course of daily treatments. The number of the most severe seizures (stage 5, tonic/clonic seizures) in the mice was suppressed to zero by KRM-II-81. Although the selectivity of KRM-II-81 for GABAAR α2/3 receptor subtypes might imbue KRM-II-81 with a reduced side-effect liability, other mechanisms are possible, and the potentiation of β1-containing GABAARs has been implicated in inducing sedation. The role of β subunit composition has yet to be determined for KRM-II-81. In electrophysiological studies with cells transfected with αxβ1γ2 or αxβ3γ2, KRM-II-81 preferentially potentiated GABA responses in cells containing β3 subunits in α2/3-containing GABAARs. Conclusions: The present findings confirm the robust antiseizure activity of KRM-II-81, now extended to a virus-induction model, and suggest a possible role of reduced β1-potentiation in the low side-effect profile of KRM-II-81.
Keywords: Theiler’s murine encephalomyelitis virus; seizures; KRM-II-81; GABA; sedation; β subunit; mice Theiler’s murine encephalomyelitis virus; seizures; KRM-II-81; GABA; sedation; β subunit; mice

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MDPI and ACS Style

Sharmin, D.; Pandey, K.P.; Golani, L.K.; Rezvanian, S.; Mian, M.Y.; Fisher, J.L.; Lippa, A.; Cook, J.M.; Radin, D.P.; Smith, J.L.; et al. KRM-II-81, a β3-Preferring GABAA Receptor Potentiator, Blocks Handling-Induced Seizures in Theiler’s Murine Encephalomyelitis Virus-Infected Mice. Future Pharmacol. 2025, 5, 25. https://doi.org/10.3390/futurepharmacol5020025

AMA Style

Sharmin D, Pandey KP, Golani LK, Rezvanian S, Mian MY, Fisher JL, Lippa A, Cook JM, Radin DP, Smith JL, et al. KRM-II-81, a β3-Preferring GABAA Receptor Potentiator, Blocks Handling-Induced Seizures in Theiler’s Murine Encephalomyelitis Virus-Infected Mice. Future Pharmacology. 2025; 5(2):25. https://doi.org/10.3390/futurepharmacol5020025

Chicago/Turabian Style

Sharmin, Dishary, Kamal P. Pandey, Lalit K. Golani, Sepideh Rezvanian, Md Yeunus Mian, Janet L. Fisher, Arnold Lippa, James M. Cook, Daniel P. Radin, Jodi L. Smith, and et al. 2025. "KRM-II-81, a β3-Preferring GABAA Receptor Potentiator, Blocks Handling-Induced Seizures in Theiler’s Murine Encephalomyelitis Virus-Infected Mice" Future Pharmacology 5, no. 2: 25. https://doi.org/10.3390/futurepharmacol5020025

APA Style

Sharmin, D., Pandey, K. P., Golani, L. K., Rezvanian, S., Mian, M. Y., Fisher, J. L., Lippa, A., Cook, J. M., Radin, D. P., Smith, J. L., Witkin, J. M., Shafique, H., & Cerne, R. (2025). KRM-II-81, a β3-Preferring GABAA Receptor Potentiator, Blocks Handling-Induced Seizures in Theiler’s Murine Encephalomyelitis Virus-Infected Mice. Future Pharmacology, 5(2), 25. https://doi.org/10.3390/futurepharmacol5020025

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