{"doi":"10.3390/futurepharmacol5020025","title":"KRM-II-81, a β3-Preferring GABAA Receptor Potentiator, Blocks Handling-Induced Seizures in Theiler’s Murine Encephalomyelitis Virus-Infected Mice","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.","journal":"Future Pharmacology","year":2025,"id":567372,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":524986,"name":"Kamal Prakash Pandey","orcid":"0000-0002-0723-2264","position":1,"is_corresponding":false},{"id":524988,"name":"Lalit K. Golani","orcid":"0000-0002-6233-7747","position":2,"is_corresponding":false},{"id":525909,"name":"Sepideh Rezvanian","orcid":null,"position":3,"is_corresponding":false},{"id":524989,"name":"Md Yeunus Mian","orcid":"0000-0002-7520-1750","position":4,"is_corresponding":false},{"id":713659,"name":"Janet L. Fisher","orcid":null,"position":5,"is_corresponding":false},{"id":642663,"name":"Arnold Lippa","orcid":"0000-0002-0536-5338","position":6,"is_corresponding":false},{"id":445008,"name":"James M. Cook","orcid":"0000-0001-5512-3022","position":7,"is_corresponding":false},{"id":284465,"name":"Daniel P. Radin","orcid":"0000-0003-3775-7712","position":8,"is_corresponding":false},{"id":477824,"name":"Jodi L. Smith","orcid":"0000-0002-9145-8548","position":9,"is_corresponding":false},{"id":477822,"name":"Jeffrey M. Witkin","orcid":"0000-0002-9048-148X","position":10,"is_corresponding":false},{"id":935673,"name":"Hana Shafique","orcid":"0000-0002-0158-893X","position":11,"is_corresponding":false},{"id":642662,"name":"Rok Cerne","orcid":"0000-0001-9208-6398","position":12,"is_corresponding":false},{"id":524992,"name":"Dishary Sharmin","orcid":"0000-0003-0417-4262","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:56:44.340853Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}