Cargando…

Screening of prototype antiseizure and anti‐inflammatory compounds in the Theiler's murine encephalomyelitis virus model of epilepsy

OBJECTIVE: Infection with Theiler's murine encephalomyelitis virus (TMEV) in C57Bl/6J mice results in handling‐induced seizures and is useful for evaluating compounds effective against infection‐induced seizures. However, to date only a few compounds have been evaluated in this model, and a com...

Descripción completa

Detalles Bibliográficos
Autores principales: Metcalf, Cameron S., Vanegas, Fabiola, Underwood, Tristan, Johnson, Kristina, West, Peter J., Smith, Misty D., Wilcox, Karen S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8886069/
https://www.ncbi.nlm.nih.gov/pubmed/34668659
http://dx.doi.org/10.1002/epi4.12550
_version_ 1784660570338754560
author Metcalf, Cameron S.
Vanegas, Fabiola
Underwood, Tristan
Johnson, Kristina
West, Peter J.
Smith, Misty D.
Wilcox, Karen S.
author_facet Metcalf, Cameron S.
Vanegas, Fabiola
Underwood, Tristan
Johnson, Kristina
West, Peter J.
Smith, Misty D.
Wilcox, Karen S.
author_sort Metcalf, Cameron S.
collection PubMed
description OBJECTIVE: Infection with Theiler's murine encephalomyelitis virus (TMEV) in C57Bl/6J mice results in handling‐induced seizures and is useful for evaluating compounds effective against infection‐induced seizures. However, to date only a few compounds have been evaluated in this model, and a comprehensive study of antiseizure medications (ASMs) has not yet been performed. Furthermore, as the TMEV infection produces marked neuroinflammation, an evaluation of prototype anti‐inflammatory compounds is needed as well. METHODS: Male C57Bl/6J mice were inoculated with TMEV (day 0) followed by daily administrations of test compounds (day 3‐7) and subsequent handling sessions (day 3‐7). Doses of ASMs, comprising several mechanistic classes, were selected based on previously published data demonstrating the effect of these compounds in reducing seizures in the 6 Hz model of pharmacoresistant seizures. Doses of anti‐inflammatory compounds, comprising several mechanistic classes, were selected based on published evidence of reduction of inflammation or inflammation‐related endpoints. RESULTS: Several prototype ASMs reduced acute seizures following TMEV infection: lacosamide, phenytoin, ezogabine, phenobarbital, tiagabine, gabapentin, levetiracetam, topiramate, and sodium valproate. Of these, phenobarbital and sodium valproate had the greatest effect (>95% seizure burden reduction). Prototype anti‐inflammatory drugs celecoxib, dexamethasone, and prednisone also moderately reduced seizure burden. SIGNIFICANCE: The TMEV model is utilized by the Epilepsy Therapy Screening Program (ETSP) as a tool for evaluation of novel compounds. Compounds reducing seizures in the TMEV comprise distinct mechanistic classes, some with mechanisms of action that extend beyond traditional ASMs.
format Online
Article
Text
id pubmed-8886069
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-88860692022-03-04 Screening of prototype antiseizure and anti‐inflammatory compounds in the Theiler's murine encephalomyelitis virus model of epilepsy Metcalf, Cameron S. Vanegas, Fabiola Underwood, Tristan Johnson, Kristina West, Peter J. Smith, Misty D. Wilcox, Karen S. Epilepsia Open Original Articles OBJECTIVE: Infection with Theiler's murine encephalomyelitis virus (TMEV) in C57Bl/6J mice results in handling‐induced seizures and is useful for evaluating compounds effective against infection‐induced seizures. However, to date only a few compounds have been evaluated in this model, and a comprehensive study of antiseizure medications (ASMs) has not yet been performed. Furthermore, as the TMEV infection produces marked neuroinflammation, an evaluation of prototype anti‐inflammatory compounds is needed as well. METHODS: Male C57Bl/6J mice were inoculated with TMEV (day 0) followed by daily administrations of test compounds (day 3‐7) and subsequent handling sessions (day 3‐7). Doses of ASMs, comprising several mechanistic classes, were selected based on previously published data demonstrating the effect of these compounds in reducing seizures in the 6 Hz model of pharmacoresistant seizures. Doses of anti‐inflammatory compounds, comprising several mechanistic classes, were selected based on published evidence of reduction of inflammation or inflammation‐related endpoints. RESULTS: Several prototype ASMs reduced acute seizures following TMEV infection: lacosamide, phenytoin, ezogabine, phenobarbital, tiagabine, gabapentin, levetiracetam, topiramate, and sodium valproate. Of these, phenobarbital and sodium valproate had the greatest effect (>95% seizure burden reduction). Prototype anti‐inflammatory drugs celecoxib, dexamethasone, and prednisone also moderately reduced seizure burden. SIGNIFICANCE: The TMEV model is utilized by the Epilepsy Therapy Screening Program (ETSP) as a tool for evaluation of novel compounds. Compounds reducing seizures in the TMEV comprise distinct mechanistic classes, some with mechanisms of action that extend beyond traditional ASMs. John Wiley and Sons Inc. 2021-11-03 /pmc/articles/PMC8886069/ /pubmed/34668659 http://dx.doi.org/10.1002/epi4.12550 Text en © 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Metcalf, Cameron S.
Vanegas, Fabiola
Underwood, Tristan
Johnson, Kristina
West, Peter J.
Smith, Misty D.
Wilcox, Karen S.
Screening of prototype antiseizure and anti‐inflammatory compounds in the Theiler's murine encephalomyelitis virus model of epilepsy
title Screening of prototype antiseizure and anti‐inflammatory compounds in the Theiler's murine encephalomyelitis virus model of epilepsy
title_full Screening of prototype antiseizure and anti‐inflammatory compounds in the Theiler's murine encephalomyelitis virus model of epilepsy
title_fullStr Screening of prototype antiseizure and anti‐inflammatory compounds in the Theiler's murine encephalomyelitis virus model of epilepsy
title_full_unstemmed Screening of prototype antiseizure and anti‐inflammatory compounds in the Theiler's murine encephalomyelitis virus model of epilepsy
title_short Screening of prototype antiseizure and anti‐inflammatory compounds in the Theiler's murine encephalomyelitis virus model of epilepsy
title_sort screening of prototype antiseizure and anti‐inflammatory compounds in the theiler's murine encephalomyelitis virus model of epilepsy
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8886069/
https://www.ncbi.nlm.nih.gov/pubmed/34668659
http://dx.doi.org/10.1002/epi4.12550
work_keys_str_mv AT metcalfcamerons screeningofprototypeantiseizureandantiinflammatorycompoundsinthetheilersmurineencephalomyelitisvirusmodelofepilepsy
AT vanegasfabiola screeningofprototypeantiseizureandantiinflammatorycompoundsinthetheilersmurineencephalomyelitisvirusmodelofepilepsy
AT underwoodtristan screeningofprototypeantiseizureandantiinflammatorycompoundsinthetheilersmurineencephalomyelitisvirusmodelofepilepsy
AT johnsonkristina screeningofprototypeantiseizureandantiinflammatorycompoundsinthetheilersmurineencephalomyelitisvirusmodelofepilepsy
AT westpeterj screeningofprototypeantiseizureandantiinflammatorycompoundsinthetheilersmurineencephalomyelitisvirusmodelofepilepsy
AT smithmistyd screeningofprototypeantiseizureandantiinflammatorycompoundsinthetheilersmurineencephalomyelitisvirusmodelofepilepsy
AT wilcoxkarens screeningofprototypeantiseizureandantiinflammatorycompoundsinthetheilersmurineencephalomyelitisvirusmodelofepilepsy