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...
Autores principales: | , , , , , , |
---|---|
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 |