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Neurotherapeutics
Published in: Neurotherapeutics 3/2023

01-04-2023 | Central Nervous System Trauma | Original Article

Acute Treatment with the M-Channel (Kv7, KCNQ) Opener Retigabine Reduces the Long-Term Effects of Repetitive Blast Traumatic Brain Injuries

Authors: Fabio A. Vigil, Hindiael Belchior, Vladislav Bugay, Isabella I. Bazaldua, Aiola Stoja, Denise C. Dantas, Sang H. Chun, Austin Farmer, Eda Bozdemir, Deborah M. Holstein, Jose E. Cavazos, James D. Lechleiter, Robert Brenner, Mark S. Shapiro

Published in: Neurotherapeutics | Issue 3/2023

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Abstract

We investigated whether pharmacological increase of “M-type” (KCNQ, Kv7) K + channel currents by the M-channel opener, retigabine (RTG), acutely after repetitive traumatic brain injuries (rTBIs), prevents or reduces their long-term detrimental effects. rTBIs were studied using a blast shock air wave mouse model. Animals were monitored by video and electroencephalogram (EEG) records for nine months after the last injury to assess the occurrence of post-traumatic seizures (PTS), post-traumatic epilepsy (PTE), sleep–wake cycle architecture alterations, and the power of the EEG signals. We evaluated the development of long-term changes in the brain associated with various neurodegenerative diseases in mice by examining transactive response DNA-binding protein 43 (TDP-43) expression and nerve fiber damage ~ 2 years after the rTBIs. We observed acute RTG treatment to reduce the duration of PTS and impair the development of PTE. Acute RTG treatment also prevented post-injury hypersomnia, nerve fiber damage, and cortical TDP-43 accumulation and translocation from the nucleus to the cytoplasm. Mice that developed PTE displayed impaired rapid eye movement (REM) sleep, and there were significant correlations between seizure duration and time spent in the different stages of the sleep–wake cycle. We observed acute RTG treatment to impair injury-induced reduction of age-related increase in gamma frequency power of the EGG, which has been suggested to be necessary for a healthy aged brain. The data show that RTG, administered acutely post-TBI, is a promising, novel therapeutic option to blunt/prevent several long-term effects of rTBIs. Furthermore, our results show a direct relationship between sleep architecture and PTE.
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Metadata
Title
Acute Treatment with the M-Channel (Kv7, KCNQ) Opener Retigabine Reduces the Long-Term Effects of Repetitive Blast Traumatic Brain Injuries
Authors
Fabio A. Vigil
Hindiael Belchior
Vladislav Bugay
Isabella I. Bazaldua
Aiola Stoja
Denise C. Dantas
Sang H. Chun
Austin Farmer
Eda Bozdemir
Deborah M. Holstein
Jose E. Cavazos
James D. Lechleiter
Robert Brenner
Mark S. Shapiro
Publication date
01-04-2023
Publisher
Springer International Publishing
Published in
Neurotherapeutics / Issue 3/2023
Print ISSN: 1933-7213
Electronic ISSN: 1878-7479
DOI
https://doi.org/10.1007/s13311-023-01361-9

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