Increase of kv7 Currents Reduces Traumatic Brain Injury-induced Blood-brain Barrier Leakage, Hyperexcitability, Hypersomnia, Chronic Traumatic Encephalopathy, and Post-traumatic Epilepsy Development
Abstract number :
1.185
Submission category :
3. Neurophysiology / 3F. Animal Studies
Year :
2022
Submission ID :
2203949
Source :
www.aesnet.org
Presentation date :
12/3/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:22 AM
Authors :
Fabio Antonio Borges Vigil, PhD – University of Texas Health San Antonio; Hindiael Belchior, N/A – Federal University of Rio Grande do Norte; Vladislav Bugay, n/a – University of Texas Health San Antonio; Aiola Stoja, n/a – University of Texas Health San Antonio; Denise Cortes, n/a – Federal University of Rio Grande do Norte; Sang Chun, n/a – University of Texas Health San Antonio; Austin Farmer, n/a – University of Texas Health San Antonio; Eda Bozdemir, n/a – University of Texas Health San Antonio; Deborah Holstein, n/a – University of Texas Health San Antonio; James Lechleiter, n/a – University of Texas Health San Antonio; Martin Paukert, n/a – University of Texas Health San Antonio; Robert Brenner, n/a – University of Texas Health San Antonio; Mark Shapiro, n/a – University of Texas Health San Antonio
Rationale: Traumatic brain injury (TBI) can result in the development of post-traumatic epilepsy (PTE) and chronic traumatic encephalopathy (CTE). Kv7 (“M-type”, KCNQ) voltage-gated K+ channels underlie the neuronal “M-current,” which plays a dominant role in control over neuronal excitability throughout the nervous system. We have previously shown, in a blunt TBI mouse model, that acute pharmacological increase of Kv7 K+ currents impairs various short-term deleterious effects of a TBI. We here tested if the same treatment could reduce/block the long-term effects of multiple air shock wave blast TBIs. Additionally, we performed important preclinical tests to move toward clinical trials and explored possible mechanistic explanations for the beneficial effects of pharmacological facilitation of Kv7 as a post-TBI treatment.
Methods: Two sets of data are presented here. In the first set of data, we have continued our line of enquiring using one single blunt TBI mouse model to determine the optimum dose and therapeutic window for treatment. We tested the therapeutic effects of the prototype Kv7 “opener,” Retigabine, and of the newer, more potent, and more selective Kv7 "opener," RL648_81. We also tested the effects of the treatment on blood-brain barrier (BBB) permeability and neuronal excitability. In our second set of data, we used a repetitive blast-TBI mouse model to test if an increase in K+ currents through Kv7 channels could occlude the development of PTE and CTE.
Results: Electroencephalogram (EEG) and video recording revealed 1 mg/kg of Retigabine to be the optimum treatment dose. Interestingly, Retigabine was more effective than RL648_81 in preventing post-TBI seizures. Furthermore, Retigabine, but not RL648_81, reduced BBB breakdown acutely (2 h) after TBI. Retigabine injection up to 1 h after injury was most effective as a treatment. In vivo two-photon microscopy shows retigabine to prevent acute TBI-induced neuronal hyperexcitability, network firing disruption, and the elevation of glutamatergic signaling. Retigabine treatment also occluded the repetitive TBI-induced development of a hypersomnia phenotype, PTE, CTE, and impairment of the EEG gamma frequency in aged mice.
Conclusions: Acute pharmacological facilitation of Kv7 opening by Retigabine may be the first treatment available for preventing short-term and long-term deleterious effects that follow one or multiple TBIs. This includes preventing the development of long-term chronic diseases such as PTE and CTE.
Funding: This work is supported by DoD grant W81XWH-22-1-0195.
Neurophysiology