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Prevention of brain damage after traumatic brain injury by pharmacological enhancement of KCNQ (Kv7, "M-type") K + currents in neurons.

Authors :
Vigil FA
Bozdemir E
Bugay V
Chun SH
Hobbs M
Sanchez I
Hastings SD
Veraza RJ
Holstein DM
Sprague SM
M Carver C
Cavazos JE
Brenner R
Lechleiter JD
Shapiro MS
Source :
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism [J Cereb Blood Flow Metab] 2020 Jun; Vol. 40 (6), pp. 1256-1273. Date of Electronic Publication: 2019 Jul 04.
Publication Year :
2020

Abstract

Nearly three million people in the USA suffer traumatic brain injury (TBI) yearly; however, there are no pre- or post-TBI treatment options available. KCNQ2-5 voltage-gated K <superscript>+</superscript> channels underlie the neuronal "M current", which plays a dominant role in the regulation of neuronal excitability. Our strategy towards prevention of TBI-induced brain damage is predicated on the suggested hyper-excitability of neurons induced by TBIs, and the decrease in neuronal excitation upon pharmacological augmentation of M/KCNQ K <superscript>+</superscript> currents. Seizures are very common after a TBI, making further seizures and development of epilepsy disease more likely. Our hypothesis is that TBI-induced hyperexcitability and ischemia/hypoxia lead to metabolic stress, cell death and a maladaptive inflammatory response that causes further downstream morbidity. Using the mouse controlled closed-cortical impact blunt TBI model, we found that systemic administration of the prototype M-channel "opener", retigabine (RTG), 30 min after TBI, reduces the post-TBI cascade of events, including spontaneous seizures, enhanced susceptibility to chemo-convulsants, metabolic stress, inflammatory responses, blood-brain barrier breakdown, and cell death. This work suggests that acutely reducing neuronal excitability and energy demand via M-current enhancement may be a novel model of therapeutic intervention against post-TBI brain damage and dysfunction.

Details

Language :
English
ISSN :
1559-7016
Volume :
40
Issue :
6
Database :
MEDLINE
Journal :
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
Publication Type :
Academic Journal
Accession number :
31272312
Full Text :
https://doi.org/10.1177/0271678X19857818