Citation

Vigil FA, Bozdemir E, Bugay V, Chun SH, Hobbs MA, Sanchez I, Hastings SD, Veraza RJ, Holstein DM, Sprague SM, Carver CM, Cavazos JE, Brenner R, Lechleiter JD, Shapiro MS. J. Cereb. Blood Flow Metab. 2019; 0271678X1985781.

Copyright

(Copyright © 2019, Nature Publishing Group)

DOI

10.1177/0271678X19857818

PMID

unavailable

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+ 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+ 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.

Keywords Cell death, K+ channels, KCNQ, seizures, traumatic brain injury

Language: en