1. Prevention of brain damage after traumatic brain injury by pharmacological enhancement of KCNQ (Kv7, "M-type") K + currents in neurons.
- Author
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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, and Shapiro MS
- Subjects
- Animals, Mice, Mice, Inbred C57BL, Anticonvulsants pharmacology, Brain Injuries, Traumatic metabolism, Carbamates pharmacology, KCNQ Potassium Channels metabolism, Neurons drug effects, Neurons metabolism, Phenylenediamines pharmacology
- 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.- Published
- 2020
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