Prevention of brain damage after traumatic brain injury by pharmacological enhancement of KCNQ (Kv7, 'M-type') K+ currents in neurons
| Autor: | Shayne D. Hastings, Rafael J. Veraza, Deborah M. Holstein, Isamar Sanchez, Sang H Chun, Mark S. Shapiro, MaryAnn Hobbs, Robert Brenner, José E Cavazos, Shane Sprague, Chase M. Carver, Fabio A. Vigil, Eda Bozdemir, Vladislav Bugay, James D. Lechleiter |
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| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Injury control Accident prevention business.industry Traumatic brain injury Treatment options Poison control Brain damage medicine.disease K currents 03 medical and health sciences 0302 clinical medicine nervous system Neurology medicine Neurology (clinical) medicine.symptom Cardiology and Cardiovascular Medicine business Neuroscience 030217 neurology & neurosurgery 030304 developmental biology K channels |
| Zdroj: | Journal of Cerebral Blood Flow & Metabolism. 40:1256-1273 |
| ISSN: | 1559-7016 0271-678X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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