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

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.

Functional responses of the hippocampus to hyperexcitability depend on directed, neuron‐specific KCNQ2 K+ channel plasticity

“…Using in situ hybridization, we confirmed that KCNQ2 transcription was increased after hyperexcitability challenge to the brain; however, KCNQ3 transcription was not altered. This is consistent with our previous finding of lack of KCNQ3 transcription in the cortex after TBI, despite increases to KCNQ2 (Vigil et al, ). As KCNQ3 is abundantly co‐assembled with KCNQ2 in neurons, any specified role of KCNQ3 plasticity in neuromodulation of hippocampus has yet to be revealed (Soh et al, ).…”

“…Specifically, upregulation of KCNQ2 expression can only occur in neurons that survive a deleterious insult that induces excitotoxicity, represented here by the stark contrast of signal between the types of principal neurons. We recently report a similar result concerning cortical neuron plasticity in responding to and surviving an adverse insult (Vigil et al, ).…”

“…Furthermore, selective neuronal death occurs in the hippocampus 1–7 days after TBI that promotes further hyperexcitability (Golarai, Greenwood, Feeney, & Connor, ). We used the controlled cortical impact (CCI) model, as recently described (Vigil et al, ). Forty‐eight hours after CCI‐TBI, we investigated changes in relative KCNQ2 transcription in hippocampus using the KCNQ2 mRNA‐EGFP reporter mice.…”

“…The controlled cortical impact injury (CCI) traumatic brain injury (TBI) model uses a pneumatic impact device, as previously described by our group (Vigil et al, ). The CCI model causes a TBI but the skull remains intact with minimal hematoma (Hunt et al, ).…”

“…Similarly, transgenic suppression of M channels in mice results in epileptic phenotypes (Greene, Kosenko, & Hoshi, ; Niday et al, 2017; Peters, Hu, Pongs, Storm, & Isbrandt, ; Singh et al, 2008; Soh, Pant, LoTurco, & Tzingounis, ). Whereas the role of M channels in acquired epileptogenesis has not been well characterized, evidence suggests that M‐channel openers can serve a protective role in preventing seizures and other insults that can progress to epilepsy, such as stroke and traumatic brain injury (Bierbower, Choveau, Lechleiter, & Shapiro, ; Sampath, Valdez, White, & Raol, ; Vigil et al, ).…”