M‐type K+ Channel Openers: In vivo Neuroprotective Role during Cerebrovascular Stroke

Abstract

Stroke is the third leading cause of human death and many models have been used to study the mechanisms of tissue damage and neuronal protection. Investigations of neuroprotection during ischemic stroke through “M‐channels” could underlie potential treatments, since K+ channels stabilize resting potentials by counterbalancing the depolarizing effects of excitatory cation currents. These voltage‐gated channels, with distinct electrophysiological and pharmacological properties, play critical roles in control of neuronal excitability and action potential firing. A known M‐channel activator, retigabine (RTG) and other novel openers, up‐regulate M‐channels by stabilizing their open states through distinct molecular mechanisms. We hypothesize that M current‐mediated neuronal silencing has a neuroprotective role by increasing opening of KCNQ channels, thus decreasing neuronal activity. We used two in vivo mouse models; a cerebral infarct produced by laser‐controlled photothrombosis and the second the middle cerebral artery occlusion (MCAo). M‐current activity was pharmacologically altered in both models and application of M‐channel activators significantly reduced lesion area. Furthermore, retigabine enhanced protection from cerebral inflammatory responses. Thus, this study uses powerful models which may provide novel therapeutics for commonly‐occurring ischemic attacks.