Activation of TRESK background potassium channels by cloxyquin exerts protective effects against excitotoxic-induced brain injury and neuroinflammation in neonatal rats

The excitotoxicity is a common pathological mechanism of perinatal brain injuries (PBI), however neuroinflammation resulting in PBI is both a cause and a consequence of excitotoxicity. TRESK background potassium channels are an important regulator of neuronal excitability. We therefore investigated effects of activation of TRESK channels by selective activator cloxyquin on excitotoxic-induced brain injury and neuroinflammation involving brain mast cells and inflammatory cytokines in neonatal rats. An excitotoxic model mimicking human perinatal brain lesions was established via intracerebral injection of the glutamatergic agonist ibotenate to into newborn rats. P5 rat pups were intraperitoneally pretreated with vehicle, three different doses of cloxyquin (0.2, 1 and 5 mg/kg), or NMDA receptor antagonist MK-801 (positive control) 30 minutes prior to intracerebral injection of 10 µg ibotenate. Rat pups were sacrificed one or five days after the injury. Coronal brain sections were stained with cresyl-violet for histopathological examinations, and with toluidine-blue for brain mast cells assessments. Concentrations of activin A, IL-1β, IL-6 and IL-10 in brain homogenates were measured using ELISA. Cloxyquin dose-dependently ameliorated ibotenate-induced impairments in the cortical and white matter, and suppressed ibotenate-induced activation and number of brain mast cells. Moreover, cloxyquin dose-dependently reduced concentrations of activin A, IL-1β and IL-6 in the brain tissue induced by ibotenate while it elevated IL-10 level. Our findings reveal for the first time that cloxyquin, a selective activator of TRESK channels, dose-dependently exerted protective effects against excitotoxic-induced neonatal brain injury and neuroinflammation. TRESK channels may be a promising new target for the treatment of PBIs.