Abstract
BackgroundAstrocyte Connexin 43 (Cx43) is essential for the trophic and protective support of neurons during brain ischemia reperfusion (I/R) injury. It is believed that dexmedetomidine participates in Cx43-mediated effects. However, its mechanisms remained unclear. This study aims to address the relationship and regulation among them.MethodsAdult male Sprague-Dawley rats were allocated to the 90-min right middle cerebral arterial occlusion with or without dexmedetomidine pretreatment (5 μg/kg). Neurological functions were evaluated and brain lesions, as well as inflammatory factors (IL-1β, IL-6, TNF-α), were assessed. Ischemic penumbral cortex was harvested to determine the expression of astrocyte Cx43. Primary astrocytes were cultured to evaluate the effect of dexmedetomidine on Cx43 after oxygen-glucose deprivation.ResultsDexmedetomidine pretreatment attenuated neurological injury, brain lesions and expression of inflammatory factors (IL-1β, IL-6, TNF-α) after brain ischemia (P < 0.05). Astrocyte Cx43 was down-regulated by brain I/R injury, both in vivo and in vitro, which were reversed by dexmedetomidine (P < 0.05). This effect was mediated by the phosphorylation of Akt and GSK-3β. Further studies with LY294002 (PI3K inhibitor) or SB216763 (GSK-3β inhibitor) confirmed the effect of dexmedetomidine on astrocyte Cx43.ConclusionsPerioperative dexmedetomidine administration attenuates neurological injury after brain I/R injury, possibly through up-regulation of astrocyte Cx43. Activation of PI3K-Akt-GSK-3β pathway might contribute to this protective effect.
Highlights
Astrocyte Connexin 43 (Cx43) is essential for the trophic and protective support of neurons during brain ischemia reperfusion (I/R) injury
Measurement of the ischemic penumbral tissues showed that pro-inflammatory factors (IL-1β, IL-6 and TNF-α) increased after middle cerebral artery occlusion (MCAO), which were attenuated by dexmedetomidine preconditioning (P < 0.001) (Fig. 2)
Dexmedetomidine attenuates the reduction of CX43 and the increase in apoptosis caused by Oxygen-Glucose Deprivation (OGD) and reoxygenation of cultured astrocytes Fr1 area of brain tissue was extracted to measure the response of astrocyte Gap junctions (GJs) to brain I/R
Summary
Astrocyte Connexin 43 (Cx43) is essential for the trophic and protective support of neurons during brain ischemia reperfusion (I/R) injury. Ischemic injury of the brain frequently occurs in stroke or cardiac arrest, and certain operative procedures that progress to perioperative stroke, including neurosurgery and bypass surgery [1, 2]. Both permanent and transient brain ischemia are characterized by cell death. During brain ischemia/reperfusion (I/R), gap junctional coupling is down-regulated and accompanied by the partial accumulation of excessive reactive oxygen species (ROS) [4]. Activation of astrocyte GJs might be an effective way to relieve brain I/R injury
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