【摘 要】
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OBJECTIVE Astrocytes, taken as the dominant type of glia in central nervous system, would take place raft of pathological changes during stroke.Amongst these deleterious alterations, the formation of
【机 构】
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State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, CAS, Shanghai 201203, C
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OBJECTIVE Astrocytes, taken as the dominant type of glia in central nervous system, would take place raft of pathological changes during stroke.Amongst these deleterious alterations, the formation of glia scar and other factors prohibit neurites growth could disturb neuronal recovery.Despite there are myriad of researches have been accomplished to attenuate the pathological alteration of astrocytes, aiming to promote neurites protrusion and neuronal recovery, the explicit molecular stabilizers in astrocytes were still unknown.METHODS Oxygen Glucose Deprivation /Reperfusion (OGD/RP) model was utilized to simulate pathological process of stroke.The whole project was composed of in vitro (primary culture of astrocytes &neuron) and ex vivo (brain slice culture) experiments.RESULTS After the treatment of OGD/RP, connexin 43 in ASR was internalized and degraded, leading to the increasing of intracellular concentration of calcium, which could activate CaMK Ⅱ/CREB and Calcineurin/NFAT pathways, inducing the expression of Ephrin-A4.This postulation could be testified by administration of KN-93 (inhibitor of CaMK Ⅱ) and cyclosporine A (inhibitor of Calcineurin).Overexpression of connexin 43 and administration of ZBB-1 (analogue of triptolide, which could inhibit the downregulation of connexin 43) abolished the above phenomena.Immature neurons stretched shorter neurites and revealed retard maturation when plated with OGD/RP model astrocytes treated by OGD/RP model.CONCLUSION OGD/RP incurs internalization and degradation of connexin 43, bringing on calcium overloading.Therein, CaMKII/CREB and Calcineurin/NFAT pathways were activated, leading to upregulated expression of Ephrin-A4, which would hamper neuronal recovery.
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