Dexmedetomidine Attenuates The Neurotoxicity Of Propofol Toward Primary Hippocampal Neurons Via Erk 1/2/CREB/BDNF Signaling Pathways

Objective: Convincing evidence have argued that dexmedetomidine attenuates propofol-induce neurotoxicity,however,the underlying molecular mechanisms remain unclear.We investigated the possible involvement of extracellular signal-regulated protein kinase1 and 2(Erk 1/2)/cAMP response element-binding protein(CREB)/brain-derived neurotrophic factor(BDNF)signaling pathways in primary hippocampal neurons.Methods: Primary hippocampal neurons were cultured for 8 days in vitro(DIV 8)and pretreated with or without dexmedetomidine or phosphorylation inhibitors prior to propofol exposure.Cell viability was measured using Cell Counting Kit-8(CCK-8)assays.Cell apoptosis was evaluated using a transmission electron microscope(TEM)and flow cytometry analyses.Levels of mRNAs encoding signaling pathway intermediates were assessed using qRT-PCR analysis.The expression of signaling pathway intermediates and apoptosis-related proteins was determined by Western blotting.Results: Propofol significantly reduced cell viability,induced neuronal apoptosis,and further down-regulated the expression of the BDNF mRNA and the levels of the phospho-Erk 1/2(p-Erk 1/2),phospho-CREB(p-CREB),and BDNF proteins.The dexmedetomidine pretreatment markedly increased neuronal viability and alleviated propofol-induced neuronal apoptosis.Additionally,pretreatment with dexmedetomidine evidently rescued the propofol-induced down-regulation of both the BDNF mRNA and the levels of the p-Erk 1/2,p-CREB and BDNF proteins.Whereas the neuroprotective effect of dexmedetomidine was abolished by an inhibitor of Erk 1/2 and CREB phosphorylation,leading to a significant reduction in neuronal viability and an increase in neuronal apoptosis.Furthermore,phosphorylation inhibitors prevented the dexmedetomidine pretreatment from rescuing the propofol-induced down-regulation of the BDNF mRNA and p-Erk 1/2,p-CREB and BDNF proteins.Conclusions: Incubation with 100 ?M propofol for 3 h can decrease the neuron viability of hippocampal neurons cultured in vitro,induce neuronal apoptosis,and inhibit the expression of p-Erk 1/2,p-CREB and BDNF.Pre-incubation with 10 ?M dexmedetomidine for 30 min can significantly alleviate the decreased viability and neuronal apoptosis of hippocampal neurons induced by propofol,and up-regulate p-Erk 1/2,p-CREB and BDNF protein expression,thus promoting neuronal survival.Dexmedetomidine alleviates propofol-induced cytotoxicity towards primary hippocampal neurons in vitro,which correlated with the activation of Erk 1/2 /CREB/BDNF signaling pathways.