Neuroprotective Effects of Dexmedetomidine against Glutamate Agonist-induced Neuronal Cell Death Are Related to Increased Astrocyte Brain-derived Neurotrophic Factor Expression
Neuroprotective Effects of Dexmedetomidine against Glutamate Agonist-induced Neuronal Cell Death Are Related to Increased Astrocyte Brain-derived Neurotrophic Factor Expression
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DOI：
10.1097/aln.0b013e318286cf36
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发表时间：
2013-05-01
期刊：
影响因子：
8.8
通讯作者：
Gressens, Pierre
中科院分区：
文献类型：
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作者：
Degos, Vincent;Le Charpentier, Tifenn;Gressens, Pierre
背景：脑源性神经营养因子（BDNF）在针对围产期脑损伤的神经保护中发挥着重要作用。右美托咪定是一种 α(2)-肾上腺素能受体的选择性激动剂，还可以提供神经保护作用，防止谷氨酸引起的损伤。由于肾上腺素能受体激动剂可以调节 BDNF 表达，我们的目标是检查右美托咪定的神经保护作用是否是通过小鼠围产期脑损伤中的 BDNF 调节介导的。方法：比较单独使用或与中和 BDNF 抗体或细胞外信号调节激酶途径抑制剂 (PD098059) 联合使用对谷氨酸诱导的 BDNF 损伤的保护作用。围产期鹅膏酯诱发的皮质损伤（n = 10-20 只幼崽/组）和小鼠神经元培养物（300 mu(M) 鹅膏酯 6 小时）。通过皮层神经元和星形胶质细胞分离培养物在体内和体外检测右美托咪定对 BDNF 表达的影响。结果：BDNF 和右美托咪定在体内和体外均产生显着的神经保护作用。右旋美托咪定增强体内 Bdnf4 和 Bdnf5 转录以及 BDNF 蛋白皮质表达。右美托咪定还增强了 Bdnf4 和 Bdnf5 的转录，并增加了分离的星形胶质细胞培养物中的 BDNF 培养基浓度，但在神经元培养物中则没有。 BDNF 抗体（平均病变大小 +/- SD：577 +/- 148 μm 对比 1028 +/- 213 μm，n = 14-20，P < 0.001）和 PD098059 在体内抑制右美托咪定的保护作用，但在分离的神经元培养物中则不然。最后，PD098059 抑制星形胶质细胞培养物中右美托咪定诱导的 BDNF 释放增加。结论：这些结果表明，右美托咪定通过细胞外信号调节激酶依赖性途径增加星形胶质细胞 BDNF 的表达，从而诱导后续的神经保护作用。
Background: Brain-derived neurotrophic factor (BDNF) plays a prominent role in neuroprotection against perinatal brain injury. Dexmedetomidine, a selective agonist of a alpha(2)-adrenergic receptors, also provides neuroprotection against glutamate-induced damage. Because adrenergic receptor agonists can modulate BDNF expression, our goal was to examine whether dexmedetomidine's neuroprotective effects are mediated by BDNF modulation in mouse perinatal brain injury.Methods: The protective effects against glutamate-induced injury of BDNF and dexmedetomidine alone or in combination with either a neutralizing BDNF antibody or an inhibitor of the extracellular signal-regulated kinase pathway (PD098059) were compared in perinatal ibotenate-induced cortical lesions (n = 10-20 pups/groups) and in mouse neuronal cultures (300 mu(M) of ibotenate for 6 h). The effect of dexmedetomidine on BDNF expression was examined in vivo and in vitro with cortical neuronal and astrocyte isolated cultures.Results: Both BDNF and dexmedetomidine produced a significant neuroprotective effect in vivo and in vitro. Dex-medetomidine enhanced Bdnf4 and Bdnf5 transcription and BDNF protein cortical expression in vivo. Dexmedetomidine also enhanced Bdnf4 and Bdnf5 transcription and increased BDNF media concentration in isolated astrocyte cultures but not in neuronal cultures. Dexmedetomidine's protective effect was inhibited with BDNF antibody (mean lesion size +/- SD: 577 +/- 148 mu m vs. 1028 +/- 213 mu m, n = 14-20, P < 0.001) and PD098059 in vivo but not in isolated neuron cultures. Finally, PD098059 inhibited the increased release of BDNF induced by dexmedetomidine in astrocyte cultures.Conclusion: These results suggest that dexmedetomidine increased astrocyte expression of BDNF through an extracellular signal-regulated kinase-dependent pathway, inducing subsequent neuroprotective effects.