Inserm, U676, Paris, France, Université Paris 7, Paris, France.
Anesthesiology. 2013 May;118(5):1123-32. doi: 10.1097/ALN.0b013e318286cf36.
Brain-derived neurotrophic factor (BDNF) plays a prominent role in neuroprotection against perinatal brain injury. Dexmedetomidine, a selective agonist of α2-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.
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 μM 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.
Both BDNF and dexmedetomidine produced a significant neuroprotective effect in vivo and in vitro. Dexmedetomidine 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 μm vs. 1028 ± 213 μm, 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.
These results suggest that dexmedetomidine increased astrocyte expression of BDNF through an extracellular signal-regulated kinase-dependent pathway, inducing subsequent neuroprotective effects.
脑源性神经营养因子（BDNF）在对抗围产期脑损伤的神经保护中起着重要作用。右美托咪定是α2-肾上腺素能受体的选择性激动剂，也能提供对抗谷氨酸诱导损伤的神经保护作用。由于肾上腺素能受体激动剂可以调节 BDNF 的表达，我们的目标是研究右美托咪定的神经保护作用是否通过 BDNF 调节来介导围产期脑损伤。
比较了 BDNF 及其与右美托咪定联合使用（或与中和 BDNF 抗体或细胞外信号调节激酶通路抑制剂（PD098059）联合使用）对围产期伊博汀诱导的皮质损伤（n = 10-20 只/组）和小鼠神经元培养物（300 μM 伊博汀作用 6 小时）的保护作用。用皮质神经元和星形胶质细胞分离培养物在体内和体外研究右美托咪定对 BDNF 表达的影响。
BDNF 和右美托咪定在体内和体外均产生显著的神经保护作用。右美托咪定增强了体内 Bdnf4 和 Bdnf5 的转录和 BDNF 蛋白皮质表达。右美托咪定还增强了星形胶质细胞培养物中的 Bdnf4 和 Bdnf5 的转录，并增加了 BDNF 的介质浓度，但在神经元培养物中没有。BDNF 抗体（平均损伤大小 ± SD：577 ± 148 μm 比 1028 ± 213 μm，n = 14-20，P < 0.001）和 PD098059 在体内抑制了右美托咪定的保护作用，但在分离的神经元培养物中没有。最后，PD098059 抑制了右美托咪定诱导的星形胶质细胞中 BDNF 的释放增加。
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，从而诱导随后的神经保护作用。
