Dexmedetomidine protects against glucocorticoid induced progenitor cell apoptosis in neonatal mouse cerebellum.
Dexmedetomidine protects against glucocorticoid induced progenitor cell apoptosis in neonatal mouse cerebellum.
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右美托咪定可防止新生小鼠小脑中糖皮质激素诱导的祖细胞凋亡。
DOI：
10.1080/14767058.2016.1241763
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Noguchi,KevinKiyoshi
中科院分区：
文献类型：
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作者：
O'Connor,ShawnDavid;Cabrera,OmarHoseá;Dougherty,JosephD;Singh,Sukrit;Swiney,BrantStephen;Salinas-Contreras,Patricia;Farber,NuriBradford;Noguchi,KevinKiyoshi
目的：糖皮质激素（GCs）用于改善早产儿的呼吸力学，尽管临床证据将新生儿GC治疗与小脑病理联系起来。在发育中的小鼠小脑中，GC地塞米松（DEX）引起GC诱导的神经祖细胞快速凋亡（GINA）。着眼于药理神经保护策略，我们研究了右美托咪定（DMT）是否对GINA有保护作用。方法：对新生小鼠在DEX攻毒前进行DMT预处理。此外，我们还对可乐定和育亨宾进行了体内实验，以确定DMT神经保护的机制。在体外研究中，小脑神经祖细胞用DMT预处理后再攻毒。结果：体内DMT对GINA的抑制作用在1 μg/kg及以上，p< 0.0001。可乐定显著减弱GINA，p< 0.0001，育亨宾逆转DMT神经保护，p< 0.0001，提示DMT神经保护可能是通过肾上腺素能信号介导的。在体外，DMT在10 μM及以上时实现了神经保护，p< 0.001，表明DMT拯救是细胞自主的。结论：在临床相关剂量下，DMT对GINA具有剂量依赖性的神经保护作用，这种作用是细胞自主的，可能是由α2肾上腺素能受体激动作用介导的。DMT与GCs联合使用可能是一种有效的策略，可以保护新生儿大脑免受GINA的影响，同时保留GCs对呼吸力学的有益作用。
Objectives: Glucocorticoids (GCs) are used to improve respiratory mechanics in preterm infants despite clinical evidence linking neonatal GC therapy to cerebellar pathology. In developing mouse cerebellum, the GC dexamethasone (DEX) causes rapid GC-induced neural progenitor cell apoptosis (GINA). Focusing on pharmacological neuroprotection strategies, we investigated whether dexmedetomidine (DMT) protects against GINA.Methods: Neonatal mice were pretreated with DMT prior to DEX challenge. Additionally, we tested clonidine and yohimbinein vivoto determine mechanism of DMT neuroprotection. Forin vitrostudies, cerebellar neural progenitor cells were pretreated with DMT before DEX challenge.Results:In vivo, DMT attenuated GINA at 1 μg/kg and above,p< 0.0001. Clonidine significantly attenuated GINA,p< 0.0001, while yohimbine reversed DMT neuroprotection,p< 0.0001, suggesting DMT neuroprotection is likely mediated via adrenergic signaling.In vitro, DMT neuroprotection was achieved at 10 μM and above,p< 0.001, indicating DMT rescue is cell autonomous.Conclusions: DMT affords dose-dependent neuroprotection from GINA at clinically relevant doses, an effect that is cell autonomous and likely mediated by α2 adrenergic receptor agonism. DMT co-administration with GCs may be an effective strategy to protect the neonatal brain from GINA while retaining the beneficial effects of GCs on respiratory mechanics.