Activation of Akt/FKHR in the medulla oblongata contributes to spontaneous respiratory recovery after incomplete spinal cord injury in adult rats
Activation of Akt/FKHR in the medulla oblongata contributes to spontaneous respiratory recovery after incomplete spinal cord injury in adult rats
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DOI：
10.1016/j.nbd.2014.05.022
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发表时间：
2014-09-01
影响因子：
6.1
通讯作者：
Matarazzo, V.
中科院分区：
文献类型：
--
作者：
Felix, M. S.;Bauer, S.;Matarazzo, V.
不完全性脊髓损伤（SCI）后，患者和动物可能会表现出一些自发的功能恢复，这可以部分归因于受损神经回路的重建。这种损伤后的可塑性意味着脊柱重建，但越来越多的证据表明，棘上结构也有助于功能恢复。在这里，我们验证了部分SCI可能在脊髓上水平激活细胞信号通路，这种分子反应可能有助于自发恢复的假设。为此，我们使用了部分颈部半切的大鼠模型，该模型损伤了起源于脑干延脑的球脊髓呼吸道，但导致瘫痪的侧膈的时间依赖性自发功能恢复。我们首先证明了SCI后，PI 3 K/Akt信号通路在脑干延髓中被激活，导致其促凋亡下游靶点叉头转录因子（FKHR/FOXO 1A）失活。延髓前运动神经元，包括呼吸的项目，膈运动神经元的逆行标记揭示了增加FKHR磷酸化在其细胞体与不变的细胞数量。髓质输注PI 3 K抑制剂LY 294002可阻止SCI诱导的Akt和FKHR磷酸化，并激活其促死亡下游靶点之一Fas配体。肌电图的定量分析表明，抑制延髓PI 3 K/Akt信号传导阻止了部分颈脊髓损伤后正常观察到的自主呼吸恢复。然而，这种抑制不影响基线收缩频率或急性呼吸激发下的呼吸反应性。总之，这些发现提供了脊髓上细胞对部分SCI后自主呼吸恢复的贡献的新证据。(C)版权所有© 2014 Elsevier Inc.
After incomplete spinal cord injury (SCI), patients and animals may exhibit some spontaneous functional recovery which can be partly attributed to remodeling of injured neural circuitry. This post-lesion plasticity implies spinal remodeling but increasing evidences suggest that supraspinal structures contribute also to the functional recovery. Here we tested the hypothesis that partial SCI may activate cell-signaling pathway(s) at the supraspinal level and that this molecular response may contribute to spontaneous recovery. With this aim, we used a rat model of partial cervical hemisection which injures the bulbospinal respiratory tract originating from the medulla oblongata of the brainstem but leads to a time-dependent spontaneous functional recovery of the paralyzed hemidiaphragm. We first demonstrate that after SCI the PI3K/Akt signaling pathway is activated in the medulla oblongata of the brainstem, resulting in an inactivation of its pro-apoptotic downstream target, forkhead transcription factor (FKHR/FOXO1A). Retrograde labeling of medullary premotoneurons including respiratory ones which project to phrenic motoneurons reveals an increased FKHR phosphorylation in their cell bodies together with an unchanged cell number. Medulla infusion of the PI3K inhibitor, LY294002, prevents the SCI-induced Akt and FKHR phosphorylations and activates one of its death-promoting downstream targets, Fas ligand. Quantitative EMG analyses of diaphragmatic contractility demonstrate that the inhibition of medulla PI3K/Akt signaling prevents spontaneous respiratory recovery normally observed after partial cervical SCI. Such inhibition does not however affect either baseline contractile frequency or the ventilatory reactivity under acute respiratory challenge. Together, these findings provide novel evidence of supraspinal cellular contribution to the spontaneous respiratory recovery after partial SCI. (C) 2014 Elsevier Inc All rights reserved.