Dock3 overexpression and p38 MAPK inhibition synergistically stimulate neuroprotection and axon regeneration after optic nerve injury.
Dock3 overexpression and p38 MAPK inhibition synergistically stimulate neuroprotection and axon regeneration after optic nerve injury.
复制标题
Dock3 过表达和 p38 MAPK 抑制协同刺激视神经损伤后的神经保护和轴突再生。
DOI：
10.1016/j.neulet.2014.08.034
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发表时间：
2014
期刊：
影响因子：
2.5
通讯作者：
T
中科院分区：
文献类型：
--
作者：
Semba K;Namekata K;Kimura A;Harada C;Katome T;Yoshida H;Mitamura Y;Harada;T
胞质分裂奉献因子3(Dock3)是一种非典型的鸟嘌呤核苷酸交换因子，主要在中枢神经系统表达。Dock3发挥神经保护作用，刺激视神经再生。P38丝裂原活化蛋白激酶位于细胞凋亡信号调节蛋白1(ASK1)信号的下游，在神经细胞死亡中起重要作用。我们评估了Dock3刺激和p38抑制对视神经损伤(ONI)所致视网膜变性的治疗效果。在活体视网膜成像中，光学相干断层扫描显示，p38抑制剂SB203580处理的WT小鼠和PBS处理的Dock3过表达(Dock3TG)小鼠的ONI诱导的视网膜退化得到改善，SB203580进一步刺激了Dock3TG小鼠的视网膜保护。此外，SB203580增加了WT和Dock3TG小鼠ONI后再生轴突的数量。ONI诱导的ASK1、p38和随后的甲基-d-天冬氨酸受体2B亚单位的磷酸化在Dock3TG小鼠的视网膜中被抑制。在Dock3TG小鼠中抑制ASK1通路表明Dock3可能具有抗氧化剂样属性。这些结果表明，Dock3的过度表达和p38的药理阻断对神经保护和轴突再生具有协同作用，因此联合应用可能有利于ONI的治疗。
The dedicator of cytokinesis 3 (Dock3) is an atypical guanine nucleotide exchange factor that is predominantly expressed in the CNS. Dock3 exerts neuroprotective effects and stimulates optic nerve regeneration. The p38 mitogen-activated protein kinase acts downstream of apoptosis signal-regulating kinase 1 (ASK1) signaling and plays an important role in neural cell death. We assessed a therapeutic efficacy of Dock3 stimulation and p38 inhibition in retinal degeneration induced by optic nerve injury (ONI).In vivoretinal imaging using optical coherence tomography revealed that ONI-induced retinal degeneration was ameliorated in SB203580 (a p38 inhibitor)-treated WT mice and PBS-treated Dock3 overexpressing (Dock3 Tg) mice, and SB203580 further stimulated retinal protection in Dock3 Tg mice. In addition, SB203580 increased the number of regenerating axons after ONI in both WT and Dock3 Tg mice. ONI-induced phosphorylation of ASK1, p38 and theN-methyl-d-aspartate receptor 2B subunit were suppressed in the retina of Dock3 Tg mice. Inhibition of the ASK1 pathway in Dock3 Tg mice suggests that Dock3 may have an antioxidant-like property. These results indicate that overexpression of Dock3 and pharmacological interruption of p38 have synergistic effects for both neuroprotection and axon regeneration, thus combined application may be beneficial for the treatment of ONI.