Neurotrophic effects of a cyanine dye via the PI3K-Akt pathway: attenuation of motor discoordination and neurodegeneration in an ataxic animal model.
Neurotrophic effects of a cyanine dye via the PI3K-Akt pathway: attenuation of motor discoordination and neurodegeneration in an ataxic animal model.
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DOI：
10.1371/journal.pone.0017137
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发表时间：
2011-02-11
期刊：
影响因子：
3.7
通讯作者：
Fukuda S
中科院分区：
文献类型：
--
作者：
Ohta H;Arai S;Akita K;Ohta T;Fukuda S
神经营养因子可能是未来神经退行性疾病的治疗药物。在筛选神经营养潜能的生物活性分子时，我们发现光敏花青素染料NK-4具有显著的神经营养活性，是一种有效的自由基清除剂。在这项研究中，我们评估了NK-4对神经元抗氧化损伤的保护作用，并研究了相关的细胞内信号通路。随后，我们评估了NK-4在神经变性动物模型中的作用。在体外，NK-4对过氧化氢（H2O2）或6-羟多巴胺（6-OHDA）引起的氧化应激诱导的PC12细胞具有剂量依赖性的保护作用。比较NK-4和神经生长因子（NGF受体TrkA抑制剂K252a）对细胞外信号调节激酶信号通路的影响，发现NK-4活性独立于NGF受体发生。磷脂酰肌醇3-激酶（PI3K）抑制剂LY294002阻断NK-4的保护作用，NK-4引起PI3K下游效应物Akt/蛋白激酶B的激活。这些结果表明，NK-4的神经保护作用是通过PI3K-Akt信号通路介导的。NK-4处理还减弱了应激诱导的SAPK/JNK的激活，这表明NK-4激活了存活信号通路，并独立于TrkA受体抑制应激激活的神经元细胞凋亡通路。在体内，NK-4可改善遗传性共济失调仓鼠的运动协调性。组织学分析显示NK-4治疗后小脑萎缩明显减轻。值得注意的是，治疗组的浦肯野细胞计数比载药组高3倍。这些结果表明NK-4是一种基于生存信号通路激活的治疗神经退行性疾病的潜在药物。
Neurotrophic factors may be future therapeutic agents for neurodegenerative disease. In the screening of biologically active molecules for neurotrophic potency, we found that a photosensitizing cyanine dye, NK-4, had remarkable neurotrophic activities and was a potent radical scavenger. In this study, we evaluated the effect of NK-4 on the protection of neurons against oxidative damage and investigated the associated intracellular signaling pathways. Subsequently, we evaluated the effect of NK-4 in an animal model of neurodegeneration. In vitro, NK-4 showed dose-dependent protection of PC12 cells from toxicity induced by oxidative stress caused by hydrogen peroxide (H2O2) or 6-hydroxydopamine (6-OHDA). Comparison of extracellular signal-regulated kinase signaling pathways between treatment with NK-4 and nerve growth factor (NGF) using K252a, an inhibitor of the NGF receptor TrkA, revealed that NK-4 activity occurs independently of NGF receptors. LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, blocked the protective effect of NK-4, and NK-4 caused activation of Akt/protein kinase B, a downstream effector of PI3K. These results suggest that the neuroprotective effects of NK-4 are mediated by the PI3K-Akt signaling pathway. NK-4 treatment also attenuated stress-induced activation of SAPK/JNK, which suggests that NK-4 activates a survival signaling pathway and inhibits stress-activated apoptotic pathways independently of the TrkA receptor in neuronal cells. In vivo, administration of NK-4 improved motor coordination in genetic ataxic hamsters, as assessed by rota-rod testing. Histological analysis showed that cerebellar atrophy was significantly attenuated by NK-4 treatment. Notably, the Purkinje cell count in the treated group was threefold higher than that in the vehicle group. These results suggest that NK-4 is a potential agent for therapy for neurodegenerative disorders based on the activation of survival signaling pathways.
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影响因子：
4.8
作者：
Cassano, Silvana;Agnese, Savina;Avvedimento, Enrico Vittorio
通讯作者：
Avvedimento, Enrico Vittorio
影响因子：
4.7
作者：
Dago, L;Bonde, C;Gronborg, M
通讯作者：
Gronborg, M
DOI：
10.1073/pnas.95.3.1253
发表时间：
1998-02-03
影响因子：
11.1
作者：
Fernandez, AM;de la Vega, AG;Torres-Aleman, I
通讯作者：
Torres-Aleman, I
影响因子：
3.5
作者：
Akita, Kenji;Arai, Shigeyuki
通讯作者：
Arai, Shigeyuki
影响因子：
11.4
作者：
Alessi, DR;Andjelkovic, M;Hemmings, BA
通讯作者：
Hemmings, BA