Endothelin-1 Induces Degeneration of Cultured Motor Neurons Through a Mechanism Mediated by Nitric Oxide and PI3K/Akt Pathway
Endothelin-1 Induces Degeneration of Cultured Motor Neurons Through a Mechanism Mediated by Nitric Oxide and PI3K/Akt Pathway
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DOI：
10.1007/s12640-017-9711-3
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发表时间：
2017-07-01
影响因子：
3.7
通讯作者：
Catania, M. V.
中科院分区：
文献类型：
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作者：
D'Antoni, S.;Ranno, E.;Catania, M. V.
内皮素-1 （ET-1）是一种由活化的星形胶质细胞和小胶质细胞产生的血管活性肽，参与神经退行性疾病中反应性胶质增生的启动和维持。我们之前已经提出ET-1可能在肌萎缩性侧索硬化症（ALS）的病理生理中发挥作用。事实上，我们报道了这种肽在SOD1-G93A小鼠和ALS患者脊髓的反应性星形胶质细胞中大量表达，并在富含反应性星形胶质细胞的混合脊髓培养的体外模型中对运动神经元（MNs）产生毒性作用。在这里，我们探讨了ET-1对培养的MNs毒性作用的可能机制。我们发现ET-1毒性不是由氧化应激或环氧化酶-2的激活直接引起的，而是需要一氧化氮的合成，并通过磷酸肌苷3激酶途径的激活降低来介导。此外，我们观察到ET-1对小胶质细胞也有毒性，尽管它对MNs的作用与这种类型的胶质细胞的存在无关。我们的研究证实了ET-1可能导致MN死亡，并证实了ET-1信号的调节可能是减缓ALS中MN变性的治疗策略。
Endothelin-1 (ET-1) is a vasoactive peptide produced by activated astrocytes and microglia and is implicated in initiating and sustaining reactive gliosis in neurodegenerative diseases. We have previously suggested that ET-1 can play a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Indeed, we reported that this peptide is abundantly expressed in reactive astrocytes in the spinal cord of SOD1-G93A mice and ALS patients and exerts a toxic effect on motor neurons (MNs) in an in vitro model of mixed spinal cord cultures enriched with reactive astrocytes. Here, we explored the possible mechanisms underlying the toxic effect of ET-1 on cultured MNs. We show that ET-1 toxicity is not directly caused by oxidative stress or activation of cyclooxygenase-2 but requires the synthesis of nitric oxide and is mediated by a reduced activation of the phosphoinositide 3-kinase pathway. Furthermore, we observed that ET-1 is also toxic for microglia, although its effect on MNs is independent of the presence of this type of glial cells. Our study confirms that ET-1 may contribute to MN death and corroborates the view that the modulation of ET-1 signaling might be a therapeutic strategy to slow down MN degeneration in ALS.