N-Stearoyltyrosine protects primary cortical neurons against Aβ(1-40)-induced injury through inhibiting endocannabinoid degradation.
N-Stearoyltyrosine protects primary cortical neurons against Aβ(1-40)-induced injury through inhibiting endocannabinoid degradation.
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DOI：
10.1016/j.lfs.2015.01.012
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发表时间：
2015-03
期刊：
影响因子：
6.1
通讯作者：
Heng-Jing Cui;Ruixu Yang;Shan Liu;Guohui Fu;Yang Lu
中科院分区：
文献类型：
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作者：
Heng-Jing Cui;Ruixu Yang;Shan Liu;Guohui Fu;Yang Lu
N-硬脂酰酪氨酸（NsTyr）作为大麻素（AEA）的类似物，不仅在结构上与AEA密切相关，而且在内源性大麻素的生物学作用方面也与AEA密切相关。鉴于β淀粉样蛋白（Aβ）诱导的神经元损伤涉及内源性大麻素系统（endocannabinoid systems，ECS）的激活，本文系统地研究了NsTyr对Aβ（1 - 40）诱导的神经元损伤的保护作用及其机制。在损伤前30 min加入NsTyr至指定浓度。关键发现NsTyr对Aβ（1-40）诱导的原代神经元损伤的最佳作用出现在10 μM。NsTyr对Aβ（1-40）诱导的细胞死亡的神经保护作用的机制首先涉及大麻素受体的激活导致的抗凋亡，然后通过抑制内源性大麻素失活而对AEA进行受体前调节。这些结果表明，NsTyr对Aβ（1-40）诱导的原代神经元损伤的保护作用可能与抑制脂肪酸酰胺水解酶（FAAH）有关（IC 50 = 16.54 nM），并阻断由花生四烯酸膜转运蛋白（AMT）介导的AEA摄取（IC_（50）= 11.74 nM）。意义通过抑制AEA的降解来激活ECS是抑制Aβ诱导的神经病理性损伤的有效药理学途径。我们的研究可能会为AD治疗提供更现实的替代方案。
AimsN-stearoyltyrosine (NsTyr) as an anandamide (AEA) analog has close relationships with AEA not only in structure but also in terms of biological actions of endocannabinoids. Since β-amyloid (Aβ)-induced primary neuronal injury involves the activation of the endocannabinoid systems (ECS), the protective effects of NsTyr against Aβ(1–40)-induced neuronal injury and the mechanism were studied systematically in this paper.Main methodsCortical neurons were incubated with Aβ(1–40) for 24 h. NsTyr was added to indicated concentrations 30 min prior to injury.Key findingsThe best effects of NsTyr on Aβ(1–40)-induced primary neuronal injury occurred at 10 μM. The mechanism of NsTyr on neuroprotective effects against Aβ(1–40)-induced cellular death first involved anti-apoptosis resulting from the activation of cannabinoid receptors, then the pre-receptor regulation of AEA by the inhibition of endocannabinoid inactivation. These data demonstrated that the protective effects of NsTyr on Aβ(1–40)-induced primary neuronal injury resulted from the inhibition of fatty acid amide hydrolase (FAAH) (IC50= 16.54 nM) and blocked AEA uptake mediated by anandamide membrane transporter (AMT) (IC50= 11.74 nM).SignificanceThe activation of ECS by inhibiting the degradation of AEA is an effective pharmacological approach to suppress Aβ-induced neuropathic injury. Our research could result in a more realistic alternative for AD treatment.