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Neuroprotective activity of new Δ3-N-acylethanolamines in a focal ischemia stroke model
Lipids ( IF 1.9 ) Pub Date : 2021-11-09 , DOI: 10.1002/lipd.12326
Rahau S Shirazi 1 , Mikhail Vyssotski 1 , Kirill Lagutin 1 , Dion Thompson 1 , Christa MacDonald 2, 3 , Vincent Luscombe 2, 3 , Michelle Glass 2, 3 , Kim Parker 4 , Emma K Gowing 4 , D Bradley G Williams 5 , Andrew N Clarkson 4
Affiliation  

N-acylethanolamines (NAE, also called ethanolamides) are significant lipid signaling molecules with anti-inflammatory, pain-relieving, cell-protective, and anticancer properties. Here, we present the use of a hitherto unreported group of Δ3-NAE and also some Δ4- and Δ5-NAE, in in vitro and in vivo assays to gain a better understanding of their structure–bioactivity relationships. We have developed an efficient synthetic method to rapidly produce novel unlabeled and 13C-labeled Δ3-NAE (NAE-18:5n-3, NAE-18:4n-6) and Δ4-NAE (NAE-22:5n-6). The new NAE with shorter carbon backbone structures confers greater neuroprotection than their longer carbon backbone counterparts, including anandamide (Δ5-NAE-20:4n-6) in a focal ischemia mouse model of stroke. This study highlights structure-dependent protective effects of new NAE following focal ischemia, in which some of the new NAE, administered intranasally, lead to significantly reduced infarct volume and improved recovery of limb use. The relative affinity of the new NAE toward cannabinoid receptors was assessed against anandamide, NAE-22:6n-3 and NAE-20:5n-3, which are known cannabinoid receptor ligands with high-binding constants. Among the newly synthesized NAE, Δ4-NAE-22:5n-6 shows the greatest relative affinity to cannabinoid receptors hCB1 and hCB2, and inhibition of cyclic adenosine monophosphate activity through hCB2 compared to anandamide.

中文翻译:

新型 Δ3-N-酰基乙醇胺在局灶性缺血中风模型中的神经保护活性

N-酰基乙醇胺(NAE,也称为乙醇酰胺)是重要的脂质信号分子,具有抗炎、镇痛、细胞保护和抗癌特性。在这里,我们介绍了迄今为止未报道的 Δ3-NAE 组以及一些 Δ4-和 Δ5-NAE 在体外和体内测定中的使用,以更好地了解它们的结构-生物活性关系。我们已经开发出一种有效的合成方法来快速生产新的未标记和13C 标记的 Δ3-NAE (NAE-18:5n-3, NAE-18:4n-6) 和 Δ4-NAE (NAE-22:5n-6)。在局部缺血小鼠中风模型中,具有较短碳骨架结构的新 NAE 比其较长碳骨架对应物(包括 anandamide (Δ5-NAE-20:4n-6))具有更大的神经保护作用。这项研究强调了局灶性缺血后新 NAE 的结构依赖性保护作用,其中一些新的 NAE 鼻内给药可显着减少梗塞体积并改善肢体使用的恢复。新 NAE 对大麻素受体的相对亲和力针对 anandamide、NAE-22:6n-3 和 NAE-20:5n-3 进行了评估,它们是已知的具有高结合常数的大麻素受体配体。在新合成的 NAE 中,Δ4-NAE-22:5n-6 对大麻素受体 hCB 1的相对亲和力最大和 hCB 2 ,以及与 anandamide 相比,通过 hCB 2抑制环磷酸腺苷活性。
更新日期:2021-11-09
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