Neuroprotective activity of (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) in vitro and in vivo in rodent models of brain ischemia.
Neuroprotective activity of (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) in vitro and in vivo in rodent models of brain ischemia.
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DOI：
10.1016/j.neuroscience.2015.02.001
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发表时间：
2015-04-16
期刊：
影响因子：
3.3
通讯作者：
Hao, J.
中科院分区：
文献类型：
--
作者：
Martins, A. H.;Hu, J.;Xu, Z.;Mu, C.;Alvarez, P.;Ford, B. D.;El Sayed, K.;Eterovic, V. A.;Ferchmin, P. A.;Hao, J.
关键词：
(1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) 是烟草属叶子中关键风味成分的前体。本研究表明 4R 可以减少啮齿动物缺血性中风模型的脑损伤。 4R预处理小鼠的梗塞体积（26.2±9.7 mm3）低于对照组（未处理：63.4±4.2 mm3，DMSO：60.2±14.2 mm3）。 4R后治疗组大鼠的梗塞体积（120±65 mm3）也比DMSO组大鼠（291±95 mm3）小。体外实验结果表明，4R可减少氧糖剥夺（OGD）诱导的神经2a细胞（神经母细胞瘤细胞）凋亡，并改善OGD下大鼠急性海马切片的群体峰值（PS）恢复；磷脂酰肌醇 3-激酶 (PI3K) 抑制剂渥曼青霉素消除了 4R 对 PS 恢复的影响。此外，4R 还抑制单核细胞与 bEND5 细胞（鼠脑源性内皮细胞）的粘附以及 OGD/复氧 (OGD/R) 诱导的细胞间粘附分子-1 (ICAM-1) 的上调，并将 bEND5 细胞中的 p-Akt 水平恢复至 OGD/R 前的值。总之，本研究表明 4R 对啮齿动物缺血性中风模型具有保护作用。抑制 ICAM-1 表达和恢复 Akt 磷酸化是 4R 参与细胞保护的可能机制。
(1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) is a precursor to key flavor ingredients in leaves of Nicotiana species. The present study shows 4R decreased brain damage in rodent ischemic stroke models. The 4R-pretreated mice had lower infarct volume (26.2±9.7 mm3) than those in control groups (untreated: 63.4±4.2 mm3, DMSO: 60.2±14.2 mm3). The 4R-posttreated rats also had less infarct volume (120±65 mm3) than those in the rats of DMSO group (291±95 mm3). The results from in vitro experiments indicate that 4R decreased neuro2a cells (neuroblastoma cells) apoptosis induced by oxygen glucose deprivation (OGD), and improved the population spikes (PSs) recovery in rat acute hippocampal slices under OGD; a phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin, abolished the effect of 4R on PSs recovery. Furthermore, 4R also inhibited monocyte adhesion to bEND5 cells (murine brain-derived endothelial cells) and upregulation of intercellular adhesion molecule-1(ICAM-1) induced by OGD/reoxygenation (OGD/R), and restored the p-Akt level to pre-OGD/R values in bEND5 cells. In conclusion, the present study indicates that 4R has a protective effect in rodent ischemic stroke models. Inhibition of ICAM-1 expression and restoration of Akt phosphorylation are the possible mechanisms involved in cellular protection by 4R.
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