雌激素(estrogen,E)是维持女性第二性征最主要的甾体物质,其在神经系统也发挥广泛的药理作用,如抗脑缺血再灌注损伤减少梗死面积,抗自由基形成,调节兴奋性氨基酸释放等。雌激素自身作为一种抗氧化剂能够通过调节体内氧化还原平衡发挥神...雌激素(estrogen,E)是维持女性第二性征最主要的甾体物质,其在神经系统也发挥广泛的药理作用,如抗脑缺血再灌注损伤减少梗死面积,抗自由基形成,调节兴奋性氨基酸释放等。雌激素自身作为一种抗氧化剂能够通过调节体内氧化还原平衡发挥神经保护作用。另外,雌激素在神经系统药理作用的发挥与其受体密不可分,经典的雌激素受体(estrogen receptor,ER)主要位于细胞核内,包括ER-α和ER-β两种亚型,二者均可在大脑皮质和海马表达:卵巢切除大鼠学习记忆能力降低的同时,ER-α在大脑皮质区和海马区表达也显著减少;ER-β基因敲除能够严重影响学习记忆行为、长时程增强(long term potentiation,LTP)和突触强度,该受体可能参与了高级脑功能的调节。N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)受体作为与学习记忆密切相关的受体,与雌激素受体在海马区存在共表达。雌激素可能通过膜相关的雌激素受体快速激活ERK1/2信号转导通路,进一步诱导NMDA受体NR2B亚基磷酸化,激活NMDA受体,三者均会影响突触可塑性。本文就雌激素及其受体和Glu-NMDA受体通路与学习记忆的相关性进行综述。展开更多
Activation of N-methyl-D-aspartate receptors（NMDARs）mediates changes in the phosphorylation status of the glutamate receptors themselves.Previous studies have indicated that during synaptic activity,tyrosine kinases...Activation of N-methyl-D-aspartate receptors（NMDARs）mediates changes in the phosphorylation status of the glutamate receptors themselves.Previous studies have indicated that during synaptic activity,tyrosine kinases（Src and Fyn）or phosphatases（PTPαand STEP）are involved in regulating the phosphorylation of NMDARs.In this study,we used immunoblotting to investigate the role of an NMDAR subpopulation on the phosphorylation level of the GluN2B subunit at the Y1336 and Y1472sites in rat brain slices after NMDA treatment.We found that NMDA stimulation dramatically decreased the phosphorylation level of GluN2B at Y1472 in a dose-and time-dependent manner,but not at Y1336.Extrasynaptic NMDAR activation did not reduce the phosphorylation of GluN2B at Y1472.In addition,ifenprodil,a selective antagonist of GluN2Bcontaining NMDARs,did not abolish the decreased phosphorylation of GluN2B at Y1472 triggered by NMDA.These results suggest that the activation of synaptic GluN2A-containing NMDARs is required for the decreased phosphorylation of GluN2B at Y1472that is induced by NMDA treatment in rat brain slices.展开更多
Ten memantine（Mema）-dihydroartemisinin（DHA） ligands were designed and synthesized. Three types of isomers including α, β, and a defined y isomer were found in each intermediates（1a--1e）. Type γ isomer was fir...Ten memantine（Mema）-dihydroartemisinin（DHA） ligands were designed and synthesized. Three types of isomers including α, β, and a defined y isomer were found in each intermediates（1a--1e）. Type γ isomer was firstly reported here and confirmed as a less stable eclipsed conformation. The bonding of Mema with DHA through different carbon chains generally makes the new entities more cytotoxic than either Mema or artemisinm（Arte）. The β Mema/DHA ligands are a little bit more cytotoxic than a ligands. By applying corticosterone（Cort）-impaired PC12 cells models, it was found that Mema and those ligands with more than 3 carbon chains showed weak or no neuroprotective activities against the insults. However, two ligands, 2a（β） and 2b（β） showed better effects than either Arte or their combination（Mema/Arte in 1：1 molar ratio） at a dose of 5 μmol/L. Furthermore, ligands 2a（β）, 2b（β） and 2c（β） were confn-med as mild N-methyl-D-aspartate（NMDA） antagonists, and their corresponding α isomers are weak NMDA antagonists. All the data indicate that the bonding of Mema/DHA in compacted β conformation mode results in enhanced effects against Cort-induced insults in PC12 ceils and might reverse memantine as an anti-depression NMDA antagonist.展开更多
文摘雌激素(estrogen,E)是维持女性第二性征最主要的甾体物质,其在神经系统也发挥广泛的药理作用,如抗脑缺血再灌注损伤减少梗死面积,抗自由基形成,调节兴奋性氨基酸释放等。雌激素自身作为一种抗氧化剂能够通过调节体内氧化还原平衡发挥神经保护作用。另外,雌激素在神经系统药理作用的发挥与其受体密不可分,经典的雌激素受体(estrogen receptor,ER)主要位于细胞核内,包括ER-α和ER-β两种亚型,二者均可在大脑皮质和海马表达:卵巢切除大鼠学习记忆能力降低的同时,ER-α在大脑皮质区和海马区表达也显著减少;ER-β基因敲除能够严重影响学习记忆行为、长时程增强(long term potentiation,LTP)和突触强度,该受体可能参与了高级脑功能的调节。N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid,NMDA)受体作为与学习记忆密切相关的受体,与雌激素受体在海马区存在共表达。雌激素可能通过膜相关的雌激素受体快速激活ERK1/2信号转导通路,进一步诱导NMDA受体NR2B亚基磷酸化,激活NMDA受体,三者均会影响突触可塑性。本文就雌激素及其受体和Glu-NMDA受体通路与学习记忆的相关性进行综述。
基金supported by grants from the National Natural Science Foundation of China (30900418)the Natural Science Program of Department of Education of Zhejiang Province,China (Y201122469)
文摘Activation of N-methyl-D-aspartate receptors（NMDARs）mediates changes in the phosphorylation status of the glutamate receptors themselves.Previous studies have indicated that during synaptic activity,tyrosine kinases（Src and Fyn）or phosphatases（PTPαand STEP）are involved in regulating the phosphorylation of NMDARs.In this study,we used immunoblotting to investigate the role of an NMDAR subpopulation on the phosphorylation level of the GluN2B subunit at the Y1336 and Y1472sites in rat brain slices after NMDA treatment.We found that NMDA stimulation dramatically decreased the phosphorylation level of GluN2B at Y1472 in a dose-and time-dependent manner,but not at Y1336.Extrasynaptic NMDAR activation did not reduce the phosphorylation of GluN2B at Y1472.In addition,ifenprodil,a selective antagonist of GluN2Bcontaining NMDARs,did not abolish the decreased phosphorylation of GluN2B at Y1472 triggered by NMDA.These results suggest that the activation of synaptic GluN2A-containing NMDARs is required for the decreased phosphorylation of GluN2B at Y1472that is induced by NMDA treatment in rat brain slices.
基金Supported by the National Natural Science Foundation of China（No.81172982）, the Natural Science Foundation of Guang- dong Province of China（No.2015A030311012） and the Fundamental Research Funds for the Central Universities of China（No. 11615323）.
文摘Ten memantine（Mema）-dihydroartemisinin（DHA） ligands were designed and synthesized. Three types of isomers including α, β, and a defined y isomer were found in each intermediates（1a--1e）. Type γ isomer was firstly reported here and confirmed as a less stable eclipsed conformation. The bonding of Mema with DHA through different carbon chains generally makes the new entities more cytotoxic than either Mema or artemisinm（Arte）. The β Mema/DHA ligands are a little bit more cytotoxic than a ligands. By applying corticosterone（Cort）-impaired PC12 cells models, it was found that Mema and those ligands with more than 3 carbon chains showed weak or no neuroprotective activities against the insults. However, two ligands, 2a（β） and 2b（β） showed better effects than either Arte or their combination（Mema/Arte in 1：1 molar ratio） at a dose of 5 μmol/L. Furthermore, ligands 2a（β）, 2b（β） and 2c（β） were confn-med as mild N-methyl-D-aspartate（NMDA） antagonists, and their corresponding α isomers are weak NMDA antagonists. All the data indicate that the bonding of Mema/DHA in compacted β conformation mode results in enhanced effects against Cort-induced insults in PC12 ceils and might reverse memantine as an anti-depression NMDA antagonist.
