Curcumin-induced degradation of PKCδ is associated with enhanced dentate NCAM PSA expression and spatial learning in adult and aged Wistar rats
Curcumin-induced degradation of PKCδ is associated with enhanced dentate NCAM PSA expression and spatial learning in adult and aged Wistar rats
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DOI：
10.1016/j.bcp.2008.12.011
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发表时间：
2009-04-01
影响因子：
5.8
通讯作者：
Regan, Ciaran M.
中科院分区：
文献类型：
--
作者：
Conboy, Lisa;Foley, Andrew G.;Regan, Ciaran M.
神经细胞粘附分子（NCAM PSA）的聚唾液酸化对于基于校园的学习的巩固过程是必要的。以前，我们已经发现蛋白激酶C δ（PKC δ）的抑制与多聚唾液酸转移酶（PST）活性的增加有关，这表明这种激酶的抑制剂可能会改善认知缺陷。使用rottlerin模板（一种以前被认为是PKC δ抑制剂的药物），我们用Alfreys的催化剂程序搜索了可供购买的化合物（CAP）数据库，寻找结构相似的分子，并使用PKC δ的佛波醇结合结构域的可用晶体结构，发现二阿魏酰甲烷（姜黄素）有效地对接到佛波醇位点。姜黄素增加培养的neuro-2A神经母细胞瘤细胞NCAM PSA表达，这与PKC δ蛋白表达呈负相关。Curcurnin不直接抑制PKC δ活性，但与酶形成紧密复合物。随着姜黄素剂量的增加，已知指导其降解的PKC δ的Tyr（131）残基逐渐磷酸化，这与许多Tyr（131）-磷酸化-PKC δ片段相关。姜黄素在体内的慢性给药也增加了在齿状颗粒下区的聚唾液酸化细胞的频率，并显着提高了收购和巩固的水迷宫空间学习范式在成年和老年队列的Wistar大鼠。这些结果进一步证实了PKC δ在调节PST和NCAM PSA表达中的作用，并提供了证据表明该系统的药物调节增强了记忆巩固的过程。(C)2009 Elsevier Inc. All rights reserved.
Polysialylation of the neural cell adhesion molecule (NCAM PSA) is necessary for the consolidation processes of hippocampus-based learning. Previously, we have found inhibition of protein kinase C delta (PKC delta) to be associated with increased polysialyltransferase (PST) activity, suggesting inhibitors of this kinase might ameliorate cognitive deficits. Using a rottlerin template, a drug previously considered an inhibitor of PKC delta, we searched the Compounds Available for Purchase (CAP) database with the Accelrys" Catalyst programme for structurally similar molecules and, using the available crystal structure of the phorbol-binding domain of PKC delta, found that diferuloylmethane (curcumin) docked effectively into the phorbol site. Curcumin increased NCAM PSA expression in cultured neuro-2A neuroblastoma cells and this was inversely related to PKC delta protein expression. Curcurnin did not directly inhibit PKC delta activity but formed a tight complex with the enzyme. With increasing doses of curcumin, the Tyr(131) residue of PKC delta, which is known to direct its degradation, became progressively phosphorylated and this was associated with numerous Tyr(131)-phospho-PKC delta fragments. Chronic administration of curcumin in vivo also increased the frequency of polysialylated cells in the dentate infragranular zone and significantly improved the acquisition and consolidation of a water maze spatial learning paradigm in both adult and aged cohorts of Wistar rats. These results further confirm the role of PKC delta in regulating PST and NCAM PSA expression and provide evidence that drug modulation of this system enhances the process of memory consolidation. (C) 2009 Elsevier Inc. All rights reserved.