Inhibition of glycogen synthase kinase-3β enhances cognitive recovery after stroke: the role of TAK1.
Inhibition of glycogen synthase kinase-3β enhances cognitive recovery after stroke: the role of TAK1.
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DOI：
10.1101/lm.038083.115
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
McCullough LD
中科院分区：
文献类型：
--
作者：
Venna VR;Benashski SE;Chauhan A;McCullough LD
记忆力缺陷在中风幸存者中很常见。确定可以防止记忆障碍或改善记忆恢复的神经保护剂是一个重要的研究领域。糖原合成酶激酶-3 β（Glycogen synthase kinase-3 β，GSK-3β）参与多种重要的细胞内信号转导途径。与许多其他激酶不同，GSK-3β仅在去磷酸化时才有活性，活化促进炎症和凋亡。相反，磷酸化增加导致GSK-3β（pGSK-3β）活性降低。GSK-3β抑制对其他疾病模型中的记忆具有有益作用。GSK-3β调节5 'AMP激活激酶（AMPK）和转化生长因子β激活激酶（TEK 1）途径。在这项工作中，我们检查了GSK-3β抑制剂的作用，无论是独立的，与TAK抑制剂联合使用，还是在AMPK-α2缺陷小鼠中，在中风后研究这些途径之间的机制相互作用。GSK-3β抑制具有神经保护作用，并改善了卒中诱导的认知障碍。这与AMPK信号传导无关，因为在AMPK缺陷小鼠中观察到GSK-3β抑制的保护作用。然而，GSK-3β抑制在TAK抑制剂处理的小鼠中未提供叠加保护，表明TAK 1是GSK-3β的上游调节因子。以GSK-3β为靶点可能成为脑卒中后认知功能障碍的一种新的治疗策略。
Memory deficits are common among stroke survivors. Identifying neuroprotective agents that can prevent memory impairment or improve memory recovery is a vital area of research. Glycogen synthase kinase-3β (GSK-3β) is involved in several essential intracellular signaling pathways. Unlike many other kinases, GSK-3β is active only when dephosphorylated and activation promotes inflammation and apoptosis. In contrast, increased phosphorylation leads to reduced GSK-3β (pGSK-3β) activity. GSK-3β inhibition has beneficial effects on memory in other disease models. GSK-3β regulates both the 5′AMP-activated kinase (AMPK) and transforming growth factor-β-activated kinase (TAK1) pathways. In this work, we examined the effect of GSK-3β inhibition, both independently, in conjunction with a TAK inhibitor, and in AMPK-α2 deficient mice, after stroke to investigate mechanistic interactions between these pathways. GSK-3β inhibition was neuroprotective and ameliorated stroke-induced cognitive impairments. This was independent of AMPK signaling as the protective effects of GSK-3β inhibition were seen in AMPK deficient mice. However, GSK-3β inhibition provided no additive protection in mice treated with a TAK inhibitor suggesting that TAK1 is an upstream regulator of GSK-3β. Targeting GSK-3β could be a novel therapeutic strategy for post-stroke cognitive deficits.
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影响因子：
37.8
作者：
Go AS;Mozaffarian D;Roger VL;Benjamin EJ;Berry JD;Blaha MJ;Dai S;Ford ES;Fox CS;Franco S;Fullerton HJ;Gillespie C;Hailpern SM;Heit JA;Howard VJ;Huffman MD;Judd SE;Kissela BM;Kittner SJ;Lackland DT;Lichtman JH;Lisabeth LD;Mackey RH;Magid DJ;Marcus GM;Marelli A;Matchar DB;McGuire DK;Mohler ER 3rd;Moy CS;Mussolino ME;Neumar RW;Nichol G;Pandey DK;Paynter NP;Reeves MJ;Sorlie PD;Stein J;Towfighi A;Turan TN;Virani SS;Wong ND;Woo D;Turner MB;American Heart Association Statistics Committee and Stroke Statistics Subcommittee
通讯作者：
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
影响因子：
6.1
作者：
Hu S;Begum AN;Jones MR;Oh MS;Beech WK;Beech BH;Yang F;Chen P;Ubeda OJ;Kim PC;Davies P;Ma Q;Cole GM;Frautschy SA
通讯作者：
Frautschy SA
影响因子：
4.8
作者：
McCullough, LD;Zeng, ZY;Ronnett, GV
通讯作者：
Ronnett, GV
影响因子：
4.8
作者：
Liang, Min-Huei;Chuang, De-Maw
通讯作者：
Chuang, De-Maw
影响因子：
5.3
作者：
Koh, Seong-Ho;Kim, Youngchul;Kim, Seung H.
通讯作者：
Kim, Seung H.