Treatment of stroke with a synthetic liver X receptor agonist, TO901317, promotes synaptic plasticity and axonal regeneration in mice.
Treatment of stroke with a synthetic liver X receptor agonist, TO901317, promotes synaptic plasticity and axonal regeneration in mice.
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DOI：
10.1038/jcbfm.2009.187
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发表时间：
2010-01
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在这项研究中，我们测试了 TO901317 促进中风后突触可塑性和轴突再生的假设。对成年雄性 C57BL/6J 小鼠进行大脑中动脉闭塞 (MCAo)，并在 MCAo 后每天 24 小时开始用或不用 TO901317 治疗，持续 14 天。通过免疫染色评估轴突损伤和再生。 TO901317 显着增加缺血脑中突触素表达和轴突再生，并降低淀粉样βA4前体蛋白和Nogo受体（NgR）的表达。为了测试 TO901317 是否调节缺血脑中磷脂酰肌醇 3-激酶 (p-PI3K) 的磷酸化和 Akt (p-Akt) 活性，MCAo 小鼠每天在 MCAo 后 24 小时开始用或不用 TO901317 治疗，持续 4 天，然后在 MCAo 后第 5 天处死。 TO901317治疗显着增加了缺血脑中p-PI3K和p-Akt活性，但没有增加总PI3K表达。使用原代皮质神经元 (PCN) 培养物，与未处理的对照相比，TO901317 显着增加了突触素表达、p-PI3K 活性，并降低了 NgR 表达。在培养的缺氧 PCN 中，TO901317 还显着增加了神经突生长，并且 LY294002 对 PI3K/Akt 通路的抑制减少了对照组和 TO901317 治疗组的神经突生长。这些数据表明 TO901317 促进突触可塑性和轴突再生，并且 PI3K/Akt 信号传导活性有助于神经突生长。
In this study, we tested the hypothesis that TO901317 promotes synapse plasticity and axonal regeneration after stroke. Adult male C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo) and treated with or without TO901317 starting 24 h after MCAo daily for 14 days. Axonal damage and regeneration were evaluated by immunostaining. TO901317 significantly increased synaptophysin expression and axonal regeneration, as well as decreased the expressions of amyloid betaA4 precursor protein and Nogo receptor (NgR) in the ischemic brain. To test whether TO901317 regulates the phosphorylation of phosphatidylinositol 3-kinase (p-PI3K) and Akt (p-Akt) activity in the ischemic brain, MCAo mice were treated with or without TO901317 starting 24 h after MCAo daily for 4 days and were then killed at 5 days after MCAo. TO901317 treatment significantly increased p-PI3K and p-Akt activity, but did not increase total PI3K expression in the ischemic brain. Using primary cortical neuron (PCN) culture, TO901317 significantly increased synaptophysin expression, p-PI3K activity, and decreased NgR expression compared with nontreated controls. TO901317 also significantly increased neurite outgrowth, and inhibition of the PI3K/Akt pathway by LY294002 decreased neurite outgrowth in both controls and TO901317-treated groups in cultured hypoxic PCN. These data indicate that TO901317 promotes synaptic plasticity and axonal regeneration, and that PI3K/Akt signaling activity contributes to neurite outgrowth.
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影响因子：
4.7
作者：
Pan, J;Kao, YL;Singh, US
通讯作者：
Singh, US
影响因子：
8.3
作者：
Liu Z;Li Y;Zhang X;Savant-Bhonsale S;Chopp M
通讯作者：
Chopp M
DOI：
10.1073/pnas.0711599105
发表时间：
2008-02-12
影响因子：
11.1
作者：
Kim, Hyun-Jin;Fan, Xiaotang;Gustafsson, Jan-Ake
通讯作者：
Gustafsson, Jan-Ake
影响因子：
20.1
作者：
Chen, JL;Zhang, ZG;Chopp, M
通讯作者：
Chopp, M
影响因子：
16.2
作者：
Domeniconi, M;Cao, ZU;Filbin, MT
通讯作者：
Filbin, MT