Brief ampakine treatments slow the progression of Huntington's disease phenotypes in R6/2 mice.
Brief ampakine treatments slow the progression of Huntington's disease phenotypes in R6/2 mice.
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DOI：
10.1016/j.nbd.2010.10.015
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发表时间：
2011-02
影响因子：
6.1
通讯作者：
Lynch, Gary
中科院分区：
文献类型：
--
作者：
Simmons, Danielle A.;Mehta, Rishi A.;Lauterborn, Julie C.;Gall, Christine M.;Lynch, Gary
每日全身注射阳性AMPA型谷氨酸受体调节剂（ampakine）已显示可减少衰老和早期亨廷顿病（HD）啮齿动物模型中的突触可塑性缺陷。在这里，我们报告说，长期的ampakine治疗显着减缓纹状体神经病理学和运动功能障碍的R6/2 HD小鼠模型的进展。值得注意的是，这些效果是由一种半衰期很短的安巴金CX 929产生的。每天注射一次，持续4-7周，该化合物增加了R6/2小鼠新皮质和纹状体中脑源性神经营养因子（BDNF）的蛋白水平，但野生型小鼠没有。此外，ampakine治疗防止了总纹状体面积的减少，阻断了纹状体DARPP-32免疫反应性的丧失，并将R6/2纹状体中核内亨廷顿蛋白聚集体的面积减少了36%。CX 929治疗还在几个测量（旋转棒、垂直杆下降）上显著改善了R6/2小鼠的运动性能，但不影响体重或寿命。这些发现描述了一种微创、合理的治疗HD和潜在的其他神经病理学疾病的策略。
Daily, systemic injections of a positive AMPA-type glutamate receptor modulator (ampakine) have been shown to reduce synaptic plasticity defects in rodent models of aging and early-stage Huntington’s Disease (HD). Here we report that long-term ampakine treatment markedly slows the progression of striatal neuropathology and locomotor dysfunction in the R6/2 HD mouse model. Remarkably, these effects were produced by an ampakine, CX929, with a short half-life. Injected once daily for 4–7 weeks, the compound increased protein levels of brain-derived neurotrophic factor (BDNF) in neocortex and striatum of R6/2 but not wild-type mice. Moreover, ampakine treatments prevented the decrease in total striatal area, blocked the loss of striatal DARPP-32 immunoreactivity and reduced the area of intranuclear huntingtin aggregates in R6/2 striatum by 36%. The CX929 treatments also markedly improved motor performance of R6/2 mice on several measures (rotarod, vertical pole descent) but did not influence body weight or lifespan. These findings describe a minimally invasive, pharmacologically plausible strategy for treatment of HD and, potentially, other neuropathological diseases.
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影响因子：
3.3
作者：
Hickey MA;Kosmalska A;Enayati J;Cohen R;Zeitlin S;Levine MS;Chesselet MF
通讯作者：
Chesselet MF
影响因子：
5.3
作者：
Canals, JM;Pineda, JR;Alberch, J
通讯作者：
Alberch, J
影响因子：
4.7
作者：
Chou, SY;Lee, YC;Chern, YJ
通讯作者：
Chern, YJ
影响因子：
4.8
作者：
Bogush, Alexey;Pedrini, Steve;Ehrlich, Michelle E.
通讯作者：
Ehrlich, Michelle E.
影响因子：
4.7
作者：
Deltheil, T.;Guiard, B. P.;Gardier, A. M.
通讯作者：
Gardier, A. M.