Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA.
Neurobiol Dis. 2011 Feb;41(2):436-44. doi: 10.1016/j.nbd.2010.10.015. Epub 2010 Oct 23.
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 the 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 by 36% the size of intra-nuclear huntingtin aggregates in R6/2 striatum. 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.
每日对啮齿动物衰老和早发性亨廷顿病（HD）模型进行系统注射一种正 AM-PA 型谷氨酸受体调节剂（ampakine），已被证明可减少突触可塑性缺陷。在这里，我们报告称，长效 ampakine 治疗可显著减缓 R6/2 HD 小鼠模型纹状体神经病理学和运动功能障碍的进展。值得注意的是，这些作用是由半衰期短的ampakine CX929 产生的。该化合物每天注射一次，持续 4-7 周，可增加 R6/2 而非野生型小鼠新皮层和纹状体中脑源性神经营养因子（BDNF）的蛋白水平。此外，ampakine 治疗可防止纹状体总面积减少，阻止纹状体 DARPP-32 免疫反应丧失，并使 R6/2 纹状体中的核内亨廷顿蛋白聚集体减少 36%。CX929 治疗还显著改善了 R6/2 小鼠在多项指标（转棒、垂直杆下降）上的运动表现，但对体重或寿命没有影响。这些发现描述了一种微创、药理学上合理的治疗 HD 策略，并且可能适用于其他神经病理学疾病。
