Combined Treatment with the Mood Stabilizers Lithium and Valproate Produces Multiple Beneficial Effects in Transgenic Mouse Models of Huntington's Disease
Combined Treatment with the Mood Stabilizers Lithium and Valproate Produces Multiple Beneficial Effects in Transgenic Mouse Models of Huntington's Disease
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DOI：
10.1038/npp.2011.128
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发表时间：
2011-11-01
影响因子：
7.6
通讯作者：
Chuang, De-Maw
中科院分区：
文献类型：
--
作者：
Chiu, Chi-Tso;Liu, Guangping;Chuang, De-Maw
新的证据表明，情绪稳定剂锂和丙戊酸盐(VPA)具有广泛的神经保护和神经营养特性，这些特性分别通过抑制糖原合成酶-3(GSK-3)和组蛋白脱乙酰酶(HDAC)而发生。亨廷顿病(HD)是一种遗传性神经退行性疾病，其特征是运动障碍、认知和精神障碍以及过早死亡。我们对N171-82Q和YAC128小鼠，两种遗传背景和病理进展不同的HD小鼠模型进行了治疗，饮食中含有治疗量的锂和/或VPA。未经治疗，这些转基因小鼠在行为障碍开始前后，纹状体和大脑皮层中GSK-3β丝氨酸9磷酸化和组蛋白H3乙酰化水平下降，表明GSK-3β和HDACs过度活跃。通过多项有效的行为测试，我们发现锂和VPA联合治疗更有效地缓解了两种HD模型小鼠的自发运动缺陷和抑郁样行为。此外，与单独使用任何一种药物相比，联合治疗更成功地改善了N171-82Q小鼠的运动技能学习和协调性，并抑制了YAC128小鼠的焦虑样行为。这种联合治疗持续抑制GSK-3β和HDAC，并导致纹状体和皮质脑源性神经营养因子和热休克蛋白70持续升高。重要的是，联合治疗显著延长了N171-82Q小鼠的中位生存期，从31.6周延长到41.6周。鉴于目前尚无已证实的治疗HD的方法，我们的结果表明，锂和VPA这两种在人类中长期安全使用的情绪稳定剂的联合治疗可能对HD患者具有重要的治疗潜力。神经精神药理学(2011年)36,2406-2421；DOI：10.1038/npp.2011.128；2011年7月27日在线发布
Emerging evidence suggests that the mood stabilizers lithium and valproate (VPA) have broad neuroprotective and neurotrophic properties, and that these occur via inhibition of glycogen synthase kinase 3 (GSK-3) and histone deacetylases (HDACs), respectively. Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by impaired movement, cognitive and psychiatric disturbances, and premature death. We treated N171-82Q and YAC128 mice, two mouse models of HD varying in genetic backgrounds and pathological progressions, with a diet containing therapeutic doses of lithium, VPA, or both. Untreated, these transgenic mice displayed a decrease in levels of GSK-3 beta serine 9 phosphorylation and histone H3 acetylation in the striatum and cerebral cortex around the onset of behavioral deficits, indicating a hyperactivity of GSK-3 beta and HDACs. Using multiple well-validated behavioral tests, we found that co-treatment with lithium and VPA more effectively alleviated spontaneous locomotor deficits and depressive-like behaviors in both models of HD mice. Furthermore, compared with monotherapy with either drug alone, co-treatment more successfully improved motor skill learning and coordination in N171-82Q mice, and suppressed anxiety-like behaviors in YAC128 mice. This combined treatment consistently inhibited GSK-3 beta and HDACs, and caused a sustained elevation in striatal as well as cortical brain-derived neurotrophic factor and heat shock protein 70. Importantly, co-treatment markedly prolonged median survival of N171-82Q mice from 31.6 to 41.6 weeks. Given that there is presently no proven treatment for HD, our results suggest that combined treatment with lithium and VPA, two mood stabilizers with a long history of safe use in humans, may have important therapeutic potential for HD patients. Neuropsychopharmacology (2011) 36, 2406-2421; doi:10.1038/npp.2011.128; published online 27 July 2011