Centre for Molecular Medicine and Therapeutics, University of British Columbia, and Child and Family Research Institute, Vancouver, BC, Canada.
Neurobiol Dis. 2012 Dec;48(3):282-9. doi: 10.1016/j.nbd.2012.06.026. Epub 2012 Jul 10.
Huntington disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene, remains without a treatment to modify the course of the illness. Lithium, a drug widely used for the treatment of bipolar disorder, has been shown to exert neuroprotective effects in a number of models of neurological disease but may have various toxic effects at conventional therapeutic doses. We examined whether NP03, a novel low-dose lithium microemulsion, would improve the disease phenotypes in the YAC128 mouse model of HD. We demonstrate that NP03 improves motor function, ameliorates the neuropathological deficits in striatal volume, neuronal counts, and DARPP-32 expression, and partially rescues testicular atrophy in YAC128 mice. These positive effects were accompanied by improvements in multiple biochemical endpoints associated with the pathogenesis of HD, including normalization of caspase-6 activation and amelioration of deficits in BDNF levels, and with no lithium-related toxicity. Our findings demonstrate that NP03 ameliorates the motor and neuropathological phenotypes in the YAC128 mouse model of HD, and represents a potential therapeutic approach for HD.
亨廷顿病（HD）是一种由 HTT 基因中 CAG 重复扩展引起的神经退行性疾病，目前尚无治疗方法可以改变疾病进程。锂是一种广泛用于治疗双相情感障碍的药物，已被证明在许多神经疾病模型中具有神经保护作用，但在常规治疗剂量下可能具有各种毒性作用。我们研究了新型低剂量锂微乳液 NP03 是否会改善 HD 的 YAC128 小鼠模型的疾病表型。我们证明 NP03 可改善运动功能，减轻纹状体体积、神经元计数和 DARPP-32 表达的神经病理缺陷，并部分挽救 YAC128 小鼠的睾丸萎缩。这些积极影响伴随着与 HD 发病机制相关的多个生化终点的改善，包括半胱天冬酶-6 激活的正常化和 BDNF 水平缺陷的改善，且没有锂相关毒性。我们的研究结果表明，NP03 可改善 YAC128 小鼠 HD 模型的运动和神经病理表型，代表了治疗 HD 的一种潜在治疗方法。
