Polyzos Aris, Holt Amy, Brown Christopher, Cosme Celica, Wipf Peter, Gomez-Marin Alex, Castro Maríadel R, Ayala-Peña Sylvette, McMurray Cynthia T
Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd., Berkeley, CA 94720, USA.
Molecular Cellular Biology Program, University of California Berkeley, Berkeley, CA 94720, USA.
Hum Mol Genet. 2016 May 1;25(9):1792-802. doi: 10.1093/hmg/ddw051. Epub 2016 Feb 21.
Oxidative damage to mitochondria (MT) is a major mechanism for aging and neurodegeneration. We have developed a novel synthetic antioxidant, XJB-5-131, which directly targets MT, the primary site and primary target of oxidative damage. XJB-5-131 prevents the onset of motor decline in an HdhQ(150/150) mouse model for Huntington's disease (HD) if treatment starts early. Here, we report that XJB-5-131 attenuates or reverses disease progression if treatment occurs after disease onset. In animals with well-developed pathology, XJB-5-131 promotes weight gain, prevents neuronal death, reduces oxidative damage in neurons, suppresses the decline of motor performance or improves it, and reduces a graying phenotype in treated HdhQ(150/150) animals relative to matched littermate controls. XJB-5-131 holds promise as a clinical candidate for the treatment of HD.
线粒体（MT）的氧化损伤是衰老和神经退行性变的主要机制。我们研发了一种新型合成抗氧化剂XJB - 5 - 131，它直接作用于MT，而MT是氧化损伤的主要部位和主要靶点。如果在早期开始治疗，XJB - 5 - 131可预防亨廷顿舞蹈病（HD）的HdhQ(150/150)小鼠模型中运动功能衰退的发生。在此，我们报告，如果在疾病发作后进行治疗，XJB - 5 - 131可减轻或逆转疾病进展。在病理状况已充分发展的动物中，相对于匹配的同窝对照动物，XJB - 5 - 131可促进HdhQ(150/150)动物体重增加、预防神经元死亡、减少神经元中的氧化损伤、抑制运动能力下降或改善运动能力，并减轻毛发变白的表型。XJB - 5 - 131有望成为治疗HD的临床候选药物。
