NP03, a novel low-dose lithium formulation, is neuroprotective in the YAC128 mouse model of Huntington disease

Neurobiology of Disease

Elsa Brillaud¹  Paola Conforti²  Patrick Poucheret²  Sonia Franciosi²  Weining Zhang²  Dagmar E. Ehrnhoefer²  Mahmoud A. Pouladi²  Rona K. Graham³  Elena Cattaneo³  Christian Néri³  Michael R. Hayden⁴  Elsa Compte⁵  Chiara Zuccato⁶  Yuanyun Xie⁶  Jean-Claude Maurel⁶ 

[1] Translational Laboratory in Genetic Medicine (TLGM), Department of Medicine, National University of Singapore, and Agency for Science, Technology and Research (A*STAR), Singapore 117609, Singapore;Centre for Molecular Medicine and Therapeutics, University of British Columbia, and Child and Family Research Institute, Vancouver, BC, Canada;Department of Pharmacological Sciences and Centre for Stem Cell Research, University of Milan, Milano, Italy;Inserm, Unit 894, Laboratory of Neuronal Cell Biology and Pathology, 75014 Paris, France;Laboratoire de Pharmacologie et Physiopathologie Expérimentale, UMR 95 Qualisud, Faculté de Pharmacie, Université Montpellier I, 15 Avenue Charles Flahault, F-34093 Montpellier Cedex 5, France;Medesis Pharma, Baillargues, France;

关键词: Huntington disease;    Transgenic mouse model;    Lithium;    Caspase-6;    BDNF;    GSK-3;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown