Résumé
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.
► NP03, a novel formulation, allows delivery of significantly lower yet pharmacologically active amounts of lithium. ► NP03 ameliorates motor dysfunction and neuropathology in YAC128 HD mice. ► NP03 corrects multiple HD-related molecular deficits in YAC128 HD mice. ► NP03 is safe with no toxicity associated with long-term use in YAC128 HD mice. ► NP03 is neuroprotective in the YAC128 HD mice and a promising approach to treatment of HD.