NP03, a novel low-dose lithium formulation, is neuroprotective in the YAC128 mouse model of Huntington disease.
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.
Centre for Molecular Medicine and Therapeutics, University of British Columbia, and Child and Family Research Institute, Vancouver, BC, Canada.
Mahmoud A
MA
Pouladi
Elsa
E
Brillaud
Yuanyun
Y
Xie
Paola
P
Conforti
Rona K
RK
Graham
Dagmar E
DE
Ehrnhoefer
Sonia
S
Franciosi
Weining
W
Zhang
Patrick
P
Poucheret
Elsa
E
Compte
Jean-Claude
JC
Maurel
Chiara
C
Zuccato
Elena
E
Cattaneo
Christian
C
Néri
Michael R
MR
Hayden
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology; D015151:Immunoblotting; D008094:Lithium / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018696:Neuroprotective Agents; D008094:Lithium