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Experimental therapeutics: preclinical
B13 NP03, a low dose lithium microemulsion, improves motor function and rescues striatal pathology without toxicity in the YAC128 mouse model of Huntington's disease
  1. M A Pouladi1,
  2. E Brilluad2,
  3. Y Xie1,
  4. S Franciosi1,
  5. W-N Zhang1,
  6. M Zapala1,
  7. E Compte2,
  8. P Poucheret2,
  9. J-C Maurel2,
  10. C Néri3,
  11. M R Hayden1
  1. 1Centre for Molecular Medicine and Therapeutics, University of British Columbia, and Child and Family Research Institute, Vancouver, British Columbia, Canada
  2. 2Medesis Pharma, Baillargues, France
  3. 3Inserm, Unit 857 Neuronal Cell Biology and Pathology, Centre Paul Broca, Paris, France

Abstract

Background Huntington's disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the HD gene, remains without a cure. 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, including Alzheimer's disease, spinocerebellar ataxia type 1 and fragile X syndrome but has various toxic effects at conventional therapeutic doses.

Aims To examine whether treatment with NP03, a low dose lithium microemulsion, would improve the phenotype of the YAC128 mouse model of HD.

Methods YAC128 mice were treated with 0, 20 or 40 μg Li/kg of lithium carbonate in the form of NP03, a microemulsion of reverse micelles, via a daily deposit on rectal mucosa for 10 months, starting at 2 months of age. The microemulsion preparation allows for an increase in cellular bioavailability of lithium. Low doses of lithium in NP03 form are sufficient to achieve the intended therapeutic levels, while mitigating the toxic side effects associated with conventional lithium preparations. Wild-type (WT) animals were treated with NP03 either at 0 or 40 μg Li/kg. Motor function was assessed using the accelerating rotarod test at 2, 4, 6, 8, 10 and 12 months of age. Striatal pathology was assessed using unbiased stereology at 12 months of age.

Results Treatment with NP03 at 40 μg Li/kg resulted in significant improvements in motor function in YAC128 HD mice. Further, the deficits in striatal volume, neuronal counts and DARPP-32 expression observed in YAC128 HD animals treated with vehicle alone were prevented in YAC128 HD animals treated with NP03 at 40 μg Li/kg. The motor function, striatal volume and neuronal counts of WT animals treated with NP03 at 40 μg Li/kg were similar to those of WT animals treated with vehicle alone. Furthermore, treatment with NP03 at 40μg Li/kg resulted in significant rescue of the testicular weight loss observed in YAC128 HD. Finally, treatment with NP03 at 40 μg Li/kg resulted in improved survival in YAC128 mice compared with animals treated with vehicle alone. There were no obvious toxic side effects associated with long term lithium treatment in YAC128 or WT animals.

Conclusions Our findings, demonstrating multiple positive effects of low dose lithium in the form of NP03 on behavioural and neuropathological endpoints in an animal model of HD, support its further development as a potential therapeutic agent in HD.

  • Huntington disease
  • preclinical
  • therapeutic trial
  • lithium
  • neuroprotection
  • YAC128
  • mouse model

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