2,4 DNP improves motor function, preserves medium spiny neuronal identity, and reduces oxidative stress in a mouse model of Huntington's disease

Bin Wu, Mali Jiang, Qi Peng, Gang Li, Zhipeng Hou, Ginger L. Milne, Susumu Mori, Robert Alonso, John G. Geisler, Wenzhen Duan

Research output: Research - peer-reviewArticle

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the gene huntingtin. There is no treatment to prevent or delay the disease course of HD currently. Oxidative stress and mitochondrial dysfunction have emerged as key determinants of the disease progression in HD. Therefore, counteracting mutant huntingtin (mHtt)-induced oxidative stress and mitochondrial dysfunction appears as a new approach to treat this devastating disease. Interestingly, mild mitochondrial uncoupling improves neuronal resistance to stress and facilitates neuronal survival. Mild mitochondrial uncoupling can be induced by the proper dose of 2,4-dinitrophenol (DNP), a proton ionophore that was previously used for weight loss. In this study, we evaluated the effects of chronic administration of DNP at three doses (0.5, 1, 5 mg/kg/day) on mHtt-induced behavioral deficits and cellular abnormalities in the N171-82Q HD mouse model. DNP at a low dose (1 mg/kg/day) significantly improved motor function and preserved medium spiny neuronal marker DARPP32 and postsynaptic protein PSD95 in the striatum of HD mice. Further mechanistic study suggests that DNP at this dose reduced oxidative stress in HD mice, which was indicated by reduced levels of F2-isoprostanes in the brain of HD mice treated with DNP. Our data indicated that DNP provided behavioral benefit and neuroprotective effect at a weight neutral dose in HD mice, suggesting that the potential value of repositioning DNP to HD treatment is warranted in well-controlled clinical trials in HD.

LanguageEnglish (US)
Pages83-90
Number of pages8
JournalExperimental Neurology
Volume293
DOIs
StatePublished - Jul 1 2017

Fingerprint

2,4-Dinitrophenol
Huntington Disease
Oxidative Stress
Proton Ionophores
F2-Isoprostanes
Controlled Clinical Trials
Brain Diseases
Neuroprotective Agents
Neurodegenerative Diseases
Disease Progression
Weight Loss
Exons
Weights and Measures
Genes
Proteins

Keywords

  • 2,4-dinitrophenol
  • Huntington's disease
  • Mitochondrial uncoupling
  • Oxidative stress, DARPP32

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

2,4 DNP improves motor function, preserves medium spiny neuronal identity, and reduces oxidative stress in a mouse model of Huntington's disease. / Wu, Bin; Jiang, Mali; Peng, Qi; Li, Gang; Hou, Zhipeng; Milne, Ginger L.; Mori, Susumu; Alonso, Robert; Geisler, John G.; Duan, Wenzhen.

In: Experimental Neurology, Vol. 293, 01.07.2017, p. 83-90.

Research output: Research - peer-reviewArticle

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