title: 2,4 DNP improves motor function, preserves medium spiny neuronal identity, and reduces oxidative stress in a mouse model of Huntington's disease.
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, 5mg/kg/day) on mHtt-induced behavioral deficits and cellular abnormalities in the N171-82Q HD mouse model. DNP at a low dose (1mg/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.
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of General Practice, The First hospital of China Medical University, Shenyang, Liaoning Province, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Mali
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Peng
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Pharmacology, Inner Mongolian Medical University School of Pharmacy, Hohhot, Inner Mongolian, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Eicosanoid Core Laboratory, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, United States.
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.affiliation: Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Susumu
authors.initials: S
authors.lastname: Mori
authors.affiliation: Mitochon Pharmaceuticals Inc., Radnor, PA, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Alonso
authors.affiliation: Mitochon Pharmaceuticals Inc., Radnor, PA, United States.
authors.forename: John G
authors.initials: JG
authors.lastname: Geisler
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States. Electronic address: wduan2@jhmi.edu.
authors.forename: Wenzhen
authors.initials: W
authors.lastname: Duan
mesh_terms: D019297:2,4-Dinitrophenol / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000473:pathology; D000076122:Disks Large Homolog 4 Protein; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D051528:Guanylate Kinases / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D000071058:Huntingtin Protein; D008565:Membrane Proteins; C497929:Ppp1r1b protein, mouse; D051528:Guanylate Kinases; D019297:2,4-Dinitrophenol
keywords: 2,4-dinitrophenol; Huntington's disease; Mitochondrial uncoupling; Oxidative stress, DARPP32