Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. Oxidative damage has been associated with pathological neuronal loss in HD. The therapeutic modulation of oxidative stress and mitochondrial function using low molecular weight compounds may be an important strategy for delaying the onset and slowing the progression of HD. In the present study, we found a marked increase of 4-hydroxy-2-nonenal (4-HNE) adducts, a lipid peroxidation marker, in the caudate and putamen of HD brains and in the striatum of HD mice. Notably, 4-HNE immunoreactivity was colocalized with mutant huntingtin inclusions in the striatal neurons of R6/2 HD mice. Administration of nordihydroguaiaretic acid (NDGA), an antioxidant that functions by inhibiting lipid peroxidation, markedly reduced 4-HNE adduct formation in the nuclear inclusions of R6/2 striatal neurons. NDGA also protected cultured neurons against oxidative stress-induced cell death by improving ATP generation and mitochondrial morphology and function. In addition, NDGA restored mitochondrial membrane potential, mitochondrial structure, and synapse structure in the striatum of R6/2 mice and increased their lifespan. The present findings suggest that further therapeutic studies using NDGA are warranted in HD and other neurodegenerative diseases characterized by increased oxidative stress and altered mitochondrial function.
Publication types
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Research Support, N.I.H., Extramural
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Video-Audio Media
MeSH terms
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Adenosine Triphosphate / metabolism
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Age Factors
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Aldehydes / metabolism
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Analysis of Variance
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Animals
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Cells, Cultured
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Cerebral Cortex / cytology
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Embryo, Mammalian
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Glutamic Acid / pharmacology
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Humans
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Huntingtin Protein
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Huntington Disease / drug therapy
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Huntington Disease / genetics
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Huntington Disease / pathology*
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Imaging, Three-Dimensional / methods
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In Situ Nick-End Labeling / methods
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Indoles
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Lipid Peroxidation / drug effects
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Lipid Peroxidation / physiology*
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Lipoxygenase Inhibitors / therapeutic use
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Male
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Masoprocol / therapeutic use
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Membrane Potential, Mitochondrial / drug effects
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Membrane Potential, Mitochondrial / genetics
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Mice
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Mice, Transgenic
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Microscopy, Electron, Transmission / methods
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Mitochondria / drug effects
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Mitochondria / pathology*
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Mitochondria / ultrastructure
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Neostriatum / drug effects
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Neostriatum / pathology*
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Nerve Tissue Proteins / genetics
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Neurons / metabolism
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Neurons / pathology
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Neurons / ultrastructure
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Nuclear Proteins / genetics
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Oxidative Stress / drug effects
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Oxidative Stress / genetics
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Synapses / drug effects
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Synapses / pathology
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Synapses / ultrastructure
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Tetrazolium Salts
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Thiazoles
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Trinucleotide Repeat Expansion / genetics
Substances
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Aldehydes
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Htt protein, mouse
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Huntingtin Protein
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Indoles
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Lipoxygenase Inhibitors
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Nerve Tissue Proteins
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Nuclear Proteins
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Tetrazolium Salts
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Thiazoles
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Glutamic Acid
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DAPI
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Masoprocol
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Adenosine Triphosphate
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thiazolyl blue
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4-hydroxy-2-nonenal