한빛사 논문
Junghee Lee • Bela Kosaras • Steve J. Del Signore • Kerry Cormier • Ann McKee • Rajiv R. Ratan • Neil W. Kowall • Hoon Ryu*
J. Lee S. J. Del Signore K. Cormier A. McKee
N. W. Kowall H. Ryu
Department of Neurology and Pathology,
Boston University School of Medicine,
Boston, MA 02118, USA
J. Lee N. W. Kowall H. Ryu
VA Boston Healthcare System, Building 1A,
Rm 109, Boston, MA 02130, USA
B. Kosaras
Department of Neurology, Beth Israel Deaconess Medical
Center and Harvard Medical School, Boston, MA 02115, USA
S. J. Del Signore K. Cormier A. McKee
Bedford VA Medical Center, Bedford, MA 01730, USA
R. R. Ratan
Department of Neurology, Weill Medical College of Cornell
University, Burke-Cornell Medical Research Institute,
White Plains, NY 10605, USA
*Corresponding author.
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.
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