Therapeutic attenuation of mitochondrial dysfunction and oxidative stress in neurotoxin models of Parkinson's disease

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1782

Article

Stack, Edward C.^1,2  Ferro, Joellyn L.²  Kim, Jinho²  Del Signore, Steven J.²  Goodrich, Sarah²  Matson, Samantha²  Hunt, Bonnie B.²  Cormier, Kerry²  Smith, Karen^1,2  Matson, Wayne R.¹  Ryu, Hoon²  Ferrante, Robert J.^1,2,3,4 

[1] Bedford VA Med Ctr, GRECC Unit 182B, New England Net Adm VISN 1, Bedford, MA 01730 USA

[2] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA

[3] Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA

[4] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA

关键词: cystamine;    MPTP;    6-OHDA;    basal ganglia;    ATP;    capsase-3;    dopamine;   

DOI  :  10.1016/j.bbadis.2007.12.006

来源: Elsevier

【 摘 要 】

Parkinson's disease (PD) is a progressive neurodegenerative disorder for which there is no current therapy preventing cumulative neuronal loss. There is substantial evidence that mitochondrial dysfunction, oxidative stress, and associated caspase activity underlie the neurodegeneration observed. One potential drug therapy is the potent free radical scavenger and antioxidant cystamine, which has demonstrated significant clinical potential in models of neurodegenerative disorders and human neurological disease. This study examined the oral efficacy of cystamine in the MPTP and 6-hydroxydopamine neurotoxin models of PD. The neuroprotective effects of cystamine treatment significantly ameliorated nigral neuronal loss, preserved striatal dopaminergic projections, and improved striatal dopamine and metabolite levels, as compared to MPTP alone. Cystamine normalized striatal 8-hydroxy-2'-deoxyguanosine levels and ATP concentrations, consistent with reduced oxidative stress and improved mitochondrial function. Cystamine also protected against MPTP-induced mitochondrial loss, as identified by mitochondrial heat shock protein 70 and superoxide dismutase 2, with concomitant reductions in cytochrome c and caspase-3 activities. The neuroprotective value of cystamine was confirmed in the 6-hydroxydopamine model. Together these findings show cystamine's therapeutic benefit to reduce neuronal loss through attenuation of oxidative stress and mitochondrial dysfunction, providing the rationale for human clinical trials in PD patients. Published by Elsevier B.V.

【 授权许可】

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