Therapeutic attenuation of mitochondrial dysfunction and oxidative stress in neurotoxin models of Parkinson's disease.
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.
Stack
Edward C
EC
Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
Ferro
Joellyn L
JL
Kim
Jinho
J
Del Signore
Steven J
SJ
Goodrich
Sarah
S
Matson
Samantha
S
Hunt
Bonnie B
BB
Cormier
Kerry
K
Smith
Karen
K
Matson
Wayne R
WR
Ryu
Hoon
H
Ferrante
Robert J
RJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D003538:Cystamine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D008297:Male; D028361:Mitochondrial Diseases / Q000188:drug therapy*; D009498:Neurotoxins; D018384:Oxidative Stress / Q000187:drug effects*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology
D009498:Neurotoxins; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D003538:Cystamine