Neuroprotection by a mitochondria-targeted drug in a Parkinson's disease model.
The objective of this study was to assess the neuroprotective effects of a mitochondria-targeted antioxidant, Mito-Q(10), the coenzyme-Q analog attached to a triphenylphosphonium cation that targets the antioxidant to mitochondria, in experimental models of Parkinson's disease (PD). Primary mesencephalic neuronal cells and cultured dopaminergic cells were treated with 1-methyl-4-phenylpyridinium (MPP(+)), an active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and mice were used for testing the efficacy of Mito-Q(10). MPP(+) treatment caused a dose-dependent loss of tyrosine hydroxylase and membrane potential and an increase in caspase-3 activation in dopaminergic cells, which were reversed by Mito-Q(10). MPTP treatment induced a loss of striatal dopamine and its metabolites, inactivation of mitochondrial aconitase in the substantia nigra, and a loss of locomotor activity in mice. Treatment with Mito-Q(10) significantly inhibited both MPP(+)- and MPTP-induced neurotoxicity in cell culture and mouse models. Collectively, these results indicate that mitochondrial targeting of antioxidants is a promising neuroprotective strategy in this preclinical mouse model of PD.
Ghosh
Anamitra
A
Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA.
Chandran
Karunakaran
K
Kalivendi
Shasi V
SV
Joseph
Joy
J
Antholine
William E
WE
Hillard
Cecilia J
CJ
Kanthasamy
Arthi
A
Kanthasamy
Anumantha
A
Kalyanaraman
Balaraman
B
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D009498:Neurotoxins; D009943:Organophosphorus Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D009994:Osmolar Concentration; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D014451:Ubiquinone / Q000008:administration & dosage* / Q000494:pharmacology / Q000031:analogs & derivatives
D018696:Neuroprotective Agents; D009498:Neurotoxins; D009943:Organophosphorus Compounds; D014451:Ubiquinone; C429014:mitoquinone; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine