Mitochondria targeted peptides protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity.
A large body of evidence suggests that mitochondrial dysfunction and oxidative damage play a role in the pathogenesis of Parkinson's disease (PD). A number of antioxidants have been effective in animal models of PD. We have developed a family of mitochondria-targeted peptides that can protect against mitochondrial swelling and apoptosis (SS peptides). In this study, we examined the ability of two peptides, SS-31 and SS-20, to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice. SS-31 produced dose-dependent complete protection against loss of dopamine and its metabolites in striatum, as well as loss of tyrosine hydroxylase immunoreactive neurons in substantia nigra pars compacta. SS-20, which does not possess intrinsic ability in scavenging reactive oxygen species, also demonstrated significant neuroprotective effects on dopaminergic neurons of MPTP-treated mice. Both SS-31 and SS-20 were very potent (nM) in preventing MPP+ (1-methyl-4-phenylpyridinium)-induced cell death in cultured dopamine cells (SN4741). Studies with isolated mitochondria showed that both SS-31 and SS-20 prevented MPP+-induced inhibition of oxygen consumption and ATP production, and mitochondrial swelling. These findings provide strong evidence that these neuroprotective peptides, which target both mitochondrial dysfunction and oxidative damage, are a promising approach for the treatment of PD.
Yang
Lichuan
L
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, New York 10021, USA.
Zhao
Kesheng
K
Calingasan
Noel Y
NY
Luo
Guoxiong
G
Szeto
Hazel H
HH
Beal
M Flint
MF
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D020267:MPTP Poisoning / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption; D010455:Peptides / Q000494:pharmacology*; D013378:Substantia Nigra / Q000473:pathology
D010455:Peptides; D000255:Adenosine Triphosphate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine