Oxidative stress is implicated in the death of dopaminergic neurons in
Parkinson's disease and in the 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (
MPTP) model of
Parkinson's disease. Oxidative species that might mediate this damage include
hydroxyl radical, tyrosyl radical, or
reactive nitrogen species such as
peroxynitrite. In mice, we showed that
MPTP markedly increased levels of
o, o'-dityrosine and
3-nitrotyrosine in the striatum and midbrain but not in brain regions resistant to
MPTP. These two stable compounds indicate that tyrosyl radical and
reactive nitrogen species have attacked
tyrosine residues. In contrast,
MPTP failed to alter levels of
ortho-tyrosine in any brain region we studied. This marker accumulates when
hydroxyl radical oxidizes
protein-bound
phenylalanine residues. We also showed that treating whole-brain
proteins with
hydroxyl radical markedly increased levels of
ortho-tyrosine in vitro. Under identical conditions, tyrosyl radical, produced by the
heme protein myeloperoxidase, selectively increased levels of
o,o'-dityrosine, whereas
peroxynitrite increased levels of
3-nitrotyrosine and, to a lesser extent, of
ortho-tyrosine. These in vivo and in vitro findings implicate
reactive nitrogen species and tyrosyl radical in
MPTP neurotoxicity but argue against a deleterious role for
hydroxyl radical in this model. They also show that
reactive nitrogen species and tyrosyl radical (and consequently
protein oxidation) represent an early and previously unidentified biochemical event in
MPTP-induced
brain injury. This finding may be significant for understanding the pathogenesis of
Parkinson's disease and developing neuroprotective
therapies.