MPP+ produces progressive neuronal degeneration which is mediated by oxidative stress.
The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces Parkinsonism, is mediated by its metabolite 1-methyl-4-phenylpyridinium ion (MPP+). When injected into the striatum MPP+ is accumulated by dopaminergic nerve terminals and is then retrogradely transported to the substantia nigra compacta. The mechanism by which it mediates cell death involves both inhibition of complex I of the electron transport chain and free radical generation. In the present experiments we found that administration of the free radical spin trap N-tert-butyl-alpha-(2-sulfophenyl) nitrone (S-PBN) significantly attenuated substantia nigra cell loss produced by MPP+ administration into rat striatum. We also found that coadministration of coenzyme Q10 with nicotinamide, which attenuates energy depletion, significantly blocked MPP(+)-induced substantia nigra damage. Last, we found that a single administration of MPP+ into rat striatum can produce progressive cell loss in the substantia nigra and that administration of S-PBN starting 7 days after administration of MPP+ can block the ensuing neuronal damage. These observations suggest that a one-time exposure to a neurotoxic agent may result in progressive neuronal degeneration mediated by oxidative stress.
Fallon
J
J
Alzheimer's Disease Research Unit, Massachusetts General Hospital, Boston, USA.
Matthews
R T
RT
Hyman
B T
BT
Beal
M F
MF
D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D003067:Coenzymes; D003497:Cyclic N-Oxides; D015259:Dopamine Agents / Q000494:pharmacology*; D004338:Drug Combinations; D007477:Ions; D008297:Male; D009410:Nerve Degeneration; D009536:Niacinamide / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000494:pharmacology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013378:Substantia Nigra / Q000187:drug effects*; D013997:Time Factors; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology
D003067:Coenzymes; D003497:Cyclic N-Oxides; D015259:Dopamine Agents; D004338:Drug Combinations; D007477:Ions; D009589:Nitrogen Oxides; D013113:Spin Labels; D014451:Ubiquinone; D009536:Niacinamide; C029217:phenyl-N-tert-butylnitrone; C024989:coenzyme Q10; D015655:1-Methyl-4-phenylpyridinium