Neuronal antioxidant system and MPTP-induced oxidative stress in the striatum and brain stem of the rat.
Levels of ascorbic acid (AA), dehydroascorbic acid (DHAA), glutathione (GSH), uric acid, dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT), noradrenaline (NA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and 1-methyl-4-phenylpyridinium ion (MPP+) were determined in the striatum, striatal synaptosomes, and/or brain stem of 3- and 6-month-old male Wistar rats given MPTP 35-52 mg/kg IP. In older rats, MPTP 35 mg/kg caused a 38% death rate within 15 min-12 h. Levels of MPTP and MPP+ in the striatum, synaptosomes, and brain stem were directly correlated with the absolute MPTP dose/rat. MPTP decreased striatal DA metabolites and NA levels in the striatum and brain stem, and increased uric acid levels in all regions in all rats. All these changes were significantly correlated with MPP+ levels. GSH levels were increased in younger rats and decreased in older rats. AA oxidation was increased mainly in older rats. We conclude that acute lethality and regional brain MPTP and MPP+ levels depend upon the absolute dose of MPTP/rat rather than the relative dose/kg. In younger rats, the neuronal antioxidant GSH system is more efficient than in older rats, in which the response to MPP(+)-induced oxidative stress also involves AA oxidation. The increase in uric acid levels provides further evidence for a mechanism of MPTP neurotoxicity involving oxidative stress mediated by xanthine oxidase.
Desole
M S
MS
Institute of Pharmacology, University of Sassari, Italy.
Miele
M
M
Esposito
G
G
Fresu
L G
LG
Migheli
R
R
Zangani
D
D
Sircana
S
S
Grella
G
G
Miele
E
E
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001205:Ascorbic Acid / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D020267:MPTP Poisoning; D008297:Male; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism
D000975:Antioxidants; D014527:Uric Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D005978:Glutathione; D001205:Ascorbic Acid; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine; D009638:Norepinephrine