Effects of ageing on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxic effects on striatum and brainstem in the rat.
In 3- and 18-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), noradrenaline (NA), uric acid, glutathione (GSH) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined by HPLC in the striatum and/or in the brainstem 24 h after single injections of MPTP (12-35 mg/kg i.p.). Aged rats had lower baseline levels of AA and GSH, compared to young rats. In aged rats, MPTP 35 mg/kg induced a 70% death rate and a decrease in striatal DOPAC/DA ratio which was significantly correlated to MPP+ concentrations (r = -0.840, P < 0.005); in addition, MPTP did not increase AA oxidation. In the brainstem, the MPTP-induced decrease in NA levels and increase in uric acid levels were significantly correlated to the MPP+ concentrations (r = -0.709, P < 0.05, and r = +0.888, P < 0.001, respectively). In conclusion, evidence is given of a mechanism of toxicity of MPTP involving oxidative stress produced by xanthine oxidase; in addition, in aged rats the neuronal antioxidant system (levels of AA and GSH) is considerably lower than in young rats and may play an enabling role in the MPTP age-related neurotoxic effects on striatum and brainstem.
Desole
M S
MS
Institute of Pharmacology, University of Sassari, Italy.
Esposito
G
G
Enrico
P
P
Miele
M
M
Fresu
L
L
De Natale
G
G
Miele
E
E
Grella
G
G
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000378:metabolism; D001933:Brain Stem / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D020267:MPTP Poisoning; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011726:Pyridinium Compounds / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014527:Uric Acid / Q000378:metabolism
D000975:Antioxidants; D009419:Nerve Tissue Proteins; D011726:Pyridinium Compounds; D015102:3,4-Dihydroxyphenylacetic Acid; D014527:Uric Acid; C026560:1-(4-methoxyphenyl)pyridinium; D005978:Glutathione; D001205:Ascorbic Acid; D004298:Dopamine