Correlation between 1-methyl-4-phenylpyridinium ion (MPP+) levels, ascorbic acid oxidation and glutathione levels in the striatal synaptosomes of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rat.
In 6-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), uric acid, glutathione (GSH) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined by HPLC in the crude striatal synaptosomal fraction after single injections of MPTP 35 mg/kg i.p. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced a 32.5% death rate within 15 min to 10 h. Groups of surviving rats were sacrificed 1, 3, 8 and 24 h after MPTP. MPTP significantly increased levels of DHAA and uric acid and decreased levels of DOPAC and GSH. Individual synaptosomal levels of MPP+ were correlated inversely with DOPAC (r = -0.601, P < 0.002) and GSH levels (r = -0.496, P < 0.02) and directly with levels of uric acid (r = +0.627, P < 0.001); these latter, in turn, were correlated with DHAA (r = +0.418, P < 0.05) and GSH levels (r = -0.357, P = 0.07). In conclusion, the response of the endogenous antioxidant system (increase in AA oxidation, decrease in GSH levels) correlates well with the MPTP-induced increase in uric acid levels and provides further evidence for a mechanism of MPTP neurotoxicity involving oxidative stress produced by xanthine oxidase.
Desole
M S
MS
Institute of Pharmacology, University of Sassari, Italy.
Esposito
G
G
Fresu
L
L
Migheli
R
R
Enrico
P
P
Miele
M
M
De Natale
G
G
Miele
E
E
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism*; D020267:MPTP Poisoning; D008297:Male; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D011726:Pyridinium Compounds / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D014527:Uric Acid / Q000378:metabolism
D015259:Dopamine Agents; D011726:Pyridinium Compounds; D015102:3,4-Dihydroxyphenylacetic Acid; C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; D014527:Uric Acid; C026560:1-(4-methoxyphenyl)pyridinium; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D005978:Glutathione; D001205:Ascorbic Acid; D004298:Dopamine