Effect of MPTP on brain mitochondrial H2O2 and ATP production and on dopamine and DOPAC in the striatum.
An experimental rat model of Parkinson's disease was established by injecting rats directly in the striatum with the neurotoxic agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In order to study the action mechanism of this neurotoxic agent, MPTP and its main metabolite 1-methyl-4-phenylpyridinium (MPP+) were also added to suspensions of pyruvate/malate-supplemented nonsynaptic brain mitochondria, and the rates of hydrogen peroxide and ATP production were measured. Intrastriatal administration of MPTP produced a pronounced decrease in striatal dopamine levels (p < 0.005) and a strong increase in 3,4-hydroxiphenylacetic acid/dopamine ratio (an indicator of dopamine catabolism; p < 0.005) in relation to controls, as evaluated by in situ microdialysis. MPTP addition to rat brain mitochondria increased hydrogen peroxide production by 90%, from 1.37+/-0.35 to 2.59+/-0.48 nanomoles of H2O2/minute . mg of protein (p < 0.01). The metabolite MPP+ produced a marked decrease on the rate of ATP production of brain mitochondria (p < 0.005). These findings support the mitochondria-oxidative stress-energy failure hypothesis of MPTP-induced brain neurotoxicity.
Fabre
E
E
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University of Madrid, Spain.
Monserrat
J
J
Herrero
A
A
Barja
G
G
Leret
M L
ML
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D020267:MPTP Poisoning / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D015102:3,4-Dihydroxyphenylacetic Acid; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine