Effect of MPTP on Brain Mitochondrial H2O2 and ATP Production and on Dopamine and DOPAC in the StriatumEfecto del MPTP sobre la producción de H2O2 y ATP en mitocondrias de cerebro y sobre el catabolismo de la dopamina en el estriado

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-l,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-hydroxiphenylacctic 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.