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 injecti ng rats directly in the striatum with the neurotoxic agent 1-methyl-4-pheny l-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-phenylpy ridinium (MPP+) were also added to suspensions of pyruvate/malate-supplemen ted 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 d opamine catabolism; p < 0.005) in relation to controls, as evaluated by in situ microdialysis. MPTP addition to rat brain mitochondria increased hydro gen peroxide production by 90%, from 1.37 +/- 0.35 to 2.59 +/- 0.48 nanomol es 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 fail ure hypothesis of MPTP-induced brain neurotoxicity.