Implication of dopamine transporter system on 1-methyl-4-phenylpyridinium and rotenone effect in striatal synaptosomes.
The neurotoxic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) seems to be produced by the inhibition of the respiratory chain by its metabolite 1-methyl-4-phenylpyridinium ion (MPP+). At the same time, its specific selectivity seems to be related especially to the dopamine uptake system. However, it is possible that other specific differences in dopaminergic neurons at the nigrostriatal system, such as constitutive metabolic deficiencies or other differences related to the energy capacity, could determine the greater vulnerability to MPP+. We have addressed this point by studying the effect of MPP+ and different inhibitors of the respiratory chain (rotenone, antimycin A and KCN) on the maximal respiratory rate from both synaptosomes and isolated synaptosomal mitochondria from different brain areas, i.e. cortex, hippocampus and striatum, and in isolated liver mitochondria. The results demonstrate the absence of differences in the effect of the inhibitors in isolated mitochondria. In contrast, a greater inhibition was found in striatal synaptosomes than in cortical or hippocampal synaptosomes when MPP+ and rotenone were used. Moreover, nomifensine or 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl) piperazine dihydrochloride (GBR-12909), inhibitor of the dopamine uptake system, has a protective effect in both cases. Our study indicates the great importance of the dopamine uptake system in the vulnerability of the dopamine striatum system. Moreover, our results show the low selectivity of this dopamine uptake system that is able to transport actively compounds with different chemical structures such as dopamine, MPP+ and rotenone.
Bougria
M
M
Departamento de Bioquimica, Bromatologia y Toxicologia, Facultad de Farmacia, Universidad de Sevilla, Spain.
Vitorica
J
J
Cano
J
J
Machado
A
A
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D001933:Brain Stem / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D019069:Cell Respiration / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003486:Cyanides / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008928:Mitochondria / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects; D009419:Nerve Tissue Proteins; D009627:Nomifensine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology*
D002352:Carrier Proteins; D003486:Cyanides; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014475:Uncoupling Agents; D012402:Rotenone; D009627:Nomifensine; D000968:Antimycin A; D015655:1-Methyl-4-phenylpyridinium