Implication of dopamine transporter system on 1-methyl-4-phenylpyridinium and rotenone effect in striatal synaptosomes
Implication of dopamine transporter system on 1-methyl-4-phenylpyridinium and rotenone effect in striatal synaptosomes
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DOI：
10.1016/0922-4106(95)90083-7
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发表时间：
1995-11-30
期刊：
影响因子：
--
通讯作者：
Machado, A
中科院分区：
文献类型：
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作者：
Bougria, M;Vitorica, J;Machado, A
1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）的神经毒性作用可能是通过其代谢产物1-甲基-4-苯基吡啶离子（MPP（+））抑制呼吸链而产生的。同时，其特异性选择性似乎与多巴胺摄取系统特别相关。然而，黑质纹状体系统多巴胺能神经元的其他特定差异，如组成性代谢缺陷或与能量容量相关的其他差异，可能决定了对MPP（+）的更大脆弱性。我们通过研究MPP（+）和不同的呼吸链抑制剂（鱼藤酮、抗霉素A和KCN）对来自不同脑区（即皮质、海马和纹状体）的突触体和分离的突触体线粒体以及分离的肝线粒体的最大呼吸速率的影响，解决了这一点。结果表明在分离的线粒体中抑制剂的作用没有差异。相反，当MPP（+）和鱼藤酮被使用时，在纹状体突触体中发现比在皮质或海马突触体中更大的抑制。此外，多巴胺摄取系统抑制剂诺米芬辛或1-[2-[双（4-氟苯基）甲氧基]乙基]-4-（3 -苯基丙基）哌嗪二盐酸盐（GBR-12909）在两种情况下均具有保护作用。我们的研究表明，多巴胺摄取系统的多巴胺纹状体系统的脆弱性的重要性。此外，我们的研究结果表明，这种多巴胺摄取系统的选择性低，能够积极运输具有不同化学结构的化合物，如多巴胺，MPP（+）和鱼藤酮。
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.