Extracellular Zn2+ Influx into Nigral Dopaminergic Neurons Plays a Key Role for Pathogenesis of 6-Hydroxydopamine-Induced Parkinson's Disease in Rats
Extracellular Zn2+ Influx into Nigral Dopaminergic Neurons Plays a Key Role for Pathogenesis of 6-Hydroxydopamine-Induced Parkinson's Disease in Rats
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DOI：
10.1007/s12035-018-1075-z
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发表时间：
2019-01-01
影响因子：
5.1
通讯作者：
Takeda, Atsushi
中科院分区：
文献类型：
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作者：
Tamano, Haruna;Nishio, Ryusuke;Takeda, Atsushi
帕金森病（PD）是一种进行性神经系统疾病，其特征是黑质纹状体多巴胺能神经元的选择性丢失。神经元缺失的确切原因尚不清楚。在这里，我们报告了一个独特的机制，黑质纹状体多巴胺能神经变性，其中细胞外锌离子内流起着关键作用的PD发病机制与6-羟基多巴胺（6-OHDA）在大鼠。6-OHDA仅在脑片的黑质黑部（SNpc）中迅速增加细胞内Zn 2+，并且这种增加在CaEDTA（一种细胞外Zn 2+螯合剂）和6-氰基-7-硝基喹喔啉-2，3-二酮（CNQX）（一种氨基-3-羟基-5-甲基-4-异恶唑丙酸酯（AMPA）受体拮抗剂）存在下被阻断，这表明6-OHDA通过SNpc中的AMPA受体激活迅速增加细胞外Zn 2+内流。在体内SNpc灌注6-OHDA时，细胞外Zn 2+浓度降低，并且这种降低通过与CNQX共灌注来阻断，支持6-OHDA诱导的通过SNpc中AMPA受体活化的Zn 2+内流。有趣的是，6-OHDA诱导的黑质纹状体多巴胺能神经元的损失和对阿朴吗啡的转向行为都通过共注射细胞内Zn 2+螯合剂来改善，即，ZnAF-2DA和N，N，N，N-四（2-吡啶基甲基）乙二胺（TPEN）。将TPEN共注射到SNpc中阻断了6-OHDA诱导的细胞内Zn 2+的增加，但不阻断细胞内Ca 2+的增加。这些结果表明，细胞外Zn 2+的快速流入多巴胺能神经元通过AMPA受体激活SNPC诱导黑质纹状体多巴胺能神经元变性，导致6-OHDA诱导的PD大鼠。
Parkinson's disease (PD) is a progressive neurological disease characterized by a selective loss of nigrostriatal dopaminergic neurons. The exact cause of the neuronal loss remains unclear. Here, we report a unique mechanism of nigrostriatal dopaminergic neurodegeneration, in which extracellular Zn2+ influx plays a key role for PD pathogenesis induced with 6-hydroxydopamine (6-OHDA) in rats. 6-OHDA rapidly increased intracellular Zn2+ only in the substantia nigra pars compacta (SNpc) of brain slices and this increase was blocked in the presence of CaEDTA, an extracellular Zn2+ chelator, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an -amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist, indicating that 6-OHDA rapidly increases extracellular Zn2+ influx via AMPA receptor activation in the SNpc. Extracellular Zn2+ concentration was decreased under in vivo SNpc perfusion with 6-OHDA and this decrease was blocked by co-perfusion with CNQX, supporting 6-OHDA-induced Zn2+ influx via AMPA receptor activation in the SNpc. Interestingly, both 6-OHDA-induced loss of nigrostriatal dopaminergic neurons and turning behavior to apomorphine were ameliorated by co-injection of intracellular Zn2+ chelators, i.e., ZnAF-2DA and N,N,N,N-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). Co-injection of TPEN into the SNpc blocked 6-OHDA-induced increase in intracellular Zn2+ but not in intracellular Ca2+. These results suggest that the rapid influx of extracellular Zn2+ into dopaminergic neurons via AMPA receptor activation in the SNpc induces nigrostriatal dopaminergic neurodegeneration, resulting in 6-OHDA-induced PD in rats.