Extracellular Zn2+ Influx into Nigral Dopaminergic Neurons Plays a Key Role for Pathogenesis of 6-Hydroxydopamine-Induced Parkinson's Disease in Rats.
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 α-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.
['Tamano|Haruna|H|', 'Nishio|Ryusuke|R|', 'Morioka|Hiroki|H|', 'Takeda|Atsushi|A|http://orcid.org/0000-0001-7519-2957']
D000818:Animals D002118:Calcium D002614:Chelating Agents D004195:Disease Models, Animal D059290:Dopaminergic Neurons D005029:Ethylenediamines D005110:Extracellular Space D042541:Intracellular Space D008297:Male D009410:Nerve Degeneration D016627:Oxidopamine D010300:Parkinson Disease D017208:Rats, Wistar D013378:Substantia Nigra D015032:Zinc
Dopaminergic neuron 6-hydroxydopamine Substantia nigra Parkinson’s disease Zinc