Paraquat as an Environmental Risk Factor in Parkinson's Disease Accelerates Age-Related Degeneration Via Rapid Influx of Extracellular Zn ²⁺ into Nigral Dopaminergic Neurons.

Publisher: Humana Press Country of Publication: United States NLM ID: 8900963 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-1182 (Electronic) Linking ISSN: 08937648 NLM ISO Abbreviation: Mol Neurobiol Subsets: MEDLINE

Original Publication: Clifton, NJ : Humana Press, c1987-

Aging/*pathology ; Dopaminergic Neurons/*metabolism ; Extracellular Space/*metabolism ; Paraquat/*toxicity ; Parkinson Disease/*pathology ; Substantia Nigra/*pathology ; Zinc/*metabolism; Animals ; Dopaminergic Neurons/drug effects ; Dopaminergic Neurons/pathology ; Exocytosis/drug effects ; Glutamic Acid/metabolism ; Male ; Presynaptic Terminals/drug effects ; Presynaptic Terminals/metabolism ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Receptors, AMPA/metabolism ; Risk Factors ; Substantia Nigra/drug effects

On the basis of the evidence that paraquat (PQ)-induced extracellular Zn ²⁺ influx causes PQ-induced pathogenesis in the substantia nigra pars compacta (SNpc) of rats, we postulated that the transient receptor potential melastatin 2 (TRPM2) cation channels activated with PQ-induced reactive oxygen species (ROS) are linked with extracellular glutamate accumulation in the SNpc, followed by age-related intracellular Zn ²⁺ dysregulation. Presynaptic activity (glutamate exocytosis), which was determined with FM4-64, was enhanced in the SNpc after exposure to PQ, and the enhancement was inhibited in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of TRPM2 cation channels, suggesting that PQ-induced ROS enhances presynaptic activity in the SNpc, probably via TRPM2 channel activation. Extracellular glutamate concentration in the SNpc was increased almost to the same extent under the SNpc perfusion with PQ of young and aged rats, and was suppressed by co-perfusion with ACA, suggesting that PQ-induced TRPM2 cation channel activation enhances glutamate exocytosis in the SNpc. Interestingly, PQ more markedly increased intracellular Zn ²⁺ in the aged SNpc, which was also blocked by co-injection of ACA and CaEDTA, an extracellular Zn ²⁺ chelator. Loss of nigrostriatal dopaminergic neurons was more severely increased in aged rats and completely blocked by co-injection of PQ and CaEDTA into the SNpc. The present study indicates that rapid influx of extracellular Zn ²⁺ into dopaminergic neurons via PQ-induced TRPM2 cation channel activation accelerates nigrostriatal dopaminergic degeneration in aged rats. It is likely that vulnerability to PQ-induced pathogenesis in the aged SNpc is due to accelerated intracellular Zn ²⁺ dysregulation.

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Keywords: Aging; Dopaminergic neuron; Paraquat; Parkinson’s disease; Substantia nigra; TRPM2 cation channel; Zn2+

0 (Reactive Oxygen Species)
0 (Receptors, AMPA)
3KX376GY7L (Glutamic Acid)
J41CSQ7QDS (Zinc)
PLG39H7695 (Paraquat)

Date Created: 20190524 Date Completed: 20200312 Latest Revision: 20200312

20221213

10.1007/s12035-019-01642-5

31119555