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  • Title: Paraquat as an Environmental Risk Factor in Parkinson's Disease Accelerates Age-Related Degeneration Via Rapid Influx of Extracellular Zn2+ into Nigral Dopaminergic Neurons.
    Author: Tamano H, Nishio R, Morioka H, Furuhata R, Komata Y, Takeda A.
    Journal: Mol Neurobiol; 2019 Nov; 56(11):7789-7799. PubMed ID: 31119555.
    Abstract:
    On the basis of the evidence that paraquat (PQ)-induced extracellular Zn2+ 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 Zn2+ 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 Zn2+ in the aged SNpc, which was also blocked by co-injection of ACA and CaEDTA, an extracellular Zn2+ 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 Zn2+ 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 Zn2+ dysregulation.
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