Journal
JOURNAL OF TRACE ELEMENTS IN MEDICINE AND BIOLOGY
Volume 61, Issue -, Pages -Publisher
ELSEVIER GMBH
DOI: 10.1016/j.jtemb.2020.126545
Keywords
Zn2+; Substantia nigra; Dopaminergic neuron; Paraquat; 6-Hydroxydopamine; Parkinson's disease
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Background: Parkinson's disease (PD) is the common neurodegenerative disorder in the elderly characterized by motor symptoms such as tremors, which is caused by selective loss of nigral dopaminergic neurons. Oxidative stress induced by the auto-oxidation of dopamine has been implicated as a key cause of the selective loss of dopaminergic neurons. Methods: To understand the selective loss of nigral dopaminergic neurons, the PD pathogenesis is reviewed focused on paraquat (PQ) and 6-hydroxydopamine (6-OHDA)-induced PD in rats. Results: Reactive oxygen species (ROS), which are produced by PQ and 6-OHDA, are retrogradely transported to presynaptic glutamatergic neuron terminals. ROS activate presynaptic transient receptor potential melastatin 2 (TRPM2) cation channels and induce extracellular glutamate accumulation in the substantia nigra pars compacta (SNpc), followed by age-related intracellular Zn2+ dysregulation. Loss of nigral dopaminergic neurons is accelerated by age-related intracellular Zn2+ dysregulation in the SNpc of rat PD models. The intracellular Zn2+ dysregulation in nigral dopaminergic neurons is linked with the rapid influx of extracellular Zn2+ via postsynaptic AMPA receptor activation, suggesting that PQ- and 6-OHDA-induced pathogenesis is linked with age-related intracellular Zn2+ dysregulation in the SNpc. Postsynaptic TRPM2 channels may be also involved in intracellular Zn2+ dysregulation in the SNpc. Conclusion: A novel mechanism of nigral dopaminergic degeneration, in which ROS induce rapid intracellular Zn2+ dysregulation, figures out the PD pathogenesis induced by PQ and 6-OHDA in rats. This review deals with new insight into PD pathogenesis from ROS-mediated extracellular Zn(2+ )influx and its proposed defense strategy.
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