Intracellular hydrogen peroxide produced by 6-hydroxydopamine is a trigger for nigral dopaminergic degeneration of rats via rapid influx of extracellular Zn.

To elucidate the mechanism and significance of 6-hydroxydopamine (6-OHDA)-induced Zn toxicity, which is involved in neurodegeneration in the substantia nigra pars compacta (SNpc) of rats, we postulated that intracellular hydrogen peroxide (HO) produced by 6-OHDA is a trigger for intracellular Zn dysregulation in the SNpc. Intracellular HO level elevated by 6-OHDA in the SNpc was completely inhibited by co-injection of GBR 13069 dihydrochloride (GBR), a dopamine reuptake inhibitor, suggesting that 6-OHDA taken up through dopamine transporters produces HO in the intercellular compartment of dopaminergic neurons. When the SNpc was perfused with HO, glutamate accumulated in the extracellular compartment and the accumulation was inhibited in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of the transient receptor potential melastatin 2 (TRPM2) channels.

Preventive effect of Ninjin-yoei-to, a Kampo medicine, on amyloid β-induced neurodegeneration via intracellular Zn toxicity in the dentate gyrus.

Ninjin-yoei-to (NYT), a Kampo medicine, has ameliorative effects on cognitive dysfunction via enhancing cholinergic neuron activity. To explore an efficacy of NYT administration for prevention and cure of Alzheimer's disease, here we examined the effect of NYT on amyloid β (Aβ)-induced neurodegeneration in the dentate gyrus. A diet containing 3% NYT was administered to mice for 2 weeks and human Aβ was intracerebroventricularly injected.

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

On the basis of the evidence that paraquat (PQ)-induced extracellular Zn 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 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.