Intracellular Hydrogen Peroxide Produced by 6-Hydroxydopamine is a Trigger for Nigral Dopaminergic Degeneration Via Rapid Influx of Extracellular Zn2+

Abstract To elucidate the mechanism of 6-hydroxydopamine (6-OHDA)-induced Zn2+ toxicity, which is involved in neurodegeneration in the substantia nigra pars compacta (SNpc) of rats, we postulated that intracellular hydrogen peroxide (H2O2) produced by 6-OHDA is a trigger for intracellular Zn2+ dysregulation in the SNpc. Intracellular H2O2 level in the SNpc elevated by 6-OHDA 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 H2O2 in the intercellular compartment of dopaminergic neurons. When the SNpc was perfused with H2O2, H2O2 accumulated glutamate 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. In addition to 6-OHDA, H2O2 also induced intracellular Zn2+ dysregulation via AMPA receptor activation followed by nigral dopaminergic degeneration. Furthermore, 6-OHDA-induced nigral dopaminergic degeneration was completely inhibited by co-injection of HYDROP, an intracellular H2O2 scavenger or GBR into the SNpc. The present study indicates that H2O2 is produced by 6-OHDA taken up through dopamine transporters in the SNpc, is retrogradely transported to presynaptic glutamatergic terminals, activates TRPM2 channels, accumulates glutamate in the extracellular compartment, and induces intracellular Zn2+ dysregulation via AMPA receptor activation, resulting in nigral dopaminergic degeneration. It is likely that intracellular H2O2, but not extracellular H2O2, is a key trigger for nigral dopaminergic degeneration via intracellular Zn2+ dysregulation.

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Intracellular hydrogen peroxide produced by 6-hydroxydopamine is a trigger for nigral dopaminergic degeneration of rats via rapid influx of extracellular Zn2+

NeuroToxicology ◽

10.1016/j.neuro.2021.12.006 ◽

2021 ◽

Author(s):

Ryusuke Nishio ◽

Hiroki Morioka ◽

Azusa Takeuchi ◽

Nana Saeki ◽

Ryo Furuhata ◽

...

Keyword(s):

Hydrogen Peroxide ◽

6 Hydroxydopamine ◽

Intracellular Hydrogen Peroxide ◽

Dopaminergic Degeneration

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Age-related vulnerability to nigral dopaminergic degeneration in rats via Zn2+-permeable GluR2-lacking AMPA receptor activation

NeuroToxicology ◽

10.1016/j.neuro.2020.12.014 ◽

2021 ◽

Vol 83 ◽

pp. 69-76

Author(s):

Satoko Nakajima ◽

Nana Saeki ◽

Haruna Tamano ◽

Ryusuke Nishio ◽

Misa Katahira ◽

...

Keyword(s):

Ampa Receptor ◽

Receptor Activation ◽

Age Related ◽

Dopaminergic Degeneration

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Paraquat-induced intracellular Zn2+ dysregulation causes dopaminergic degeneration in the substantia nigra, but not in the striatum

10.21203/rs.3.rs-852809/v1 ◽

2021 ◽

Author(s):

Haruna Tamura ◽

Ryusuke Nishio ◽

Nana Saeki ◽

Misa Katahira ◽

Hiroki Morioka ◽

...

Keyword(s):

Substantia Nigra ◽

Ampa Receptors ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Receptor Activation ◽

Substantia Nigra Pars Compacta ◽

Extracellular Glutamate ◽

Transient Receptor Potential Melastatin ◽

The Difference ◽

Dopaminergic Degeneration

Abstract Parkinson's disease (PD) is characterized by a selective death of nigrostriatal dopaminergic neurons, while the difference in the vulnerability to the death between the substantia nigra pars compacta (SNpc) and the striatum is poorly understood. Here we tested the difference focused on paraquat (PQ)-induced intracellular Zn2+ toxicity via extracellular glutamate accumulation. When PQ was locally injected into the SNpc and the striatum, dopaminergic degeneration was observed in the SNpc, but not in the striatum. Intracellular hydrogen peroxide (H2O2) produced by PQ was increased in both the SNpc and the striatum. In contrast, extracellular glutamate accumulation was observed only in the SNpc and rescued in the presence of N-(p-amylcinnamoyl)anthranilic acid (ACA), a blocker of the transient receptor potential melastatin 2 (TRPM2) cation channels. PQ increased intracellular Zn2+ level in the SNpc, but not in the striatum. The increase was rescued by 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptors. PQ-induced dopaminergic degeneration in the SNpc was rescued by ACA, NASPM, and GBR, a dopamine reuptake inhibitor. The present study indicates intracellular H2O2 produced by PQ, which is taken up through dopamine transporters, is retrogradely transported to presynaptic glutamatergic terminals, activates TRPM2 channels, accumulates glutamate in the extracellular compartment, and induces intracellular Zn2+ dysregulation via Ca2+- and Zn2+-permeable GluR2-lacking AMPA receptor activation, resulting in dopaminergic degeneration in the SNpc. However, H2O2 signaling is not the case in the striatum. Paraquat-induced Zn2+ dysregulation plays a key role for neurodegeneration in the SNpc, but not in the striatum.

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Localization and function of dopamine receptors in the subthalamic nucleus of normal and parkinsonian monkeys

Journal of Neurophysiology ◽

10.1152/jn.00849.2013 ◽

2014 ◽

Vol 112 (2) ◽

pp. 467-479 ◽

Cited By ~ 22

Author(s):

Adriana Galvan ◽

Xing Hu ◽

Karen S. Rommelfanger ◽

Jean-Francois Pare ◽

Zafar U. Khan ◽

...

Keyword(s):

Dopamine Receptors ◽

Subthalamic Nucleus ◽

Receptor Agonist ◽

Rhesus Macaques ◽

Extracellular Recording ◽

Receptor Activation ◽

D1 Receptors ◽

Substantia Nigra Pars Compacta ◽

D1 And D2 Receptors ◽

And Function

The subthalamic nucleus (STN) receives a dopaminergic innervation from the substantia nigra pars compacta, but the role of this projection remains poorly understood, particularly in primates. To address this issue, we used immuno-electron microscopy to localize D1, D2, and D5 dopamine receptors in the STN of rhesus macaques and studied the electrophysiological effects of activating D1-like or D2-like receptors in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys. Labeling of D1 and D2 receptors was primarily found presynaptically, on preterminal axons and putative glutamatergic and GABAergic terminals, while D5 receptors were more significantly expressed postsynaptically, on dendritic shafts of STN neurons. The electrical spiking activity of STN neurons, recorded with standard extracellular recording methods, was studied before, during, and after intra-STN administration of the dopamine D1-like receptor agonist SKF82958, the D2-like receptor agonist quinpirole, or artificial cerebrospinal fluid (control injections). In normal animals, administration of SKF82958 significantly reduced the spontaneous firing but increased the rate of intraburst firing and the proportion of pause-burst sequences of firing. Quinpirole only increased the proportion of such pause-burst sequences in STN neurons of normal monkeys. In MPTP-treated monkeys, the D1-like receptor agonist also reduced the firing rate and increased the proportion of pause-burst sequences, while the D2-like receptor agonist did not change any of the chosen descriptors of the firing pattern of STN neurons. Our data suggest that dopamine receptor activation can directly modulate the electrical activity of STN neurons by pre- and postsynaptic mechanisms in both normal and parkinsonian states, predominantly via activation of D1 receptors.

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Electrochemical Visualization of Intracellular Hydrogen Peroxide at Single Cells

Analytical Chemistry ◽

10.1021/acs.analchem.6b00150 ◽

2016 ◽

Vol 88 (4) ◽

pp. 2006-2009 ◽

Cited By ~ 35

Author(s):

Ruiqin He ◽

Huifen Tang ◽

Dechen Jiang ◽

Hong-yuan Chen

Keyword(s):

Hydrogen Peroxide ◽

Single Cells ◽

Intracellular Hydrogen Peroxide

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Light-induced intracellular hydrogen peroxide generation through genetically encoded photosensitizer KillerRed-SOD1

Free Radical Research ◽

10.1080/10715762.2018.1540042 ◽

2018 ◽

Vol 52 (10) ◽

pp. 1170-1181 ◽

Cited By ~ 3

Author(s):

Anna Laporte ◽

Anke Nordenbrock ◽

Sigurd Lenzen ◽

Matthias Elsner

Keyword(s):

Hydrogen Peroxide ◽

Hydrogen Peroxide Generation ◽

Intracellular Hydrogen Peroxide

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Imaging of Intracellular Hydrogen Peroxide Production with HyPer upon Stimulation of HeLa Cells with EGF

Redox-Mediated Signal Transduction - Methods in Molecular Biology ◽

10.1007/978-1-4939-9463-2_7 ◽

2019 ◽

pp. 85-91 ◽

Cited By ~ 1

Author(s):

Kseniya N. Markvicheva ◽

Ekaterina A. Bogdanova ◽

Dmitry B. Staroverov ◽

Sergei Lukyanov ◽

Vsevolod V. Belousov

Keyword(s):

Hydrogen Peroxide ◽

Hela Cells ◽

Hydrogen Peroxide Production ◽

Intracellular Hydrogen Peroxide ◽

Stimulation Of

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Roles of intracellular hydrogen peroxide accumulation in abscisic acid signaling in Arabidopsis guard cells

Journal of Plant Physiology ◽

10.1016/j.jplph.2011.05.006 ◽

2011 ◽

Vol 168 (16) ◽

pp. 1919-1926 ◽

Cited By ~ 39

Author(s):

Rayhanur Jannat ◽

Misugi Uraji ◽

Miho Morofuji ◽

Mohammad Muzahidul Islam ◽

Rachel E. Bloom ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Abscisic Acid ◽

Guard Cells ◽

Abscisic Acid Signaling ◽

Hydrogen Peroxide Accumulation ◽

Intracellular Hydrogen Peroxide

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Stimulation of the nigrostriatal dopamine system produces hypertension and tachycardia in rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.6.h2489 ◽

1994 ◽

Vol 266 (6) ◽

pp. H2489-H2496 ◽

Cited By ~ 5

Author(s):

M. T. Lin ◽

J. J. Yang

Keyword(s):

Corpus Striatum ◽

Substantia Nigra Pars Compacta ◽

Dopamine System ◽

Arterial Blood ◽

Nigrostriatal Dopamine ◽

Induced Hypertension ◽

Bilateral Vagotomy ◽

6 Hydroxydopamine ◽

Da Release ◽

Stimulation Of

To test for the ability of the nigrostriatal dopamine (DA) system to influence cardiovascular function, experiments were carried out to assess the effects of electrical or chemical stimulation of the nigrostriatal DA system on arterial blood pressure, heart rate, and striatal DA release in anesthetized rats. Electrical stimulation of the substantia nigra pars compacta (SNC), in addition to enhancing the DA release in the corpus striatum (CS), elicited proportional hypertension and tachycardia. This could be mimicked by microinjection of two excitatory amino acids, kainic acid and glutamate, into the SNC area of rat brain. The SNC stimulation-induced hypertension, tachycardia, and increased striatal DA release were attenuated by prior destruction of the nigrostriatal DA system produced by intramedial forebrain bundle injection of 6-hydroxydopamine and by prior blockade of postsynaptic DA receptors produced by intra-CS injection of DA receptor antagonists, haloperidol or pimozide. The SNC stimulation-induced hypertension was attenuated by spinal transection, whereas the SNC stimulation-induced tachycardia was attenuated by bilateral vagotomy. The data suggest that stimulation of the nigrostriatal DA system produces both hypertension and tachycardia in rats.

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