Are Dopamine, Norepinephrine, and Serotonin Precursors of Biologically Reactive Intermediates Involved in the Pathogenesis of Neurodegenerative Brain Disorders?

Dryhurst, Glenn

doi:10.1007/978-1-4615-0667-6_61

Cited by 7 publications

(3 citation statements)

References 177 publications

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“…DA can be converted rapidly to a variety of reactive oxygen species and derived quinones that can be toxic to cells (Stokes et al, 1999;Blum et al, 2001;Dryhurst, 2001). These products can damage and modify macromolecules and impair energy production (Stokes et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Dopamine Depletion Does Not Protect against Acute 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine ToxicityIn Vivo

Hasbani¹,

Perez²,

Palmiter³

et al. 2005

J. Neurosci.

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Dopamine (DA) has been postulated to play a role in the loss of dopaminergic substantia nigra (SN) neurons in Parkinson's disease because of its propensity to oxidize and form quinones and other reactive oxygen species that can alter cellular function. Moreover, DA depletion can attenuate dopaminergic cell loss in vitro. To test the contribution of DA to SN impairment in vivo, we used DA-deficient mice, which lack the enzyme tyrosine hydroxylase in dopaminergic cells, and mice pharmacologically depleted of DA by ␣-methyl-ptyrosine pretreatment. Mice were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that produces parkinsonian pathology in humans, nonhuman primates, and rodents. In contrast to in vitro results, genetic or pharmacologic DA depletion did not attenuate loss of dopaminergic neurons in the SN or dopaminergic neuron terminals in the striatum. These results suggest that DA does not contribute to acute MPTP toxicity in vivo.

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Section: Introductionmentioning

confidence: 99%

Dopamine Depletion Does Not Protect against Acute 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine ToxicityIn Vivo

Hasbani¹,

Perez²,

Palmiter³

et al. 2005

J. Neurosci.

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“…Moreover, the mechanism of dopamine neurotoxicity is highly linked to increased production of oxidizing species, which has been implicated in the pathogenesis of PD (Liang et al 2005; Teismann et al 2003a). Several reports have shown that dopamine can be oxidized to dopamine-quinone, which is toxic to cells (Blum et al 2001; Dryhurst 2001). A study has also shown that treatment with dopamine of HEK293 cells or rat striatal neuronal cultures induces apoptosis through a mechanism dependent on ROS (Luo et al 1998).…”

Section: Discussionmentioning

confidence: 99%

MPP+-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress

Hsieh

Mounsey

Teismann

2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Accumulating evidence suggests that endogenous dopamine may act as a neurotoxin and thereby participate in the pathophysiology of Parkinson’s disease (PD). Cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of PD due to its ability to generate reactive oxygen species (ROS). Inhibition of COX-2 leads to neuroprotection by preventing the formation of dopamine-quinone. In this study, we examined whether dopamine mediates 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity in primary ventral mesencephalic (VM) neurons, an in vitro model of PD, and if so, whether the protective effects of COX-2 inhibitors on dopamine mediated MPP+-induced VM neurotoxicity and VM dopaminergic cell apoptosis result from the reduction of ROS. Reserpine, a dopamine-depleting agent, significantly reduced VM neurotoxicity induced by MPP+, whereas dopamine had an additive effect on MPP+-induced VM neurotoxicity and VM dopaminergic cell apoptosis. However, inhibition of COX-2 by a selective COX-2 inhibitor (DFU) or ibuprofen significantly attenuated MPP+-induced VM cell toxicity and VM dopaminergic cell apoptosis, which was accompanied by a decrease in ROS production in VM dopaminergic neurons. These results suggest that dopamine itself mediates MPP+-induced VM neurotoxicity and VM dopaminergic cell apoptosis in the presence of COX-2.

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“…DA oxidation products (defined as quinones, semi-quinones and other radical containing metabolites) are thought to play a role in the neurotoxic mechanisms contributing to neurodegenerative disorders such as PD (Dryhurst, 2001;Krezel et al, 2007). The mechanism by which oxidized DA products react with MT and other biomolecules is though to occur via the arylation of cysteine residues.…”

Section: Discussionmentioning

confidence: 99%

Covalent arylation of metallothionein by oxidized dopamine products: A possible mechanism for zinc-mediated enhancement of dopaminergic neuron survival

et al. 2008

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Metallothioneins are a group of low molecular weight proteins which can be induced upon exposure to metal ions, including Zn(II). These cysteine-rich proteins are believed to have antioxidant-like properties due to their ability to scavenge free radicals with their multiple sulfhydryl groups. Dopamine is a neurotransmitter that can form toxic quinone and semi-quinone products in an oxidative environment. While Zn(II) is known to be toxic to some neuron subtypes, here we report a beneficial effect of Zn(II) on dopaminergic neurons and identify a mechanism through which metallothionein may scavenge toxic dopamine oxidation products. Cultured embryonic neurons were treated with Zn(II), and the number of dopaminergic neurons surviving after two or three weeks in culture was determined. We demonstrate that under these conditions metallothionein is upregulated and is able to form covalent arylation products with dopamine and 6-hydroxydopamine both in vitro and in culture. These experiments suggest that Zn(II) enhances the survival of dopaminergic neurons, and we propose that as a mechanism, upregulated metallothioneins form covalent adducts with both dopamine and 6-hydroxydopamine, resulting in the observed neuroprotective effect of Zn(II) on these cells. As Zn(II) homeostasis and modulation of metallothionein expression are hallmarks of neurodegeneration, these studies may have significant implications for understanding the underlying basis of degenerative diseases involving dopaminergic neurons, including Parkinson's disease.

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Are Dopamine, Norepinephrine, and Serotonin Precursors of Biologically Reactive Intermediates Involved in the Pathogenesis of Neurodegenerative Brain Disorders?

Cited by 7 publications

References 177 publications

Dopamine Depletion Does Not Protect against Acute 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine ToxicityIn Vivo

Dopamine Depletion Does Not Protect against Acute 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine ToxicityIn Vivo

MPP+-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress

Covalent arylation of metallothionein by oxidized dopamine products: A possible mechanism for zinc-mediated enhancement of dopaminergic neuron survival

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