Paraquat leads to dopaminergic neural vulnerability in organotypic midbrain culture

Shimizu, Keiko; Matsubara, Kazuo; Ohtaki, Ko-ichi; Shiono, Hiroshi

doi:10.1016/s0168-0102(03)00163-9

Cited by 72 publications

(46 citation statements)

References 56 publications

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“…These results suggest a model in which paraquat, which is highly similar in structure to MPP ϩ (Dinis-Oliveira et al, 2006), has unique access to dopaminergic neurons that could be modified by competition with extracellular DA. The mechanism by which paraquat confers selective damage to dopaminergic neurons, however, is unresolved, and although evidence demonstrating the effects of DA reuptake inhibitors on paraquat toxicity supports specific access to DA neurons (Shimizu et al, 2003), definitive evidence is lacking. Our results suggest that this Drosophila model may be an ideal system in which to test such models.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model

Chaudhuri¹,

Bowling²,

Funderburk³

et al. 2007

J. Neurosci.

194

216

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Catastrophic loss of dopaminergic neurons is a hallmark of Parkinson's disease. Despite the recent identification of genes associated with familial parkinsonism, the etiology of most Parkinson's disease cases is not understood. Environmental toxins, such as the herbicide paraquat, appear to be risk factors, and it has been proposed that susceptibility is influenced by genetic background. The genetic model organism Drosophila is an advantageous system for the identification of genetic susceptibility factors. Genes that affect dopamine homeostasis are candidate susceptibility factors, because dopamine itself has been implicated in neuron damage. We find that paraquat can replicate a broad spectrum of parkinsonian behavioral symptoms in Drosophila that are associated with loss of specific subsets of dopaminergic neurons. In parallel with epidemiological studies that show an increased incidence of Parkinson's disease in males, male Drosophila exhibit paraquat symptoms earlier than females. We then tested the hypothesis that variation in dopamine-regulating genes, including those that regulate tetrahydrobiopterin, a requisite cofactor in dopamine synthesis, can alter susceptibility to paraquatinduced oxidative damage. Drosophila mutant strains that have increased or decreased dopamine and tetrahydrobiopterin production exhibit variation in susceptibility to paraquat. Surprisingly, protection against the neurotoxicity of paraquat is conferred by mutations that elevate dopamine pathway function, whereas mutations that diminish dopamine pools increase susceptibility. We also find that loss-of-function mutations in a negative regulator of dopamine production, Catecholamines-up, delay the onset of neurological symptoms, dopaminergic neuron death, and morbidity during paraquat exposure but confer sensitivity to hydrogen peroxide.

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Section: Discussionmentioning

confidence: 99%

Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model

Chaudhuri¹,

Bowling²,

Funderburk³

et al. 2007

J. Neurosci.

194

216

View full text Add to dashboard Cite

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“…Nitric oxide may then diffuse into DA terminals, further inducing mitochondrial dysfunction, and leading to continuous and prolonged dopamine overflow in a DATdependent manner (91). Corroborating these findings, PQmediated DA neuron loss is attenuated by inhibitors of NMDA and NOS as well as by inhibition of caspase cascades (92).…”

Section: Mitochondria Both Mppmentioning

confidence: 92%

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Martinez

Greenamyre

2012

Antioxidants & Redox Signaling

228

155

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Significance: Parkinson's disease (PD) is a neurodegenerative disorder characterized, in part, by the progressive and selective loss of dopaminergic neuron cell bodies within the substantia nigra pars compacta (SNpc) and the associated deficiency of the neurotransmitter dopamine (DA) in the striatum, which gives rise to the typical motor symptoms of PD. The mechanisms that contribute to the induction and progressive cell death of dopaminergic neurons in PD are multi-faceted and remain incompletely understood. Data from epidemiological studies in humans and molecular studies in genetic, as well as toxin-induced animal models of parkinsonism, indicate that mitochondrial dysfunction occurs early in the pathogenesis of both familial and idiopathic PD. In this review, we provide an overview of toxin models of mitochondrial dysfunction in experimental Parkinson's disease and discuss mitochondrial mechanisms of neurotoxicity. Recent Advances: A new toxin model using the mitochondrial toxin trichloroethylene was recently described and novel methods, such as intranasal exposure to toxins, have been explored. Additionally, recent research conducted in toxin models of parkinsonism provides an emerging emphasis on extranigral aspects of PD pathology. Critical Issues: Unfortunately, none of the existing animal models of experimental PD completely mimics the etiology, progression, and pathology of human PD. Future Directions: Continued efforts to optimize established animal models of parkinsonism, as well as the development and characterization of new animal models are essential, as there still remains a disconnect in terms of translating mechanistic observations in animal models of experimental PD into bona fide diseasemodifying therapeutics for human PD patients. Antioxid. Redox Signal. 16, 920-934.

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“…The second is the static membrane model developed by Stoppini and colleagues (1988); in this technique, tissue rests on a porous membrane exposed to culture medium below while the upper surface is exposed to air so that tissue oxygenation can occur. Regardless of the culture method used, the organotypic preparation allows the study of an in vivo-like anatomical system with the ease of in vitro sample manipulations, such as administration of controlled levels of growth factors (Jaumotte and Zigmond, 2005;Hoglinger et al, 1998;Meyer et al, 2001;Schatz et al, 1999) or neurotoxicants (Kotake et al, 2003;Shimizu et al, 2003;Kress and Reynolds, 2005;Testa et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…Researchers have used the VM cultured alone (Dickie et al, 1996;Hoglinger et al, 1998;Meyer et al, 2001;Shimizu et al, 2003), the VM in coculture with striatum (the target of VM DA neuron terminals) (Katsuki et al, 2001;Schatz et al, 1999;Gates et al, 2004;Kotake et al, 2003;Snyder-Keller et al, 2001), and the VM, striatum, and cortex in triple-cultures, to model the basal ganglia DA system (Plenz and Kitai, 1996;Snyder-Keller et al, 2001). However, to date, studies have not adequately described the DA development, in terms of neurochemical and protein analyses, of the VM and striatum in co-culture, something that is necessary if we are to fully understand the utility of this increasingly used model system.…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic development of prenatal ventral mesencephalon and striatum in organotypic co-cultures

2007

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Using organotypic co-cultures of rat embryonic day 14 (E14) ventral mesencephalon (VM and E21 striatum, we have described the developmental changes in (i) dopamine (DA) neurochemistry; (ii) numbers of DA neurons; and (iii) protein expression of tyrosine hydroxylase (TH), DA transporter (DAT), and glutamic acid decarboxylase (GAD 65/67), over 17 days in vitro (DIV). Co-cultures demonstrated changes in DA development similar to those observed in vivo. The numbers of VM DA neurons remained relatively constant, while levels of VM DA progressively increased through 10 DIV. After 3 DIV, the levels of striatal DA increased substantially, through 10 DIV. Tissue levels of DA metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) reflected changes in tissue DA concentrations, indicating that release and metabolism of DA are similar to these characteristics observed in vivo. Western blot analysis of TH protein expression revealed large increases in VM TH after only 3 DIV, followed by a decline in levels through 17 DIV; levels of striatal TH, in contrast, increased through this period. Additionally, DAT and GAD 65/67 expression increased, in both the VM and striatum, over 17 DIV. By 17 DIV, many measures of DA function had decreased from those assessed at 10 DIV, thus providing an approximate limit to the effective duration of use of this co-culture model. Our results provide a much-needed description of the neurochemical changes that occur during the maturation of VM and striatum in organotypic cocultures. Additionally, these results provide a foundation for future studies to assess toxic challenges of the developing nigrostriatal DA system, in vitro.

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Paraquat leads to dopaminergic neural vulnerability in organotypic midbrain culture

Cited by 72 publications

References 56 publications

Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model

Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Dopaminergic development of prenatal ventral mesencephalon and striatum in organotypic co-cultures

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