Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models?

Cicchetti, Francesca; Drouin‐Ouellet, Janelle; Gross, Robert E.

doi:10.1016/j.tips.2009.06.005

Cited by 264 publications

(188 citation statements)

References 62 publications

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“…There is considerable evidence that several synthetic pesticides are associated with increased risk of PD (7,24,25). However, PD was first observed long before synthetic pesticides and industrial solvents were produced, suggesting that natural compounds may contribute to the etiology of PD.…”

Section: Discussionmentioning

confidence: 99%

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

Inamdar

Hossain

Bernstein

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Parkinson disease (PD) is the most common movement disorder and, although the exact causes are unknown, recent epidemiological and experimental studies indicate that several environmental agents may be significant risk factors. To date, these suspected environmental risk factors have been man-made chemicals. In this report, we demonstrate via genetic, biochemical, and immunological studies that the common volatile fungal semiochemical 1-octen-3-ol reduces dopamine levels and causes dopamine neuron degeneration in Drosophila melanogaster. Overexpression of the vesicular monoamine transporter (VMAT) rescued the dopamine toxicity and neurodegeneration, whereas mutations decreasing VMAT and tyrosine hydroxylase exacerbated toxicity. Furthermore, 1-octen-3-ol also inhibited uptake of dopamine in human cell lines expressing the human plasma membrane dopamine transporter (DAT) and human VMAT ortholog, VMAT2. These data demonstrate that 1-octen-3-ol exerts toxicity via disruption of dopamine homeostasis and may represent a naturally occurring environmental agent involved in parkinsonism.building-related illness | mold | mushroom alcohol

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Section: Discussionmentioning

confidence: 99%

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

Inamdar

Hossain

Bernstein

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Inconsistency in symptomatic phenotype has been observed among different strains of rats, and striatal degeneration in addition to nigral neuron loss has also been reported (20). However, much valuable insight into the pathophysiological mechanisms of DA neurotoxicity has been gained as a result of experiments conducted in rotenone animal models.…”

Section: Rotenone Metabolism and Mitochondrial Mechanisms Of Neurotoxmentioning

confidence: 99%

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Martinez

Greenamyre

2012

Antioxidants & Redox Signaling

222

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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“…Use of pesticides has been associated with an increased risk factor for PD and its toxicity mechanism has been much studied in cell culture and animal models (Cicchetti et al 2009). However, a recent study reported that the correlation between the history of psychotropic drug use and a later PD diagnosis is higher than that between pesticide exposure and PD (Dick et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Perphenazine and trifluoperazine induce mitochondria-mediated cell death in SH-SY5Y cells

Hong

Lee

Shin

et al. 2012

Animal Cells and Systems

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Drug-induced parkinsonism has been associated with an increased risk for Parkinson's disease. Antipsychotic drugs have long been known to cause parkinsonian symptoms. However, it remains unclear whether antipsychotics can directly damage the nigrostriatal pathway. In the present study, we investigated the toxicity mechanism of two typical antipsychotics, perphenazine and trifluoperazine, in a human dopaminergic cell line, SH-SY5Y. Perphenazine and trifluoperazine induced mitochondrial damage as evidenced by fragmentation of mitochondria, activation of Bax, cytochrome c release and a decrease in cellular ATP level. In addition, activation of caspase-3 and apoptotic nuclei were observed following the drug treatment. However, pan-caspase inhibitor did not suppress the cell death induced by the antipsychotics, suggesting that the initiated apoptosis was possibly shifted to necrosis upon caspase inhibition. Damaged mitochondria may have induced oxidative stress since the drug-induced cell death was partially suppressed by an antioxidant. Taken together, our results suggest that perphenazine and trifluoperazine can induce apoptotic cell death in a dopaminergic cell line via mitochondrial damage accompanied by oxidative stress.

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Environmental toxins and Parkinson's disease: what have we learned from pesticide-induced animal models?

Cited by 264 publications

References 62 publications

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Perphenazine and trifluoperazine induce mitochondria-mediated cell death in SH-SY5Y cells

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