Developmental Pesticide Models of the Parkinson Disease Phenotype

Cory‐Slechta, Deborah A.; Thiruchelvam, Mona; Barlow, Brian K.; Richfield, Eric K.

doi:10.1289/ehp.7570

Cited by 116 publications

(50 citation statements)

References 55 publications

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“…Thus, all of these data suggest that PD is a systemic degenerative disease that is not only affecting tissues in the BG, but also non cerebral tissues. This is consistent with the multiple-hit hypothesis (Cory-Slechta et al, 2005;Carvey et al, 2006) which predicts that multiple concurrent insults occurring at different target sites within a system (here nigrostriatal dopamine) may constrict the range and flexibility of compensatory mechanisms, thereby compromising the integrity and viability of the system.…”

Section: Introductionsupporting

confidence: 85%

A rat model of Parkinsonism shows depletion of dopamine in the retina

Biehlmaier

Alam

Schmidt

2007

Neurochemistry International

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A rat model of Parkinsonism shows depletion of dopamine in the retina AbstractThe retinal dopamine (DA) deficiency is an important feature of the pathogenesis in Parkinson's disease (PD) visual dysfunction. Systemic inhibition of complex I (rotenone) in rats has been proposed as a model of PD. In this study, we investigated whether systemic inhibition of complex I can induce impairment of DA-ergic cells in the retina, similar to the destruction of retinal cells found in PD patients. Rotenone (2.5mg/kg i.p., daily) was administered over 60 days. Neurochemically, rotenone treated rats showed a depletion of DA in the striatum and substantia nigra (SN). In addition, the number of retinal DA-ergic amacrine cells was significantly reduced in the rotenone treated animals. This study is the first one giving highlight towards a deeper understanding of systemic complex I inhibition (rotenone as an environmental toxin) and the connection between both, DA-ergic degeneration in the nigrostriatal pathway, and in the DA-ergic amacrine cells of the retina.Retinal degeneration in a rotenone PD model This study is the first one giving highlight towards a deeper understanding of systemic complex I inhibition (rotenone as an environmental toxin) and the connection between both, DA-ergic degeneration in the nigrostriatal pathway, and in the DA-ergic amacrine cells of the retina.

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Section: Introductionsupporting

confidence: 85%

A rat model of Parkinsonism shows depletion of dopamine in the retina

Biehlmaier

Alam

Schmidt

2007

Neurochemistry International

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“…Various animal models have been developed to study the mechanistic and therapeutic intervention of PD, such as MPTP, paraquat, and maneb [15,16,20,22]. Combined exposure to paraquat and maneb is consistently used as pesticide-induced animal model of PD in mouse [7,15,16,20].…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profiles of Mouse Striatum in Control and Maneb + Paraquat-induced Parkinson’s Disease Phenotype: Validation of Differentially Expressed Energy Metabolizing Transcripts

Patel

Singh

et al. 2008

Mol Biotechnol

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The present study was undertaken to investigate the gene expression patterns of the striatum of control and maneb + paraquat-induced Parkinson's disease (PD) phenotype in mouse to identify the differentially expressed transcripts. The animals were treated with and without maneb (30 mg/kg, i.p.) + paraquat (10 mg/kg, i.p.), twice a week, for 3, 6, and 9 weeks. The RNA was isolated from control and treated mouse striatum and reverse transcribed, and equal quantities of labeled cDNA were mixed and hybridized with mouse 15 k arrays. Comparative transcription patterns showed the time of exposure dependent alteration in the expression of several transcripts associated with various pathways. RT-PCR reconfirmed the differential expression of some energy metabolizing transcripts. The study provides maneb + paraquat-induced differential expression of many transcripts using high-density microarray approach. Few transcripts, which were previously not reported to be associated with neuronal degeneration, were also identified. The results obtained thus suggest that maneb + paraquat induce neurotoxicity in the striatum in a time of exposure dependent manner via multiple pathways and defective energy metabolism could play a critical role.

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“…Cory-Schlecta suggested that when there are multiple risk factors, the system can no partial recovery of DA neurons. In PD progressive loss of DA neurons continues until the end of life; therefore longer "homeostatically reregulate itself," thus leading to damage (22,23). We have been testing the concept in this model does not reflect true progression.…”

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confidence: 99%

Progressive Dopamine Neuron Loss in Parkinson's Disease: The Multiple Hit Hypothesis

2006

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Animal models have been an essential tool for researchers and clinicians in their efforts to study and treat Parkinson's disease (PD). Thus, the various ways 6-hydroxydopamine is employed, the use of MPTP in rodents and nonhuman primates, the prenatal exposure to bacterial endotoxin, the postnatal exposure to environmental toxins such as paraquat and rotenone, the assessment of dopamine (DA) neurons in genetic knockout mouse, and even the behavioral analysis of fruit flies and worms have added significantly to our knowledge base of PD-or have they? Are these animal models manifesting a true model of PD? Have the 7786 published studies (to date) on PD with animal models led to a clearer understanding of its etiology, treatment, or progression? In this review we critically assess this question. We begin with a succinct history of the major contributions, which have led to the current animal models of PD. We then evaluate the primary issue of the progressive loss of DA neurons, which, except for a few studies, has not been addressed in animal models of PD, even though this is the major pathological characteristic of the disease. Lastly, we discuss the possibility that more than one risk factor for PD may be necessary to develop an animal model that shows synergy-the progressive loss of DA neurons. Thus, the multiple hit hypothesis of PD-that is, the effect of more then one risk factor-may be the start of new era in animal models of PD that is one step closer to mimicking the pathology of PD in humans. Key words: Parkinson's disease Dopamine neurons Progression Multiple hit hypothesis PARKINSON'S DISEASEwith an estimated 50-60% loss of DA neurons in the substantia nigra pars compacta (SNpc) (2,26,81). Idiopathic PD generally develops after the age of 60. HowJames Parkinson first systematically described the symptoms of Parkinson's disease (PD) in the early ever, patients younger than 40 years of age have been identified, and many have been shown to have one of 1800s, which he labeled the "shaking palsy." The cardinal features of PD are tremor, rigidity, brady-/akinesis, several genetic mutations, suggesting that early onset PD may be familial (18,41,69,88). PD is a progressive and postural instability. Approximately 40,000 people in the US are diagnosed with PD every day, and over 1 neurodegenerative disease. When first diagnosed, most patients exhibit mild unilateral symptoms that inexoramillion Americans have this disease. The daily cost is estimated at $66 million, including direct and indirect bly progress to bilateral debilitating signs and symptoms that require full-time nursing care in late-stage disease. costs such as the inability to work and medical/longterm care (75). PD is the second most prevalent neuroTo date there is no proven strategy to stop or slow the progression of PD. However, significant advancements degenerative disease next to Alzheimer's disease. No cure currently exists.in alleviating the symptoms of PD using drug therapy and surgical procedures have evolved. The most widely The symptoms of...

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Developmental Pesticide Models of the Parkinson Disease Phenotype

Cited by 116 publications

References 55 publications

A rat model of Parkinsonism shows depletion of dopamine in the retina

A rat model of Parkinsonism shows depletion of dopamine in the retina

Gene Expression Profiles of Mouse Striatum in Control and Maneb + Paraquat-induced Parkinson’s Disease Phenotype: Validation of Differentially Expressed Energy Metabolizing Transcripts

Progressive Dopamine Neuron Loss in Parkinson's Disease: The Multiple Hit Hypothesis

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