Manganese mixture inhalation is a reliable Parkinson disease model in rats

Sánchez-Betancourt, Javier; Anaya-Martı́nez, Verónica; Gutiérrez-Valdez, Ana Luisa; Ordóñez-Librado, José Luis; Montiel-Flores, Enrique; Espinosa-Villanueva, Jesús; Reynoso-Erazo, Leonardo; Avila-Costa, Marı́a Rosa

doi:10.1016/j.neuro.2012.08.012

Cited by 38 publications

(42 citation statements)

References 89 publications

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“…In the HSDN, we found that PD has highly similar symptoms with substance-related diseases like mercury poisoning (0.60), MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a toxin) poisoning (0.58) and manganese poisoning (0.52). MPTP is an established disease model for PD 37 , and manganese poisoning has also been proposed recently 38 . Similarly, it has been suggested that the molecular response to mercury exposure may increase dopamine neuron vulnerability and the propensity to develop PD 39 .…”

Section: Resultsmentioning

confidence: 99%

Human symptoms–disease network

Zhou¹,

Menche²,

Barabási³

et al. 2014

Nat Commun

600

484

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In the post-genomic era, the elucidation of the relationship between the molecular origins of diseases and their resulting phenotypes is a crucial task for medical research. Here, we use a large-scale biomedical literature database to construct a symptom-based human disease network and investigate the connection between clinical manifestations of diseases and their underlying molecular interactions. We find that the symptom-based similarity of two diseases correlates strongly with the number of shared genetic associations and the extent to which their associated proteins interact. Moreover, the diversity of the clinical manifestations of a disease can be related to the connectivity patterns of the underlying protein interaction network. The comprehensive, high-quality map of disease-symptom relations can further be used as a resource helping to address important questions in the field of systems medicine, for example, the identification of unexpected associations between diseases, disease etiology research or drug design.

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Section: Resultsmentioning

confidence: 99%

Human symptoms–disease network

Zhou¹,

Menche²,

Barabási³

et al. 2014

Nat Commun

600

484

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“…Our results are in line with those of Ingersoll et al [56] who reported that Mn in the drinking water significantly increased the level of dopamine and DOPAC in the striatum. However, it has been shown that DA contents were decreased after intrathecal administration [56] or inhalation of Mn [25], [57]. Interestingly, it has been shown that at lower doses, Mn increased DA and its metabolite levels, while the opposite effect was seen at higher doses [58].…”

Section: Discussionmentioning

confidence: 99%

Manganese-Induced Atypical Parkinsonism Is Associated with Altered Basal Ganglia Activity and Changes in Tissue Levels of Monoamines in the Rat

et al. 2014

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Manganese neurotoxicity is associated with motor and cognitive disturbances known as Manganism. However, the mechanisms underlying these deficits remain unknown. Here we investigated the effects of manganese intoxication on motor and non-motor parkinsonian-like deficits such as locomotor activity, motor coordination, anxiety and “depressive-like” behaviors. Then, we studied the impact of this intoxication on the neuronal activity, the globus pallidus (GP) and subthalamic nucleus (STN). At the end of experiments, post-mortem tissue level of the three monoamines (dopamine, norepinephrine and serotonin) has been determined. The experiments were carried out in adult Sprague-Dawley rats, daily treated with MnCl2 (10 mg/kg/, i.p.) for 5 weeks. We show that manganese progressively reduced locomotor activity as well as motor coordination in parallel with the manifestation of anxiety and “depressive-like” behaviors. Electrophysiological results show that, while majority of GP and STN neurons discharged regularly in controls, manganese increased the number of GP and STN neurons discharging irregularly and/or with bursts. Biochemical results show that manganese significantly decreased tissue levels of norepinephrine and serotonin with increased metabolism of dopamine in the striatum. Our data provide evidence that manganese intoxication is associated with impaired neurotransmission of monoaminergic systems, which is at the origin of changes in basal ganglia neuronal activity and the manifestation of motor and non-motor deficits similar to those observed in atypical Parkinsonism.

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“…Mn exposures have been used to model manganism and PD in vertebrates, C. elegans, and cell culture (Settivari et al, 2009; Shi et al, 2009, Sanchez-Betancourt et al, 2012; Ved et al, 2005). In order to determine if GST-1 gene expression is induced upon exposure to the toxicants, we utilized RT-PCR to determine levels of gene expression in controls and in worms exposed to sub-lethal concentrations of Mn as previously described (Nass and Hamza, 2007; Settivari et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

“…In order to determine if GST-1 gene expression is induced upon exposure to the toxicants, we utilized RT-PCR to determine levels of gene expression in controls and in worms exposed to sub-lethal concentrations of Mn as previously described (Nass and Hamza, 2007; Settivari et al, 2009). Young nematodes exposed to MnCl 2 for 30 min show a 3-fold increase in GST-1 mRNA levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To determine whether GST-1 is expressed in C. elegans DA neurons, we generated primary cultures from RJ928 animals fed RNAi bacteria containing the empty vector (WT) or RNAi bacteria targeting gst-1 to decrease its expression ( gst-1 RNAi ) (Settivari et al, 2009). The DA neurons are easily identified under a fluorescent dissecting scope, as GFP is expressed at high levels in the neurons both in vivo and in vitro (Settivari et al, 2009; Vanduyn et al, 2010). The morphology of the DA neurons in animals in which GST-1 expression is reduced appears identical to WT, suggesting that GST-1 does not play a significant role in maintaining DA neuron integrity (data not shown).…”

Section: Resultsmentioning

confidence: 99%

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The Nrf2/SKN-1-dependent glutathione S-transferase π homologue GST-1 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of manganism

et al. 2013

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Exposure to high levels of manganese (Mn) results in a neurological condition termed manganism, which is characterized by oxidative stress, abnormal dopamine (DA) signaling, and cell death. Epidemiological evidence suggests correlations with occupational exposure to Mn and the development of the movement disorder Parkinson's disease (PD), yet the molecular determinants common between the diseases are ill-defined. Glutathione S-transferases (GSTs) of the class pi (GSTπ) are phase II detoxification enzymes that conjugate both endogenous and exogenous compounds to glutathione to reduce cellular oxidative stress, and their decreased expression has recently been implicated in PD progression. In this study we demonstrate that a Caenorhabditis elegans GSTπ homologue, GST-1, inhibits Mn-induced DA neuron degeneration. We show that GST-1 is expressed in DA neurons, Mn induces GST-1 gene and protein expression, and GST-1-mediated neuroprotection is dependent on the PD-associated transcription factor Nrf2/SKN-1, as a reduction in SKN-1 gene expression results in a decrease in GST-1 protein expression and an increase in DA neuronal death. Furthermore, decreases in gene expression of the SKN-1 inhibitor WDR-23 or the GSTTπ-binding cell death activator JNK/JNK-1 result in an increase in resistance to the metal. Finally, we show that the Mn-induced DA neuron degeneration is independent of the dopamine transporter DAT, but is largely dependent on the caspases CED-3 and the novel caspase CSP-1. This study identifies a C. elegans Nrf2/SKN-1-dependent GSTπ homologue, cell death effectors of GSTTπ-associated xenobiotic-induced pathology, and provides the first in vivo evidence that a phase II detoxification enzyme may modulate DA neuron vulnerability in manganism.

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Manganese mixture inhalation is a reliable Parkinson disease model in rats

Cited by 38 publications

References 89 publications

Human symptoms–disease network

Human symptoms–disease network

Manganese-Induced Atypical Parkinsonism Is Associated with Altered Basal Ganglia Activity and Changes in Tissue Levels of Monoamines in the Rat

The Nrf2/SKN-1-dependent glutathione S-transferase π homologue GST-1 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of manganism

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