Manganese does not alter the severe neurotoxicity of MPTP

Baek, Sun‐Yong; Kim, Y. H.; Oh, Sangah; Lee, C.-R.; Yoo, Cheol-In; Lee, J. H.; Lee, H.; Sim, Chang Sun; Park, J.; Kim, J.-W.; Yoon, Chung Sik; Kim, Y.

doi:10.1177/0960327107070567

Cited by 10 publications

(13 citation statements)

References 27 publications

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“…Astrogliosis (Figure 3) persisted although Mn had been cleared from the cortex (Figure 1A). These results are in agreement with reports on increased GFAP expression in both rats and mice (Baek et al, 2007; Kern and Smith, 2011). TNF-α levels were significantly increased ( vs .…”

Section: Discussionsupporting

confidence: 94%

Evaluation of neurobehavioral and neuroinflammatory end-points in the post-exposure period in rats sub-acutely exposed to manganese

et al. 2013

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Manganese (Mn) can cause manganism, a neurological disorder similar to Parkinson's Disease (PD). The neurobehavioral and neuroinflammatory end-points in the Mn post exposure period have not been studied yet. Rats were injected on alternate days with 8 doses of MnCl2 (25 mg/Kg) or saline, then euthanized 1, 10, 30 or 70 days following the last dose. Whole-blood (WB) (p<0.05), urine (p<0.05) and brain cortical (p<0.0001) Mn levels were significantly increased 24h after the last dose. Decreases in the rats’ ambulation were noted 1, 10 and 30 days after the last Mn dose (p<0.001; p<0.05; p<0.001, respectively) and also in the rearing activity at the four time-points (p<0.05). Cortical glial fibrillary acid protein immunoreactivity (GFAP-ir) was significantly increased at 1, 10, 30 (p<0.0001) and 70 (p<0.001) days after the last Mn dose, as well as tumor necrosis α (TNF-α) levels (p<0.05) but just on day 1. Taken together, the results show that, during the 70-day clearance phase of Mn, the recovery is not immediate as behavioral alterations and neuroinflammation persist long after Mn is cleared from cortical brain compartment.

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Section: Discussionsupporting

confidence: 94%

Evaluation of neurobehavioral and neuroinflammatory end-points in the post-exposure period in rats sub-acutely exposed to manganese

et al. 2013

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“…However, pretreatment with the PKCδ-specific inhibitor rottlerin did not block Mn-induced increases in TH activity, suggesting that PKCδ does not play a role in an acute-Mn treatment paradigm. A recent study showed increased TH activity without any increase in TH protein upregulation (Baek et al , 2007). During chronic Mn treatment, we noted decreased TH activity with no significant change in TH-Ser40 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Effects of manganese on tyrosine hydroxylase (TH) activity and TH-phosphorylation in a dopaminergic neural cell line

Zhang

Kanthasamy

Anantharam

2011

Toxicology and Applied Pharmacology

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Manganese (Mn) exposure causes manganism, a neurological disorder similar to Parkinson's disease. However, the cellular mechanism by which Mn impairs the dopaminergic neurotransmitter system remains unclear. We previously demonstrated that caspase-3-dependent proteolytic activation of protein kinase C delta (PKCδ) plays a key role in Mn-induced apoptotic cell death in dopaminergic neurons. Recently, we showed that PKCδ negatively regulates tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, by enhancing protein phosphatase-2A activity in dopaminergic neurons. Here we report that Mn exposure can affect the enzymatic activity of TH, the rate-limiting enzyme in dopamine synthesis, by activating PKCδ -PP2A signaling pathway in a dopaminergic cell model. Low dose Mn (3-10 μM) exposure to differentiated mesencephalic dopaminergic neuronal cells for 3 h induced a significant increase in TH activity and phosphorylation of TH-Ser40. The PKCδ specific inhibitor rottlerin did not prevent Mn-induced TH activity or TH-Ser40 phosphorylation. On the contrary, chronic exposure to 0.1-1 μM Mn for 24 h induced a dose-dependent decrease in TH activity. Interestingly, chronic Mn treatment significantly increased PKCδ kinase activity and protein phosphatase 2A (PP2A) enzyme activity. Treatment with the PKCδ inhibitor rottlerin almost completely prevented chronic Mn-induced reduction in TH activity, as well as increased PP2A activity. Neither acute nor chronic Mn exposures induced any cytotoxic cell death or altered TH protein levels. Collectively, these results demonstrate that low dose Mn exposure impairs TH activity in dopaminergic cells through activation of PKCδ and PP2A activity.

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“…While there is characteristic striatal depletion of dopamine in iPD, acute or chronic Mn exposure in rodents decreased dopamine release with no effect on striatal dopamine (Baek et al . ; Peneder et al . ) and the number of SNpc dopaminergic neurons (Baek et al .…”

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confidence: 99%

Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease

Mythri

Raghunath

Narwade

et al. 2017

Journal of Neurochemistry

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Idiopathic Parkinson's disease and manganese-induced atypical parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to levodopa distinguish both, differences at the neuronal level are largely unknown. We studied the morphological, neurophysiological and molecular differences in dopaminergic neurons exposed to the Parkinson's disease toxin 1-methyl-4-phenylpyridinium ion (MPP ) and manganese (Mn), followed by validation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Mn mouse models. Morphological analysis highlighted loss of neuronal processes in the MPP and not the Mn model. Cellular network dynamics of dopaminergic neurons characterized by spike frequency and inter-spike intervals indicated major neuronal population (~ 93%) with slow discharge rates (0-5 Hz). While MPP exposure suppressed the firing of these neurons, Mn neither suppressed nor elevated the neuronal activity. High-throughput transcriptomic analysis revealed up-regulation of 694 and 603 genes and down-regulation of 428 and 255 genes in the MPP and Mn models respectively. Many differentially expressed genes were unique to either models and contributed to neuroinflammation, metabolic/mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeleton. Analysis of the Janus kinase-signal transducer and activator of transcription pathway with implications for neuritogenesis and neuronal proliferation revealed contrasting profile in both models. Genome-wide DNA methylomics revealed differences between both models and substantiated the epigenetic basis of the difference in the Janus kinase-signal transducer and activator of transcription pathway. We conclude that idiopathic Parkinson's disease and atypical parkinsonism have divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and evolution of novel therapeutics. Cover Image for this issue: doi. 10.1111/jnc.13821.

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Manganese does not alter the severe neurotoxicity of MPTP

Cited by 10 publications

References 27 publications

Evaluation of neurobehavioral and neuroinflammatory end-points in the post-exposure period in rats sub-acutely exposed to manganese

Evaluation of neurobehavioral and neuroinflammatory end-points in the post-exposure period in rats sub-acutely exposed to manganese

Effects of manganese on tyrosine hydroxylase (TH) activity and TH-phosphorylation in a dopaminergic neural cell line

Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease

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