Manganese-induced Parkinsonism Research Articles

Daidzein ameliorates nonmotor symptoms of manganese-induced Parkinsonism in zebrafish model: Behavioural and biochemical approach.

Parkinson's disease (PD) is a prevalent neurodegenerative movement disorder characterized by motor dysfunction. Environmental factors, especially manganese (Mn), contribute significantly to PD. Existing therapies are focused on motor coordination, whereas nonmotor features such as neuropsychiatric symptoms are often neglected. Daidzein (DZ), a phytoestrogen, has piqued interest due to its antioxidant, anti-inflammatory, and anxiolytic properties. Therefore, we anticipate that DZ might be an effective drug to alleviate the nonmotor symptoms of Mn-induced Parkinsonism. Naïve zebrafish were exposed to 2mM of Mn for 21 days and intervened with DZ. Nonmotor symptoms such as anxiety, social behaviour, and olfactory function were assessed. Acetylcholinesterase (AChE) activity and antioxidant enzyme status were measured from brain tissue through biochemical assays. Dopamine levels and histology were performed to elucidate neuroprotective mechanism of DZ. DZ exhibited anxiolytic effects in a novel environment and also improved intra and inter fish social behaviour. DZ improved the olfactory function and response to amino acid stimuli in Mn-induced Parkinsonism. DZ reduced brain oxidative stress and AChE activity and prevented neuronal damage. DZ increased DA level in the brain, collectively contributing to neuroprotection. DZ demonstrated a promising effect on alleviating nonmotor symptoms such as anxiety and olfactory dysfunction, through the mitigation of cellular damage. These findings underscore the therapeutic potential of DZ in addressing nonmotor neurotoxicity induced by heavy metals, particularly in the context of Mn-induced Parkinsonism.

Manganese-Induced Parkinsonism: Evidence from Epidemiological and Experimental Studies.

Manganese (Mn) exposure has evolved from acute, high-level exposure causing manganism to low, chronic lifetime exposure. In this latter scenario, the target areas extend beyond the globus pallidus (as seen with manganism) to the entire basal ganglia, including the substantia nigra pars compacta. This change of exposure paradigm has prompted numerous epidemiological investigations of the occurrence of Parkinson's disease (PD), or parkinsonism, due to the long-term impact of Mn. In parallel, experimental research has focused on the underlying pathogenic mechanisms of Mn and its interactions with genetic susceptibility. In this review, we provide evidence from both types of studies, with the aim to link the epidemiological data with the potential mechanistic interpretation.

An Overview of the Relationship Between Occupational Manganese Exposure and Parkinsonism.

Manganese (Mn) is an essential element used in many industries, such as welding,foundries, the production of metal alloys, especially stainless steel,and the production of dry batteries, pesticides, paints, and explosives.Individuals are exposed to Mn through inhalation of fumes, dermal absorption, and ingestion. This metal is an essential trace element required for normal growth,development, and cellular homeostasis. Ithas also toxic effects on the central nervous systemand can cause Parkinsonism symptoms in exposed patients.Studies on human and animal models reveal that neurons of the globus pallidus, the cerebellum, pons, red nucleus, the thalamus, cortex, and the anterior horn of the spinal cord could be affected by Mn toxicity. Although the diagnosis of manganese-induced Parkinsonism is primarily clinical, there are some supporting features on brain MRI images that may be helpful to objectively distinguish it. This study was designed to review the ways of exposure to Mn, clinical symptoms in case of exposure, and discover the relationship between exposure to Mn and Parkinsonism in the working population.

Manganese-Induced Parkinsonism - A Case Series (P16-11.008)

Manganese-Induced Parkinsonism - A Case Series (P16-11.008)

Protective role of mRNA demethylase FTO on axon guidance molecules of nigro-striatal projection system in manganese-induced parkinsonism

One of the major environmental factors that induce PD is Manganese (Mn). Cellular and molecular mechanism of parkinsonism caused by Mn has not been explored clearly. The results of in vivo and in vitro experiments showed that Mn exposure caused abnormal projection of dopaminergic neurons and decreased mRNA expression and protein levels of FTO. This is due to Mn-induced the upregulation of Foxo3a. Using the cell model of overexpression of FTO, we found that FTO could antagonize Mn-induced the down-regulation of axon guidance molecule ephrin-B2 through RNA-seq, MeRIP-qPCR, and RT-qPCR experiments. Through RIP-seq and actinomycin D experiments, it was found that FTO can up-regulate the mRNA m6A level of ephrin-B2, which can be recognized by YTHDF2 and degraded. Finally, it is proved that Mn induces dopaminergic neurons projection injury and motor dysfunction through Foxo3a/FTO/m6A/ephrin-B2/YTHDF2 signal pathway.

Characteristic of neuropsychological deficits in patients diagnosed with manganese encephalopathy due to ephedrone use - case series analysis.

The study presents neuropsychological characteristic of 16 individuals with manganese-induced parkinsonism due to intravenous ephedrone use. Overall cognitive function screening as well as full examination of various cognitive domains (verbal learning, visual memory, working memory, executive functions, construction and visuospatial functions) with the use of elastic neuropsychological test battery were performed. Dyshartric speech disorders were also precisely evaluated. Additionally, all individuals filled in the Beck Depression Inventory (BDI), which is used to assess mood. All patients had evident dysarthric speech disorders accompanied with palilalia and writing disorders (micrographia) in the majority of investigated individuals. Neuropsychological screening diagnosis showed no overall cognitive deficits at the level of dementia. Mild decrease in verbal learning and visual memory processes was found; as well as ideomotor but no construction praxis disorders. Results of working memory and executive function assessment indicated decrease in cognitive flexibility and logical conceptualization abilities, as well as set-shifting disorders. Patients varied significantly in their severity of executive dysfunction. Duration of ephedrone use was found nonsignificant for patients' cognition. The mean BDI score indicated moderate depression. Higher level of depressive symptoms was associated with poorer overall cognitive screening, decrease of visual and verbal learning as well as phonemic verbal fluency.

Manganese-induced Parkinsonism in mice is reduced using a novel contaminated water sediment exposure model

Heavy metals enter the aquatic environment and accumulate within water sediments, but these metal-sediment interactions remain to be explored within toxicity studies. We developed an exposure model in mice that encapsulates the aquatic microenvironment of metals before exposure. Male and female C57/BL6 mice were exposed via their drinking water to manganese contaminated sediment (Sed_Mn) or to manganese without sediment interaction (Mn) for six weeks. Sediment interaction did not alter weekly manganese ingestion from water in males or females. We analyzed motor impairment, a common feature in manganese-induced Parkinsonism, using the beam traversal, cylinder, and accelerating rotarod tests. Sed_Mn mice performed better overall compared to Mn mice and males were more sensitive to manganese than females in both Sed_Mn and Mn treatment groups. Our study indicates that metal-sediment interactions may alter metal toxicity in mammals and introduces a new exposure model to test the toxicity of metal contaminants of drinking water.

Parkinsonism and chronic manganese exposure: Pilot study with clinical, environmental and experimental evidence

Parkinsonism related to chronic Manganese exposure is notably due to focal lesions of the basal ganglia. Our study focused on epidemiological, clinical, toxicological and experimental aspects of Manganese-induced Parkinsonism in south of Morocco. It is a prospective study concerning the workers and the residents bordering on the 2 mines in the south of Morocco. The results of the study concerned 120 cases divided into 4 groups of patients: G1: 30 cases exposed to different incriminated toxic products, which present Parkinsonian signs, G2: 30 cases healthy and exposed, G3: 30 cases affected with Idiopathic Parkinson's disease, and G4: 30 cases healthy and unexposed (controls).The results from the first mine show that 5.7% of the sample developed Manganese-Induced Parkinsonism and this percentage is slightly higher (4.5%) than the second mine site. Chemical and biological analysis revealed high levels of Manganese. The majority of patients did not improve the clinical signs under L-dopa treatment. The authors underline the gravity of Manganese-induced Parkinsonism and propose a listing of the various exposures as well as a cartography of the regions of risk in Morocco.

Spermine protects alpha-synuclein expressing dopaminergic neurons from manganese-induced degeneration.

Manganese exposure is among the many environmental risk factors linked to the progression of neurodegenerative diseases, such as manganese-induced parkinsonism. In animal models, chronic exposure to manganese causes loss of cell viability, neurodegeneration, and functional deficits. Polyamines, such as spermine, have been shown to rescue animals from age-induced neurodegeneration in an autophagy-dependent manner; nonetheless, it is not understood whether polyamines can prevent manganese-induced toxicity. In this study, we used two model systems, the Caenorhabditis elegans UA44 strain and SK-MEL-28 cells, both expressing the protein alpha-synuclein (α-syn) to determine whether spermine could ameliorate manganese-induced toxicity. Manganese caused a substantial reduction in the viability of SK-MEL-28 cells and hastened neurodegeneration in the UA44 strain. Spermine protected both the SK-MEL-28 cells and the UA44 strain from manganese-induced toxicity. Spermine also reduced the age-associated neurodegeneration observed in the UA44 strain compared with a control strain without α-syn expression and led to improved avoidance behavior in a functional assay. Treatment with berenil, an inhibitor of polyamine catabolism, which leads to increased intracellular polyamine levels, also showed similar cellular protection against manganese toxicity. While both translation blocker cycloheximide and autophagy blocker chloroquine caused a reduction in the cytoprotective effect of spermine, transcription blocker actinomycin D had no effect. This study provides new insights on the effect of spermine in preventing manganese-induced toxicity, which is most likely via translational regulation of several candidate genes, including those of autophagy. Thus, our results indicate that polyamines positively influence neuronal health, even when exposed to high levels of manganese and α-syn, and supplementing polyamines through diet might delay the onset of diseases involving degeneration of dopaminergic neurons.

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

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 (0-5Hz). 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.

Structural Elements in the Transmembrane and Cytoplasmic Domains of the Metal Transporter SLC30A10 Are Required for Its Manganese Efflux Activity

Homozygous mutations in SLC30A10 lead to the development of familial manganese-induced parkinsonism. We previously demonstrated that SLC30A10 is a cell surface-localized manganese efflux transporter, and parkinsonism-causing mutations block its trafficking and efflux activity. Interestingly, other transporters in the SLC30 family mediate zinc efflux. Determining the mechanisms that allow SLC30A10 to transport manganese, which are unclear, is essential to understand its role in parkinsonism. Here, we generated a predicted structure of SLC30A10, based on the structure of the bacterial zinc transporter YiiP, and performed functional studies. In YiiP, side chains of residues Asp-45 and Asp-49 in the second and His-153 and Asp-157 in the fifth transmembrane segments coordinate zinc and are required for transport. In SLC30A10, the corresponding residues are Asn-43 and Asp-47 in the second and His-244 and Asp-248 in the fifth transmembrane segments. Surprisingly, although alanine substitution of Asp-248 abolished manganese efflux, that of Asn-43 and Asp-47 did not. Instead, side chains of charged or polar residues adjacent to Asp-248 in the first (Glu-25) or fourth (Asn-127) transmembrane segments were required. Further analyses revealed that residues His-333 and His-350 in the cytoplasmic C-terminal domain were required for full activity. However, the C-terminal domain failed to transfer manganese transport capability to a related zinc transporter. Overall, our results indicate that residues in the transmembrane and C-terminal domains together confer optimal manganese transport capability to SLC30A10 and suggest that the mechanism of ion coordination in the transmembrane domain of SLC30A10 may be substantially different from that in YiiP/other SLC30 proteins.

Some patterns of metallic nanoparticles' combined subchronic toxicity as exemplified by a combination of nickel and manganese oxide nanoparticles

Stable suspensions of NiO and/or Mn3O4 nanoparticles with a mean diameter of 16.7 ± 8.2 nm and 18.4 ± 5.4 nm, respectively, prepared by laser ablation of 99.99% pure metals in de-ionized water were repeatedly injected IP to rats at a dose of 0.50 mg or 0.25 mg 3 times a week up to 18 injections, either separately or in different combinations. Many functional indices as well as histological features of the liver, spleen, kidneys and brain were evaluated for signs of toxicity. The accumulation of Ni and Mn in these organs was measured with the help of AES and EPR methods. Both metallic nanoparticles proved adversely bio-active, but those of Mn3O4 were found to be more noxious in most of the non-specific toxicity manifestations. Moreover, they induced a more marked damaging effect in the neurons of the caudate nucleus and hippocampus which may be considered an experimental correlate of manganese-induced parkinsonism. Mathematical analysis based on the Response Surface Methodology (RSM) revealed a diversity of combined toxicity types depending not only on particular effects these types are assessed for but on their level as well. The prognostic power of the RSM model proved satisfactory.

Attenuation of Combined Nickel(II) Oxide and Manganese(II, III) Oxide Nanoparticles' Adverse Effects with a Complex of Bioprotectors.

Stable suspensions of NiO and Mn3O4 nanoparticles (NPs) with a mean (±s.d.) diameter of 16.7 ± 8.2 and 18.4 ± 5.4 nm, respectively, purposefully prepared by laser ablation of 99.99% pure nickel or manganese in de-ionized water, were repeatedly injected intraperitoneally (IP) to rats at a dose of 2.5 mg/kg 3 times a week up to 18 injections, either alone or in combination. A group of rats was injected with this combination with the background oral administration of a “bio-protective complex” (BPC) comprising pectin, vitamins A, C, E, glutamate, glycine, N-acetylcysteine, selenium, iodide and omega-3 PUFA, this composition having been chosen based on mechanistic considerations and previous experience. After the termination of injections, many functional and biochemical indices and histopathological features (with morphometric assessment) of the liver, spleen, kidneys and brain were evaluated for signs of toxicity. The Ni and Mn content of these organs was measured with the help of the atomic emission and electron paramagnetic resonance spectroscopies. We obtained blood leukocytes for performing the RAPD (Random Amplified Polymorphic DNA) test. Although both metallic NPs proved adversely bio-active in many respects considered in this study, Mn3O4-NPs were somewhat more noxious than NiO-NPs as concerns most of the non-specific toxicity manifestations and they induced more marked damage to neurons in the striatum and the hippocampus, which may be considered an experimental correlate of the manganese-induced Parkinsonism. The comparative solubility of the Mn3O4-NPs and NiO-NPs in a biological medium is discussed as one of the factors underlying the difference in their toxicokinetics and toxicities. The BPC has attenuated both the organ-systemic toxicity and the genotoxicity of Mn3O4-NPs in combination with NiO-NPs.

Manganese-Induced Parkinsonism Is Not Idiopathic Parkinson's Disease: Environmental and Genetic Evidence.

Movement abnormalities caused by chronic manganese (Mn) intoxication clinically resemble but are not identical to those in idiopathic Parkinson's disease. In fact, the most successful parkinsonian drug treatment, the dopamine precursor levodopa, is ineffective in alleviating Mn-induced motor symptoms, implying that parkinsonism in Mn-exposed individuals may not be linked to midbrain dopaminergic neuron cell loss. Over the last decade, supporting evidence from human and nonhuman primates has emerged that Mn-induced parkinsonism partially results from damage to basal ganglia nuclei of the striatal "direct pathway" (ie, the caudate/putamen, internal globus pallidus, and substantia nigra pars reticulata) and a marked inhibition of striatal dopamine release in the absence of nigrostriatal dopamine terminal degeneration. Recent neuroimaging studies have revealed similar findings in a particular group of young drug users intravenously injecting the Mn-containing psychostimulant ephedron and in individuals with inherited mutations of the Mn transporter gene SLC30A10. This review will provide a detailed discussion about the aforementioned studies, followed by a comparison with their rodent analogs and idiopathic parkinsonism. Together, these findings in combination with a limited knowledge about the underlying neuropathology of Mn-induced parkinsonism strongly support the need for a more complete understanding of the neurotoxic effects of Mn on basal ganglia function to uncover the appropriate cellular and molecular therapeutic targets for this disorder.

Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features.

Manganese (Mn) is an essential trace element necessary for physiological processes that support development, growth and neuronal function. Secondary to elevated exposure or decreased excretion, Mn accumulates in the basal ganglia region of the brain and may cause a parkinsonian-like syndrome, referred to as manganism. The present review discusses the advances made in understanding the essentiality and neurotoxicity of Mn. We review occupational Mn-induced parkinsonism and the dynamic modes of Mn transport in biological systems, as well as the detection and pharmacokinetic modeling of Mn trafficking. In addition, we review some of the shared similarities, pathologic and clinical distinctions between Mn-induced parkinsonism and Parkinson’s disease. Where possible, we review the influence of Mn toxicity on dopamine, gamma aminobutyric acid (GABA), and glutamate neurotransmitter levels and function. We conclude with a survey of the preventive and treatment strategies for manganism and idiopathic Parkinson’s disease (PD).

Manganese-induced parkinsonism does not involve degeneration of nigrostriatal dopaminergic neurons: Evidence from genetic mutations and environmental exposure in humans and non-human primates

Manganese-induced parkinsonism does not involve degeneration of nigrostriatal dopaminergic neurons: Evidence from genetic mutations and environmental exposure in humans and non-human primates

Manganese-Induced Parkinsonism: Relationship to Manganese Accumulation in Bone

Manganese-Induced Parkinsonism: Relationship to Manganese Accumulation in Bone

Manganese-induced atypical parkinsonism is associated with altered Basal Ganglia activity and changes in tissue levels of monoamines in the rat.

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.

Transcranial Sonography in Manganese-Induced Parkinsonism Caused by Drug Abuse

Transcranial Sonography in Manganese-Induced Parkinsonism Caused by Drug Abuse

Manganese-Induced Parkinsonism Among Ephedrone Users and Drug Policy in Poland

A recent government's prohibition policy in Poland was partially successful with a reduction of the synthetic drugs market and a decrease in drug-related poisoning mortality rates. However, a new threatening trend is observed. There are a growing number of individuals in Poland and other European countries using legal pharmaceuticals containing ephedrine or pseudoephedrine to produce stimulants. This case report describes a history of a male patient with polysubstance dependence who administered self-designed ephedrone derived from Sudafed using potassium permanganate. He revealed significant clinical symptoms of manganese-induced parkinsonism. No effective treatment could be recommended. Awareness of this severe neurological and social consequences should lead to prevention efforts including educational programs and initiatives reducing availability of the legal medications containing ephedrine or pseudoephedrine. More research is needed to enhance our knowledge about manganism and potential treatment regimens.