Preventive treatment with sodium para-aminosalicylic acid inhibits manganese-induced apoptosis and inflammation via the MAPK pathway in rat thalamus.

Excessive exposure to manganese (Mn) may lead to neurotoxicity, referred to as manganism. In several studies, sodium para-aminosalicylic acid (PAS-Na) has shown efficacy against Mn-induced neurodegeneration by attenuating the neuroinflammatory response. The present study investigated the effect of Mn on inflammation and apoptosis in the rat thalamus, as well as the underlying mechanism of the PAS-Na protective effect. The study consisted of sub-acute (Mn treatment for 4 weeks) and sub-chronic (Mn and PAS-Na treatment for 8 weeks) experiments. In the sub-chronic experiments, pro-inflammatory cytokines, namely tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and cyclooxygenase 2 (COX-2) were significantly increased in the Mn-exposed group compared to the control II. PAS-Na treatment led to a significant reduction in the Mn-induced neuroinflammation by inhibiting IL-1ß and COX-2 mRNA expression and reducing IL-1ß secretion and JNK/p38 MAPK pathway activity. Furthermore, immunohistochemical analysis showed that the expression of caspase-3 was significantly increased in both the sub-acute and sub-chronic experimental paradigms concomitant with a significant decrease in B-cell lymphoma 2 (Bcl-2) in the thalamus of Mn-treated rats. PAS-Na also decreased the expression levels of several apoptotic markers downstream of the MAPK pathway, including Bcl-2/Bax and caspase-3, while up-regulating anti-apoptotic Bcl-2 proteins. In conclusion, Mn exposure led to inflammation in the rat thalamus concomitant with apoptosis, which was mediated via the MAPK signaling pathway. PAS-Na treatment antagonized effectively Mn-induced neurotoxicity by inhibiting the MAPK activity in the same brain region.

Astrocyte-specific deletion of the transcription factor Yin Yang 1 in murine substantia nigra mitigates manganese-induced dopaminergic neurotoxicity.

Manganese (Mn)-induced neurotoxicity resembles Parkinson's disease (PD), but the mechanisms underpinning its effects remain unknown. Mn dysregulates astrocytic glutamate transporters, GLT-1 and GLAST, and dopaminergic function, including tyrosine hydroxylase (TH). Our previous in vitro studies have shown that Mn repressed GLAST and GLT-1 via activation of transcription factor Yin Yang 1 (YY1). Here, we investigated if in vivo astrocytic YY1 deletion mitigates Mn-induced dopaminergic neurotoxicity, attenuating Mn-induced reduction in GLAST/GLT-1 expression in murine substantia nigra (SN). AAV5-GFAP-Cre-GFP particles were infused into the SN of 8-week-old YY1 flox/flox mice to generate a region-specific astrocytic YY1 conditional knockout (cKO) mouse model. 3 weeks after adeno-associated viral (AAV) infusion, mice were exposed to 330 µg of Mn (MnCl2 30 mg/kg, intranasal instillation, daily) for 3 weeks. After Mn exposure, motor functions were determined in open-field and rotarod tests, followed by Western blotting, quantitative PCR, and immunohistochemistry to assess YY1, TH, GLAST, and GLT-1 levels. Infusion of AAV5-GFAP-Cre-GFP vectors into the SN resulted in region-specific astrocytic YY1 deletion and attenuation of Mn-induced impairment of motor functions, reduction of TH-expressing cells in SN, and TH mRNA/protein levels in midbrain/striatum. Astrocytic YY1 deletion also attenuated the Mn-induced decrease in GLAST/GLT-1 mRNA/protein levels in midbrain. Moreover, YY1 deletion abrogated its interaction with histone deacetylases in astrocytes. These results indicate that astrocytic YY1 plays a critical role in Mn-induced neurotoxicity in vivo, at least in part, by reducing astrocytic GLAST/GLT-1. Thus, YY1 might be a potential target for treatment of Mn toxicity and other neurological disorders associated with dysregulation of GLAST/GLT-1.

N-Acetylcysteine Ameliorates Neurotoxic Effects of Manganese Intoxication in Rats: A Biochemical and Behavioral Study.

Clinical and experimental evidences reveal that excess exposure to manganese is neurotoxic and leads to cellular damage. However, the mechanism underlying manganese neurotoxicity remains poorly understood but oxidative stress has been implicated to be one of the key pathophysiological features related to it. The present study investigates the effects associated with manganese induced toxicity in rats and further to combat these alterations with a well-known antioxidant N-acetylcysteine which is being used in mitigating the damage by its radical scavenging activity. The study was designed to note the sequential changes along with the motor and memory dysfunction associated with biochemical and histo-pathological alterations following exposure and treatment for 2 weeks. The results so obtained showed decrease in the body weights, behavioral deficits with increased stress markers and also neuronal degeneration in histo-pathological examination after manganese intoxication in rats. To overcome the neurotoxic effects of manganese, N-acetylcysteine was used in the current study due to its pleiotropic potential in several pathological ailments. Taken together, N-acetylcysteine helped in ameliorating manganese induced neurotoxic effects by diminishing the behavioral deficits, normalizing acetylcholinesterase activity, and augmentation of redox status.

Manganese-induced neurotoxicity and the potential protective effects of lipoic acid and Spirulina platensis.

Manganese (Mn) is essential for many physiological processes; however, its excessive accumulation in the brain causes severe dysfunctions in the nervous system. Oxidative stress is thought to be involved in Mn-induced neurotoxicity. The aim of this study was to evaluate the neurotoxic effects of Mn and the potential protective effects of alpha lipoic acid (ALA) and Spirulina platensis (SP), each alone and in combination. Sixty-four male albino rats were divided into eight equal groups: group 1 was used as control, group 2 received saline, which used as a vehicle, group 3 received ALA (50 mg/kg/day), group 4 received SP (300 mg/kg/day), group 5 received Mn (74 mg/kg, 5 days/week), group 6 received Mn + ALA, group 7 received Mn + SP, group 8 received Mn + ALA + SP. Groups 6, 7 and 8 received the same previously mentioned doses. All treatments were orally gavaged for 8 weeks. Mn administration caused neurobehavioral changes, increases of brain and serum Mn and malondialdehyde (MDA), with decreased glutathione peroxidase (GPx), dopamine and acetylcholine levels. The co-treatment with ALA and SP revealed their ability to protect against oxidative damage, neurobehavioral and biochemical changes induced by Mn.

Neurobehavioral performance of patients diagnosed with manganism and idiopathic Parkinson disease.

PURPOSE: There is a lack of knowledge about neurobehavioral performance among patients with manganism and how their performance differs from that of idiopathic Parkinson disease patients (PD). This study was initiated with the aim to describe and compare neurobehavioral performance among patients diagnosed with manganism, PD and a group of referents. MATERIALS AND METHODS: Neurobehavioral performance was assessed in 34 patients diagnosed with manganism, 13 with PD, and 43 healthy workers (turners/fitters) who served as the reference group. Seventeen of the manganism patients had also been tested approximately 65 months previously. RESULTS: Manganism patients scored substantially more poorly than referents on tests for motor speed, manual dexterity and balance. They also performed more poorly than the PD patients on the postural sway test. In contrast, the PD patients had higher postural tremor intensity with narrower frequency dispersion than manganism patients. The pattern of neurobehavioral performance was more asymmetrical in PD compared to manganism patients, in particular when testing for tremor intestity, grooved pegboard and static steadiness, indicating lateralized impairment in the PD patients. The amount of bradykinesia was comparable between the patient groups. Neurobehavioral performance deteriorated slightly among 17 manganism patients followed for 65 months compared with the age-related decline among referents. CONCLUSIONS: Patients with manganism had severe bradykinesia and balance disturbances, but only slight postural tremor. In contrast, PD patients had significant postural tremor and bradykinesia, but only slight balance disturbances. Their neurobehavioral performance indicated lateralized impairment, more unilateral. Neurobehavioral performance deteriorated slightly in manganism patients during a 65-month follow-up.

Manganese in Whole Blood and Hair in Patients with Long-Term Home Parenteral Nutrition.

BACKGROUND: Manganese is an essential trace element and indispensable component of nutrition mixtures in long-term home parenteral nutrition (HPN) of patients. On the other hand, neurotoxic effects of excess manganese in the organism have been known for a long time. The objective of the present study was to determine manganese concentration in whole blood and hair of patients with long-term home parenteral nutrition. METHODS: We examined 16 patients (7 men and 9 women) aged from 28 to 68 years on long-term HPN lasting from 4 to 96 months. The short bowel syndrome was an indication for HPN. The daily dose of manganese ranged between 80 and 470 microg/day (1.2 to 8.5 pg/kg/day). RESULTS: In the investigated patients we detected approximately a doubled value of manganese concentration in whole blood in comparison to the control group (16.2 microg/L; 12.9-20.4 microg/L and 7.4 microg/L; 6.4-8.4 microg/L). In five patients with symptoms of cholestatic hepatopathy, Mn concentration in whole blood exceeded the value of 20.0 microg/L. Magnetic resonance of the brain in four of these patients detected a hyperintense T1-signal in the globus pallidus without any clinical symptoms similar to the Parkinson's syndrome. The content of manganese in the patients' hair was also significantly increased (p < 0.04). CONCLUSIONS: The results of our study corroborate the necessity of careful monitoring of the manganese concentration in the organism during HPN, especially in patients with liver disorders. Individualized HPN with greater accessibility of variable mixtures of trace elements would certainly be greatly beneficial, at least with regard to problems associated with manganese substitution.

BDNF and Huntingtin protein modifications by manganese: implications for striatal medium spiny neuron pathology in manganese neurotoxicity.

High levels of manganese (Mn) exposure decrease striatal medium spiny neuron (MSN) dendritic length and spine density, but the mechanism(s) are not known. The Huntingtin (HTT) gene has been functionally linked to cortical brain-derived neurotrophic factor (BDNF) support of striatal MSNs via phosphorylation at serine 421. In Huntington's disease, pathogenic CAG repeat expansions of HTT decrease synthesis and disrupt transport of cortical-striatal BDNF, which may contribute to disease, and Mn is a putative environmental modifier of Huntington's disease pathology. Thus, we tested the hypothesis that changes in MSN dendritic morphology Mn due to exposure are associated with decreased BDNF levels and alterations in Htt protein. We report that BDNF levels are decreased in the striatum of Mn-exposed non-human primates and in the cerebral cortex and striatum of mice exposed to Mn. Furthermore, proBDNF and mature BDNF concentrations in primary cortical and hippocampal neuron cultures were decreased by exposure to Mn confirming the in vivo findings. Mn exposure decreased serine 421 phosphorylation of Htt in cortical and hippocampal neurons and increased total Htt levels. These data strongly support the hypothesis that Mn-exposure-related MSN pathology is associated with decreased BDNF trophic support via alterations in Htt.

Pivotal roles of p53 transcription-dependent and -independent pathways in manganese-induced mitochondrial dysfunction and neuronal apoptosis.

Chronic exposure to excessive manganese (Mn) has been known to lead to neuronal loss and a clinical syndrome resembling idiopathic Parkinson's disease (IPD). p53 plays an integral role in the development of various human diseases, including neurodegenerative disorders. However, the role of p53 in Mn-induced neuronal apoptosis and neurological deficits remains obscure. In the present study, we showed that p53 was critically involved in Mn-induced neuronal apoptosis in rat striatum through both transcription-dependent and -independent mechanisms. Western blot and immunohistochemistrical analyses revealed that p53 was remarkably upregulated in the striatum of rats following Mn exposure. Coincidentally, increased level of cleaved PARP, a hallmark of apoptosis, was observed. Furthermore, using nerve growth factor (NGF)-differentiated PC12 cells as a neuronal cell model, we showed that Mn exposure decreased cell viability and induced apparent apoptosis. Importantly, p53 was progressively upregulated, and accumulated in both the nucleus and the cytoplasm. The cytoplasmic p53 had a remarkable distribution in mitochondria, suggesting an involvement of p53 mitochondrial translocation in Mn-induced neuronal apoptosis. In addition, Mn-induced impairment of mitochondrial membrane potential (ΔΨm) could be partially rescued by pretreatment with inhibitors of p53 transcriptional activity and p53 mitochondrial translocation, Pifithrin-α (PFT-α) and Pifithrin-µ (PFT-µ), respectively. Moreover, blockage of p53 activities with PFT-α and PFT-µ significantly attenuated Mn-induced reactive oxidative stress (ROS) generation and mitochondrial H2O2 production. Finally, we observed that pretreatment with PFT-α and PFT-µ ameliorated Mn-induced apoptosis in PC12 cells. Collectively, these findings implicate that p53 transcription-dependent and -independent pathways may play crucial roles in the regulation of Mn-induced neuronal death.

The outcome of the movement disorder in methcathinone abusers: clinical, MRI and manganesemia changes, and neuropathology.

BACKGROUND AND PURPOSE: There is limited knowledge regarding the long-term outcome of the methcathinone/manganese-induced movement disorder. Our purpose was to define prognosis in intravenous methcathinone abusers affected by this distinctive disorder attributed to manganese (Mn) toxicity. Also, neuropathology from a globus pallidus region biopsy from a former user is reported. METHODS: Eighteen methcathinone abusers were categorized as active (five), discontinued (four) or former (nine) users. They were reassessed after a median of 32.5 months (range 3.4-59.6) clinically, on rating scales, and with MRI and blood Mn levels. The biopsy was examined ultrastructurally. RESULTS: Overall the group showed a slight tendency to deterioration at follow-up on clinical assessment of motor functioning, especially the active users. No significant change occurred on parkinsonian rating scale reassessment. Significant reduction in Mn levels occurred in former users, and decreased T1-weighted hyperintensity on basal ganglia MRI occurred in 3 of 4 former and 2 of 3 discontinued users, despite lack of clinical improvement. The biopsy consisted of white matter showing decompacted myelin sheaths and frequent abnormalities of mitochondria. CONCLUSIONS: No improvement in this Mn-induced movement disorder occurs after cessation of methcathinone abuse despite improvement of Mn blood levels and/or MRI abnormalities. Ultrastructural abnormalities in a former user confirm structural damage to white matter is associated with the disorder. Methcathinone/Mn toxicity is an important, disabling and permanent medical sequel of intravenous drug abuse in the former Soviet Union.

The protective role of sesame oil against Parkinson's-like disease induced by manganese in rats.

Chronic exposure to manganese (Mn) results in motor dysfunction, biochemical and pathological alterations in the brain. Oxidative stress, inflammation, and dysfunction of dopaminergic and GABAergic systems stimulate activating transcription factor-6 (ATF-6) and protein kinase RNA-like ER kinase (PERK) leading to apoptosis. This study aimed to investigate the protective effect of sesame oil (SO) against Mn-induced neurotoxicity. Rats received 25 mg/kg MnCl2 and were concomitantly treated with 2.5, 5, or 8 ml/kg of SO for 5 weeks. Mn-induced motor dysfunction was indicated by significant decreases in the time taken by rats to fall during the rotarod test and in the number of movements observed during the open field test. Also, Mn resulted in neuronal degeneration as observed by histological staining. The striatal levels of lipid peroxides and reduced glutathione (oxidative stress markers), interleukin-6 and tumor necrosis factor-α (inflammatory markers) were significantly elevated. Mn significantly reduced the levels of dopamine and Bcl-2, while GABA, PERK, ATF-6, Bax, and caspase-3 were increased. Interestingly, all SO doses, especially at 8 ml/kg, significantly improved locomotor activity, biochemical deviations and reduced neuronal degeneration. In conclusion, SO may provide potential therapeutic benefits in enhancing motor performance and promoting neuronal survival in individuals highly exposed to Mn.

Gray matter morphometric biomarkers for distinguishing manganese-exposed welders from healthy adults revealed by source-based morphometry.

BACKGROUND: Chronic overexposure to manganese (Mn) may result in neurotoxicity, which is characterized by motor and cognitive dysfunctions. This study aimed to utilize multivariate source-based morphometry (SBM) to explore the biomarkers for distinguishing Mn-exposed welders from healthy controls (HCs). METHODS: High-quality 3D T1-weighted MRI scans were obtained from 45 Mn-exposed full-time welders and 33 age-matched HCs in this study. After extracting gray matter structural covariation networks by SBM, multiple classic interaction linear models were applied to investigate distinct patterns in welders compared to HCs, and Z-transformed loading coefficients were compared between the two groups. A receiver operating characteristic (ROC) curve was used to identify potential biomarkers for distinguishing Mn-exposed welders from HCs. Additionally, we assessed the relationships between clinical features and gray matter volumes in the welders group. RESULTS: A total of 78 subjects (45 welders, mean age 46.23±4.93 years; 33 HCs, mean age 45.55±3.40 years) were evaluated. SBM identified five components that differed between the groups. These components displayed lower loading weights in the basal ganglia, thalamus, default mode network (including the lingual gyrus and precuneus), and temporal lobe network (including the temporal pole and parahippocampus), as well as higher loading weights in the sensorimotor network (including the supplementary motor cortex). ROC analysis identified the highest classification power in the thalamic network. CONCLUSIONS: Altered brain structures might be implicated in Mn overexposure-related disturbances in motivative modulation, cognitive control and information integration. These results encourage further studies that focus on the interaction mechanisms, including the basal ganglia network, thalamic network and default mode network. Our study identified potential neurobiological markers in Mn-exposed welders and illustrated the utility of a multivariate method of gray matter analysis.

Parkinsonism in cirrhosis: pathogenesis and current therapeutic options.

Acquired hepatolenticular degeneration, also known as "Parkinsonism in cirrhosis" is characterized by extrapyramidal symptoms including hypokinesia, dystonia and rigidity that are rapidly progressive and may be independent of the severity of cognitive dysfunction. Magnetic resonance imaging reveals T1-weighted hyperintense signals in both globus pallidus and substantia nigra. Estimates of the prevalence of Parkinsonism in cirrhosis have been reported as high as 21 %. The cause of Parkinsonism in cirrhosis has been attributed to manganese deposition in basal ganglia structures, leading to the dysfunction of the dopaminergic neurotransmitter system. In particular, there is evidence from both spectroscopic and biochemical investigations for damage to (or dysfunction of) presynaptic dopamine transporters together with a loss of post-synaptic dopamine receptors in basal ganglia of affected patients. Therapeutic options are limited; ammonia-lowering strategies are without substantial benefit, and an effective manganese chelator is not available. In many patients, L-Dopa replacement therapy and the dopamine receptor agonist bromocriptine are beneficial, and liver transplantation is generally effective. However, reports of post-transplant residual extrapyramidal symptoms suggest an element of irreversibility in some cases.

Preweaning Mn exposure leads to prolonged astrocyte activation and lasting effects on the dopaminergic system in adult male rats.

Little is known about the effects of manganese (Mn) exposure over neurodevelopment and whether these early insults result in effects lasting into adulthood. To determine if early Mn exposure produces lasting neurobehavioral and neurochemical effects, we treated neonate rats with oral Mn (0, 25, or 50 mg Mn/kg/d over PND 1-21) and evaluated (1) behavioral performance in the open arena in the absence (PND 97) and presence (PND 98) of a d-amphetamine challenge, (2) brain dopamine D1 and D2-like receptors and dopamine transporter densities in the prefrontal cortex, striatum, and nucleus accumbens (PND 107), and (3) astrocyte marker glial fibrillary acidic protein (GFAP) levels in these same brain regions (PND 24 and 107). We found that preweaning Mn exposure did not alter locomotor activity or behavior disinhibition in adult rats, though Mn-exposed animals did exhibit an enhanced locomotor response to d-amphetamine challenge. Preweaning Mn exposure led to increased D1 and D2 receptor levels in the nucleus accumbens and prefrontal cortex, respectively, compared with controls. We also found increased GFAP expression in the prefrontal cortex in Mn-exposed PND 24 weanlings, and increased GFAP levels in prefrontal cortex, medial striatum and nucleus accumbens of adult (PND 107) rats exposed to preweaning Mn, indicating an effect of Mn exposure on astrogliosis that persisted and/or progressed to other brain regions in adult animals. These data show that preweaning Mn exposure leads to lasting molecular and functional impacts in multiple brain regions of adult animals, long after brain Mn levels returned to normal.

White matter abnormalities in methcathinone abusers with an extrapyramidal syndrome.

We examined white matter abnormalities in patients with a distinctive extrapyramidal syndrome due to intravenous methcathinone (ephedrone) abuse. We performed diffusion tensor imaging in 10 patients and 15 age-matched controls to assess white matter structure across the whole brain. Diffuse significant decreases in white matter fractional anisotropy, a diffusion tensor imaging metric reflecting microstructural integrity, occurred in patients compared with controls. In addition, we identified two foci of severe white matter abnormality underlying the right ventral premotor cortex and the medial frontal cortex, two cortical regions involved in higher-level executive control of motor function. Paths connecting different cortical regions with the globus pallidus, the nucleus previously shown to be abnormal on structural imaging in these patients, were generated using probabilistic tractography. The fractional anisotropy within all these tracts was lower in the patient group than in controls. Finally, we tested for a relationship between white matter integrity and clinical outcome. We identified a region within the left corticospinal tract in which lower fractional anisotropy was associated with greater functional deficit, but this region did not show reduced fractional anisotropy in the overall patient group compared to controls. These patients have widespread white matter damage with greatest severity of damage underlying executive motor areas.

Manganese accumulation in the CNS and associated pathologies.

Manganese (Mn) is an essential metal for life. It is a key constituent of clue enzymes in the central nervous system, contributing to antioxidant defenses, energetic metabolism, ammonia detoxification, among other important functions. Until now, Mn transport mechanisms are partially understood; however, it is known that it shares some mechanisms of transport with iron. CNS is susceptible to Mn toxicity because it possesses mechanisms that allow Mn entry and favor its accumulation. Cases of occupational Mn exposure have been extensively reported in the literature; however, there are other ways of exposure, such as long-term parental nutrition and liver failure. Manganism and hepatic encephalopathy are the most common pathologies associated with the effects of Mn exposure. Both pathologies are associated with motor and psychiatric disturbances, related in turn to mechanisms of damage such as oxidative stress and neurotransmitters alterations, the dopaminergic system being one of the most affected. Although manganism and Parkinson's disease share some characteristics, they differ in many aspects that are discussed here. The mechanisms for Mn transport and its participation in manganism and hepatic encephalopathy are also considered in this review. It is necessary to find an effective therapeutic strategy to decrease Mn levels in exposed individuals and to treat Mn long term effects. In the case of patients with chronic liver failure it would be worthwhile to test a low-Mn diet in order to ameliorate symptoms of hepatic encephalopathy possibly related to Mn accumulation.

Nigral MRI features of asymptomatic welders.

INTRODUCTION: Manganese (Mn)-induced parkinsonism involves motor symptoms similar to those observed in Parkinson's disease (PD). Previous literature suggests that chronic Mn- exposure may increase PD risk, although Mn-induced clinical syndromes are considered atypical for PD. This study investigated whether asymptomatic welders display differences in the substantia nigra (SN), the key pathological locus of PD. METHOD: Brain MRI data and occupational exposure history were obtained in welders (N = 43) and matched controls (N = 31). Diffusion tensor imaging fractional anisotropy (FA; estimate of microstructural integrity) and R2* (estimate of iron and other PD-related brain differences) values in the SN pars compacta (SNc), SN reticulata (SNr), and globus pallidus (GP) were compared between the two groups. The MRI markers of the SN and GP within welders were related to exposure estimates. RESULTS: Compared to controls, welders who had chronic, but low-level, Mn-exposure had similar FA and R2* values in both SN regions (p's > 0.082), but significantly lower FA (p = 0.0013), although not R2* (p = 0.553), in the GP. In welders, FA values in the SN and GP showed a second-order polynomial relationship with cumulative lifetime welding exposure (p's < 0.03). CONCLUSION: Neurotoxic processes associated with Mn-exposure may be different from those in PD when the exposure-level is relatively low. Greater welding duration and level, however, were associated with FA differences in the GP and SN, indicating that welding exposures above a certain level may induce neurotoxicity in the SN, a finding that should be explored further in future studies.

The effects of manganese overexposure on brain health.

Manganese (Mn) is the twelfth most abundant element on the earth and an essential metal to human health. Mn is present at low concentrations in a variety of dietary sources, which provides adequate Mn content to sustain support various physiological processes in the human body. However, with the rise of Mn utility in a variety of industries, there is an increased risk of overexposure to this transition metal, which can have neurotoxic consequences. This risk includes occupational exposure of Mn to workers as well as overall increased Mn pollution affecting the general public. Here, we review exposure due to air pollution and inhalation in industrial settings; we also delve into the toxic effects of manganese on the brain such as oxidative stress, inflammatory response and transporter dysregulation. Additionally, we summarize current understandings underlying the mechanisms of Mn toxicity.

The gut microbiota attenuate neuroinflammation in manganese exposure by inhibiting cerebral NLRP3 inflammasome.

Manganese (Mn) exposure has been reported to cause neurodegenerative disorders. ß-Amyloid (Aß) induced Tau pathology in an NLRP3-dependent manner is at the heart of Alzheimer's and Parkinson's diseases. The gut microbiota plays a crucial role in the bidirectional gut-brain axis that integrates the gut and central nervous system (CNS) activities. In this study, we found that Mn exposure increases Aß1-40 and Tau production in brain, and causes hippocampal degeneration and necrosis. Meanwhile, Mn exposure can stimulate neurotoxicity by increasing inflammation either in peripheral blood and CNS. Importantly, we found that transplantation of gut microbiota from normal rats into Mn exposure rats reduced Aß and Tau expression, and the cerebral expression of NLRP3 was downregulated, and the expression of neuroinflammatory factors was also downregulated. Therefore, improving the composition of gut microbiota in Mn exposure rats can attenuate neuroinflammation, which is considered as a novel therapeutic strategy for Mn exposure by remodelling the gut microbiota.

Methionine-Mediated Protein Phosphatase 2A Catalytic Subunit (PP2Ac) Methylation Ameliorates the Tauopathy Induced by Manganese in Cell and Animal Models.

The molecular mechanism of Alzheimer-like cognitive impairment induced by manganese (Mn) exposure has not yet been fully clarified, and there are currently no effective interventions to treat neurodegenerative lesions related to manganism. Protein phosphatase 2 A (PP2A) is a major tau phosphatase and was recently identified as a potential therapeutic target molecule for neurodegenerative diseases; its activity is directed by the methylation status of the catalytic C subunit. Methionine is an essential amino acid, and its downstream metabolite S-adenosylmethionine (SAM) participates in transmethylation pathways as a methyl donor. In this study, the neurotoxic mechanism of Mn and the protective effect of methionine were evaluated in Mn-exposed cell and rat models. We show that Mn-induced neurotoxicity is characterized by PP2Ac demethylation accompanied by abnormally decreased LCMT-1 and increased PME-1, which are associated with tau hyperphosphorylation and spatial learning and memory deficits, and that the poor availability of SAM in the hippocampus is likely to determine the loss of PP2Ac methylation. Importantly, maintenance of local SAM levels through continuous supplementation with exogenous methionine, or through specific inhibition of PP2Ac demethylation by ABL127 administration in vitro, can effectively prevent tau hyperphosphorylation to reduce cellular oxidative stress, apoptosis, damage to cell viability, and rat memory deficits in cell or animal Mn exposure models. In conclusion, our data suggest that SAM and PP2Ac methylation may be novel targets for the treatment of Mn poisoning and neurotoxic mechanism-related tauopathies.

Metal-induced neurotoxicity in a RAGE-expressing C. elegans model.

Environmental and occupational metal exposure poses serious global concerns. Metal exposure have severally been associated with neurotoxicity and brain damage. Furthermore, receptor for advanced glycation end products (RAGE) is also implicated in neurological disorders, particularly those with altered glucose metabolism. Here, we examine potential compounding effect of metal exposure and RAGE expression on dopamine (DA) and serotonin (SER) neurons in C. elegans. In addition, we evaluate the effect of RAGE expression on DA and SER neurons in hyperglycemic conditions. Newly generated RAGE-expressing C. elegans tagged with green fluorescent proteins (GFP) in DAergic and SERergic neurons were treated with cadmium (Cd) or manganese (Mn). Additionally, the RAGE-expressing worms were also exposed to high glucose conditions. Results showed metals induced neurodegeneration both in the presence and absence of RAGE expression, but the manner of degeneration differed between Cd and Mn treated nematodes. Furthermore, RAGE-expressing worms showed significant neurodegeneration in both DAergic and SERergic neurons. Our results indicate co-occurrence of metal exposure and RAGE expression can induce neurodegeneration. Additionally, we show that RAGE expression can exacerbate hyperglycemic induced neurodegeneration.