Effect of Manganese Exposure on MPTP Neurotoxicities

Department of Anatomy, College of Medicine, Pusan University Hospital, Pusan, South Korea.
NeuroToxicology (Impact Factor: 3.38). 09/2003; 24(4-5):657-65. DOI: 10.1016/S0161-813X(03)00033-0
Source: PubMed


We used a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model to evaluate whether manganese (Mn) exposure can affect MPTP-induced neurotoxicity. We randomly assigned adult male C57BL/6 mice (n=5-7 per group) the following treatments: SO, Mn(-) x MPTP(-); MO, Mn(+) x MPTP(-); SM, Mn(-) x MPTP(+); MM, Mn(+) x MPTP(+). Mn (MnCl(2).4H(2)O) was administered intraperitoneally at a dose of 2 mg/kg daily for 3 weeks. MPTP was then administered intraperitoneally at a dose of 30 mg/kg daily for 5 days in the SM and MM groups. Seven days after the last MPTP injection, the animals were sacrificed. Blood Mn levels were elevated in the Mn-exposed groups. Striatal Mn levels were not influenced by Mn treatment alone, however, they were decreased following MPTP. Tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in the substantia nigra pars compacta (SNpc) were decreased significantly in the MPTP-exposed groups. Densities of TH- and dopamine transporter (DAT)-ir axon terminals in the caudate-putamen (CPU) were also decreased in the MPTP-treated groups. Furthermore, glial fibrillary acidic protein (GFAP)-ir astrocytes increased in the CPU with MPTP treatment. However, no effects were observed with Mn exposure. Concentrations of dopamine (DA), 3,4-dihydrophenyl acetic acid (DOPAC) and homovanillic acid (HVA) in the corpus striatum were also decreased significantly with MPTP treatment alone, but Mn had no effect. Thus, decreased dopaminergic activities with MPTP led to decreased DA and its metabolites. Significant hypertrophies of GFAP-ir astrocytes in the globus pallidus (GP) were observed in Mn-exposed groups, especially in the MM group. MPTP targeted dopaminergic systems whereas Mn neurotoxicities occurred in the GP. In conclusion, our data suggest that Mn does not potentiate the neurotoxicity of MPTP.

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    • "The nigrostriatal system, including the globus pallidus and substantia nigra, is the primary target of Mn (Baek et al., 2003). Accumulation of manganese in pallidal regions of the basal ganglia has been well described as 'manganese hyperintensity signals' by T1-weighted MRI imaging procedures (Krieger et al., 1995). "
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    ABSTRACT: 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 (3-10μM) exposure to differentiated mesencephalic dopaminergic neuronal cells for 3h 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 24h 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.
    Preview · Article · Feb 2011 · Toxicology and Applied Pharmacology
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    • "Although manganese-induced Parkinsonism has been recognized for some time, the primary mechanism underlying manganese neurotoxicity remains elusive. Human and animal studies have shown that toxic manganese exposure results in metal accumulations in various areas of the basal ganglia and dysfunction of cells of both the striatum and the globus pallidus (Calne et al., 1994; Eriksson et al., 1987; Erikson et al., 2004a, 2004b; Brenneman et al., 1999; Nagatomo et al., 1999; Newland, 1999; Pal et al., 1999; Baek et al., 2003). Considering the clinical similarities between Manganism and Parkinson's Disease, and the fact that manganese accumulates in brain regions rich in dopaminergic neurons, it has long been suggested that manganese neurotoxicity involves a disruption in dopaminergic neurotransmission (Neff et al., 1969; Hornykiewicz, 1972; Graham, 1984). "
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    ABSTRACT: The lateral cilia of the gill of Crassostrea virginica are controlled by a dopaminergic-serotonergic innervation. Dopamine is the neurotransmitter causing cilio-inhibition. High levels of manganese are neurotoxic to people, causing Manganism, a Parkinson-like disease. Clinical interventions for Manganism have not been very successful. Recently, p-Aminosalicylic acid (PAS) was reported as an effective treatment of severe Manganism in humans; however, its mechanism of action is unknown. Previously, we reported that manganese treatments caused disruption of the dopaminergic innervation of gill of C. virginica. Here we compared the effects of manganese on gill innervation in the presence of PAS, EDTA or Acetylsalicylic acid (ASA), and examined whether co-treating animals with PAS could block the deleterious effects of manganese on the oyster's dopaminergic innervation of the gill. Beating rates of the lateral cilia of the gill were measured by stroboscopic microscopy. Pre-treating gill preparations with PAS or EDTA blocked the neurotoxic effects of manganese, while ASA did not. In other experiments, animals exposed to three day treatments with manganese produced a dose dependent impairment of the dopaminergic, cilio-inhibitory system, which was decreased by co-treatment with PAS. The study shows that PAS protects the animal against neurotoxic effects of manganese and the mechanism of action of PAS in alleviating Manganism is more likely related to its chelating abilities than its anti-inflammatory actions.
    Full-text · Article · Nov 2009 · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology
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    • "However, compared to Parkinson's, there are some differentiating features seen with Manganism including symmetry of effects, more prominent dystonia, a characteristic " cock walk, " an intention rather than resting tremor, earlier behavioral and cognitive dysfunction, difficulty turning, and a poor response to Levodopa (Barbeau, et al., 1976; Huang, et al, 1993, 1998; Calne, et al., 1994; Lu, et al., 1994; Koller, et al., 2004; Olanow, 2004; Jankovic, 2005; Cersosimo and Koller, 2006) suggesting different or more extensive damage in the basal ganglia or to the dopaminergic system. Human and animal studies have shown that toxic exposure to manganese results in metal accumulations in various areas of the basal ganglia and dysfunction of cells of both the striatum and the globus pallidus (Eriksson, et al., 1992; Calne, et al., 1994; Brenneman, et al., 1999; Nagatomo, et al., 1999; Newland, 1999; Pal, et al., 1999; Baek, et al., 2003). Other studies have shown that manganese selectively targets dopaminergic neurons in the human basal ganglia (Pal, et al., 1999; Olanow, 2004) and decreases dopamine levels in the striatum (Mena, et al., 1970; Parenti, et al., 1986; Eriksson, et al., 1987; Vescovi, et al., 1991; Sistrunk, et al., 2007). "
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    ABSTRACT: We examined effects of manganese on the nervous system and innervation of lateral cilia of Crassostrea virginica. While essential in trace amounts, tissue manganese accumulation is neurotoxic, inducing Manganism, a Parkinson's-like disease in humans. Lateral cilia of the gill of C. virginica are controlled by a reciprocal serotonergic-dopaminergic innervation from their ganglia. Oysters were incubated 3 days in the presence of up to 1 mM manganese, followed by superfusion of the cerebral ganglia, visceral ganglia or gill with dopamine or serotonin. Beating rates of cilia were measured by stroboscopic microscopy of isolated gill preparations or gill preparations with the ipsilateral cerebral and/or visceral ganglia attached. Acute manganese treatments impaired the dopaminergic, cilio-inhibitory system, while having no effect on the serotonergic, cilio-excitatory system, which is in agreement with the proposed mechanism of manganese toxicity in humans. Manganese treatments also decreased endogenous dopamine levels in the cerebral and visceral ganglia, and gills, but not serotonin levels. We demonstrated that manganese disrupts the animal's dopaminergic system, and also that this preparation can be used to investigate mechanisms that underlie manganese neurotoxicity. It also may serve as a model in pharmacological studies of drugs to treat or prevent Manganism and other dopaminergic cell disorders.
    Full-text · Article · Sep 2008 · Comparative Biochemistry and Physiology Part C Toxicology & Pharmacology
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