Manganese Abstracts 9

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Nicotine protects against manganese and iron-induced toxicity in SH-SY5Y cells: Implication for Parkinson's disease.
            (Getachew et al., 2018)  Download
Manganese (Mn) and iron (Fe) are trace elements that are essential for proper growth and physiological functions as both play critical role in a variety of enzymatic reactions. At high concentrations, however, they can be toxic and cause neurodegenerative disorders, particularly Parkinson-like syndromes. Nicotine, on the other hand, has been shown to have neuroprotective effects against various endogenous or exogenous toxins that selectively damage the dopaminergic cells. These cells include neuroblastoma-derived SH-SY5Y cells which express significant dopaminergic activity. However, practically no information on possible neuroprotective effects of nicotine against toxicity induced by trace elements is available. Therefore, in this study we investigated the effects of nicotine on toxicity induced by manganese or iron in these cells. Exposure of SH-SY5Y cells for 24 h to manganese (20 μM) or iron (20 μM) resulted in approximately 30% and 35% toxicity, respectively. Pretreatment with nicotine (1 μM) completely blocked the toxicities of Mn and Fe. The effects of nicotine, in turn, were blocked by selective nicotinic receptor antagonists. Thus, dihydro-beta erythroidine (DHBE), a selective alpha 4-beta 2 subtype antagonist and methyllycaconitine (MLA), a selective alpha7 antagonist, as well as mecamylamine, a non-selective nicotinic antagonist all dose-dependently blocked the protective effects of nicotine against both Mn and Fe. These findings provide further support for the potential utility of nicotine or nicotinic agonists in Parkinson's disease-like neurodegenerative disorders, including those that might be precipitated by trace elements, such as Fe and Mn. Moreover, both alpha4-beta2 and alpha7 nicotinic receptor subtypes appear to mediate the neuroprotective effects of nicotine against toxicity induced by these two trace metals.


 

Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study.
            (Jiang et al., 2006)  Download
OBJECTIVE:  Chronic manganese (Mn) intoxication induces syndromes resembling Parkinson disease. The clinical intervention has largely been unsuccessful. We report a 17-year follow-up study of effective treatment of occupational Mn parkinsonism with sodium para-aminosalicylic acid (PAS). METHODS:  The patient, female and aged 50 at the time of treatment, was exposed to airborne Mn for 21 years (1963-1984). The patient had palpitations, hand tremor, lower limb myalgia, hypermyotonia, and a distinct festinating gait. She received 6 g PAS per day through an intravenous drip infusion for 4 days and rested for 3 days as one therapeutic course. Fifteen such courses were carried out between March and June 1987. RESULTS:  At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal. Recent follow-up examination at age 67 years (in 2004) showed a general normal presentation in clinical, neurologic, brain magnetic resonance imaging, and handwriting examinations with a minor yet passable gait. CONCLUSIONS:  This case study suggests that PAS appears to be an effective drug for treatment of severe chronic Mn poisoning with a promising prognosis.

A report of two cases of chronic serious manganese poisoning treated with sodium para-aminosalicylic acid.
            (Ky et al., 1992)  Download
Two cases of chronic manganese poisoning were treated with sodium para-aminosalicylic acid (PAS-Na; 6 g/day in 500 ml of 10% glucose solution by intravenous drip). The results indicated that one had been clinically cured and that the other had obviously improved in clinical symptoms and signs. Thus PAS-Na appears to be an effective drug for treatment of serious chronic manganese poisoning.

The Essential Element Manganese, Oxidative Stress, and Metabolic Diseases: Links and Interactions.
            (Li and Yang, 2018)  Download
Manganese (Mn) is an essential element that is involved in the synthesis and activation of many enzymes and in the regulation of the metabolism of glucose and lipids in humans. In addition, Mn is one of the required components for Mn superoxide dismutase (MnSOD) that is mainly responsible for scavenging reactive oxygen species (ROS) in mitochondrial oxidative stress. Both Mn deficiency and intoxication are associated with adverse metabolic and neuropsychiatric effects. Over the past few decades, the prevalence of metabolic diseases, including type 2 diabetes mellitus (T2MD), obesity, insulin resistance, atherosclerosis, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), and hepatic steatosis, has increased dramatically. Previous studies have found that ROS generation, oxidative stress, and inflammation are critical for the pathogenesis of metabolic diseases. In addition, deficiency in dietary Mn as well as excessive Mn exposure could increase ROS generation and result in further oxidative stress. However, the relationship between Mn and metabolic diseases is not clear. In this review, we provide insights into the role Mn plays in the prevention and development of metabolic diseases.

Anticancer therapeutic potential of Mn porphyrin/ascorbate system.
            (Tovmasyan et al., 2015)  Download
Ascorbate (Asc) as a single agent suppressed growth of several tumor cell lines in a mouse model. It has been tested in a Phase I Clinical Trial on pancreatic cancer patients where it exhibited no toxicity to normal tissue yet was of only marginal efficacy. The mechanism of its anticancer effect was attributed to the production of tumoricidal hydrogen peroxide (H2O2) during ascorbate oxidation catalyzed by endogenous metalloproteins. The amount of H2O2 could be maximized with exogenous catalyst that has optimized properties for such function and is localized within tumor. Herein we studied 14 Mn porphyrins (MnPs) which differ vastly with regards to their redox properties, charge, size/bulkiness and lipophilicity. Such properties affect the in vitro and in vivo ability of MnPs (i) to catalyze ascorbate oxidation resulting in the production of H2O2; (ii) to subsequently employ H2O2 in the catalysis of signaling proteins oxidations affecting cellular survival pathways; and (iii) to accumulate at site(s) of interest. The metal-centered reduction potential of MnPs studied, E1/2 of Mn(III)P/Mn(II)P redox couple, ranged from -200 to +350 mV vs NHE. Anionic and cationic, hydrophilic and lipophilic as well as short- and long-chained and bulky compounds were explored. Their ability to catalyze ascorbate oxidation, and in turn cytotoxic H2O2 production, was explored via spectrophotometric and electrochemical means. Bell-shape structure-activity relationship (SAR) was found between the initial rate for the catalysis of ascorbate oxidation, vo(Asc)ox and E1/2, identifying cationic Mn(III) N-substituted pyridylporphyrins with E1/2>0 mV vs NHE as efficient catalysts for ascorbate oxidation. The anticancer potential of MnPs/Asc system was subsequently tested in cellular (human MCF-7, MDA-MB-231 and mouse 4T1) and animal models of breast cancer. At the concentrations where ascorbate (1mM) and MnPs (1 or 5 µM) alone did not trigger any alteration in cell viability, combined treatment suppressed cell viability up to 95%. No toxicity was observed with normal human breast epithelial HBL-100 cells. Bell-shape relationship, essentially identical to vo(Asc)oxvs E1/2, was also demonstrated between MnP/Asc-controlled cytotoxicity and E1/2-controlled vo(Asc)ox. Magnetic resonance imaging studies were conducted to explore the impact of ascorbate on T1-relaxivity. The impact of MnP/Asc on intracellular thiols and on GSH/GSSG and Cys/CySS ratios in 4T1 cells was assessed and cellular reduction potentials were calculated. The data indicate a significant increase in cellular oxidative stress induced by MnP/Asc. Based on vo(Asc)oxvs E1/2 relationships and cellular toxicity, MnTE-2-PyP(5+) was identified as the best catalyst among MnPs studied. Asc and MnTE-2-PyP(5+) were thus tested in a 4T1 mammary mouse flank tumor model. The combination of ascorbate (4 g/kg) and MnTE-2-PyP(5+) (0.2mg/kg) showed significant suppression of tumor growth relative to either MnTE-2-PyP(5+) or ascorbate alone. About 7-fold higher accumulation of MnTE-2-PyP(5+) in tumor vs normal tissue was found to contribute largely to the anticancer effect.

Occupational manganese exposure, reproductive hormones, and semen quality in male workers: A cross-sectional study.
            (Yang et al., 2018)  Download
It has been found that exposure to manganese (Mn) could induce reproductive dysfunction, but its occupational risk in male workers is unclear. This study aims to assess the association of occupational Mn exposure with reproductive hormones and semen quality in a cross-sectional study. Urinary Mn, semen quality, and reproductive hormones were explored in 84 male workers occupationally exposed to Mn and 92 referents. Multiple linear regression analyses were used to assess the relationship. Urinary Mn levels in Mn-exposed workers ranged from 0.56 to 34.25 µg/L, and the average level was 15.92 ± 8.49 µg/L. Compared with the control group, gonadotropin-releasing hormone (GnRH) levels and luteinizing hormone (LH) levels increased significantly and the levels of testosterone (TSTO) decreased significantly in the Mn-exposed group. There was a significant positive linear association between urinary Mn and GnRH and LH, while the linear association between urinary Mn and TSTO was negative. Sperm progressive motility and total motility decreased significantly in the Mn-exposed group. There was a significantly negative linear association between urinary Mn and sperm progressive motility and total motility. In conclusion, occupational Mn exposure was inversely associated with reproductive health of male workers, resulting in the abnormality of hormones secretion and decrease of sperm motility.

Chelation therapy of manganese intoxication with para-aminosalicylic acid (PAS) in Sprague-Dawley rats.
            (Zheng et al., 2009)  Download
Para-aminosalicylic acid (PAS), an FDA-approved anti-tuberculosis drug, has been used successfully in the treatment of severe manganese (Mn)-induced Parkinsonism in humans [Jiang Y-M, Mo X-A, Du FQ, Fu X, Zhu X-Y, Gao H-Y, et al. Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study. J Occup Environ Med 2006;48:644-9]. This study was conducted to explore the capability of PAS in reducing Mn concentrations in body fluids and tissues of Mn-exposed animals. Sprague-Dawley rats received daily intraperitoneally (i.p.) injections of 6mg Mn/kg, 5 days/week for 4 weeks, followed by a daily subcutaneously (s.c.) dose of PAS (100 and 200mg/kg as the PAS-L and PAS-H group, respectively) for another 2, 3 or 6 weeks. Mn exposure significantly increased the concentrations of Mn in plasma, red blood cells (RBC), cerebrospinal fluid (CSF), brain and soft tissues. Following PAS-H treatment for 3 weeks, Mn levels in liver, heart, spleen and pancreas were significantly reduced by 25-33%, while 3 weeks of PAS-L treatment did not show any effect. Further therapy with PAS-H for 6 weeks reduced Mn levels in striatum, thalamus, choroid plexus, hippocampus and frontal cortex by 16-29% (p<0.05). Mn exposure greatly increased iron (Fe) and copper (Cu) concentrations in CSF, brain and liver. Treatment with PAS-H restored Fe and Cu levels comparable with control. These data suggest that PAS likely acts as a chelating agent to mobilize and remove tissue Mn. A high-dose and prolonged PAS treatment appears necessary for its therapeutic effectiveness.

 


References

Getachew, B, et al. (2018), ‘Nicotine protects against manganese and iron-induced toxicity in SH-SY5Y cells: Implication for Parkinson’s disease.’, Neurochem Int, 124 19-24. PubMed: 30557592
Jiang, YM, et al. (2006), ‘Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study.’, J Occup Environ Med, 48 (6), 644-49. PubMed: 16766929
Ky, SQ, et al. (1992), ‘A report of two cases of chronic serious manganese poisoning treated with sodium para-aminosalicylic acid.’, Br J Ind Med, 49 (1), 66-69. PubMed: 1733459
Li, L and X Yang (2018), ‘The Essential Element Manganese, Oxidative Stress, and Metabolic Diseases: Links and Interactions.’, Oxid Med Cell Longev, 2018 7580707. PubMed: 29849912
Tovmasyan, A, et al. (2015), ‘Anticancer therapeutic potential of Mn porphyrin/ascorbate system.’, Free Radic Biol Med, 89 1231-47. PubMed: 26496207
Yang, H, et al. (2018), ‘Occupational manganese exposure, reproductive hormones, and semen quality in male workers: A cross-sectional study.’, Toxicol Ind Health, 748233718810109. PubMed: 30466360
Zheng, W, et al. (2009), ‘Chelation therapy of manganese intoxication with para-aminosalicylic acid (PAS) in Sprague-Dawley rats.’, Neurotoxicology, 30 (2), 240-48. PubMed: 19150464