Glutathione Deficiency Potentiates Manganese Toxicity in Rat Striatum and Brainstem and in Pc12 Cells

Desole, Maria Speranza; Esposito, Giovanni; Migheli, Rossana; Sircana, S.; Delogu, Maria Rosaria; Fresu, Luigia Grazia; Miele, Maddalena; Natale, G. De; Miele, E

doi:10.1006/phrs.1997.0197

Cited by 52 publications

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“…Oxidative stress has also been shown to mediate manganese-induced apoptosis in several in vitro models such as PC-12 cells and HeLa cells (Desole et al, 1997b;Oubrahim et al, 2001) and in vivo in manganeseinduced neurotoxicity of the rat (Desole et al, 1997a), which is relevant within the context of combustion products of MMT-amended fuels. Because MMT seems to exert cytotoxic effects also as an organic complex of manganese, the potential danger of MMT-amended fuels is possibly enhanced by both precombustion (MMT) and postcombustion (manganese) product exposures (Garrison et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress and Mitochondrial-Mediated Apoptosis in Dopaminergic Cells Exposed to Methylcyclopentadienyl Manganese Tricarbonyl

Kitazawa

Wagner²,

Kirby

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

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Methylcyclopentadienyl manganese tricarbonyl (MMT), an organic manganese-containing gasoline additive, was investigated to determine whether MMT potentially causes dopaminergic neurotoxic effects. MMT is acutely cytotoxic and dopamine-producing cells (PC-12) seemed to be more susceptible to cytotoxic effects than nondopaminergic cells (striatal ␥-aminobutyric acidergic and cerebellar granule cells). MMT also potently depleted dopamine apparently by cytoplasmic vesicular release to the cytosol, a neurochemical change resembling other dopaminergic neurotoxicants. Generation of reactive oxygen species (ROS), an early effect in toxicantinduced apoptosis, occurred within 15 min of MMT exposure. MMT caused a loss of mitochondrial transmembrane potential (⌬⌿m), a likely source of ROS generation. The ROS signal further activated caspase-3, an important effector caspase, which could be inhibited by antioxidants (Trolox or N-acetyl cysteine). Predepletion of dopamine by using ␣-methyl-p-tyrosine (tyrosine hydroxylase inhibitor) treatment partially prevented caspase-3 activation, denoting a significant dopamine and/or dopamine by-product contribution to initiation of apoptosis. Genomic DNA fragmentation, a terminal hallmark of apoptosis, was induced concentration dependently by MMT but completely prevented by pretreatment with Trolox, deprenyl (monoamine oxidase-B inhibitor), and ␣-methyl-p-tyrosine. A final set of critical experiments was performed to verify the pharmacological studies using a stable Bcl-2-overexpressing PC-12 cell line. Bcl-2-overexpressing cells were significantly refractory to MMT-induced ROS generation, caspase-3 activation, and loss of ⌬⌿m and were completely resistant to MMTinduced DNA fragmentation. Taken together, the results presented herein demonstrate that oxidative stress plays an important role in mitochondrial-mediated apoptotic cell death in cultured dopamine-producing cells after exposure to MMT.

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Section: Discussionmentioning

confidence: 99%

Oxidative Stress and Mitochondrial-Mediated Apoptosis in Dopaminergic Cells Exposed to Methylcyclopentadienyl Manganese Tricarbonyl

Kitazawa

Wagner²,

Kirby

et al. 2002

The Journal of Pharmacology and Experimental Therapeutics

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“…Manganese can induce PC12 cell neuronal differentiation similar to that of nerve growth factor (NGF); however, it invariably leads to cell death (Lin et al, 1993). Recent studies suggest that cell death induced by manganese may be caused by either necrosis and/or apoptosis attributable to oxidative stress (Desole et al, 1996(Desole et al, , 1997aHirata et al, 1998;Schrantz et al, 1999;Roth et al, 2000). Manganese has been reported to be taken up into PC12 cells by a transport system with characteristics resembling those of DMT1 (Kim et al, 1993), although the significance of the resemblance has been questioned (Yanagiya et al, 2000).…”

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confidence: 99%

Differential Localization of Divalent Metal Transporter 1 with and without Iron Response Element in Rat PC12 and Sympathetic Neuronal Cells

Roth¹,

Horbinski²,

Feng³

et al. 2000

J. Neurosci.

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Two isoforms of divalent metal transporter 1 (DMT1) (Nramp2 and DCT1) are encoded by two mRNA species, one of which contains an iron response element (IRE) motif in the 3Ј-noncoding region. The subcellular distribution of the two isoforms of DMT1 is distinct, and the ϪIRE species accumulates in the nucleus of neuronal or neuronal-like cells. Reverse transcription-PCR and Western blot analysis of PC12 cells reveals that these cells express both forms of DMT1. Immunofluorescence and immunoblotting studies, using immunospecific antibodies to the ϪIRE form of DMT1, demonstrate that this form of the transporter, in PC12 cells, is predominantly localized in the nucleus, cell membrane, and neurites with only weak staining of the cell body. Studies using antibodies to the ϩIRE form indicate that this species of DMT1 is distributed within vesicles in the cell body and neurite projections, with minimal nuclear staining. Similar staining patterns are observed for the two forms of DMT1 in cultures of sympathetic ganglion neurons isolated from perinatal rat pups. To determine whether nuclear localization of the ϪIRE form of DMT1 is constrained to neuronal or neuronal-like cells, immunocytochemical studies were performed with human embryonic kidney 293T (HEK293T), HEP2G hepatoma and medulloblastoma, and rat Schwann cells. The ϪIRE-specific antibodies stained nuclei from medulloblastoma, whereas little nuclear staining was observed with HEK293T, hepatoma, or Schwann cells. The unexpected finding that the ϪIRE species of DMT1 selectively accumulates in the nucleus of neuronal and neuronallike cells leads us to postulate that the two proteins may have different functions in vivo.

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Section: Some Theoretical Premises Of Biological Protectionmentioning

confidence: 99%

“…The reasons for including these amino-acids into our BPCs were both theoretical (taking into consideration the above-mentioned general important role played by oxidative stress as a mechanism of Me-NP toxicity) and experimental as there were data of other researchers demonstrating that glutathione deficiency potentiates some specific metal toxicities-e.g. manganese-induced damage to the rat striatum and brainstem [96].3) Other agents of the organism's anti-oxidant system: vitamins А, Е, and С, and selenium (on the same theoretical grounds).4) Omega-3 polyunsaturated fatty acids (PUFA) whose intracellular derivativeseicosanoids-activate DNA replication and thus play an important part in its repair. Meanwhile the DNA fragmentation was found to be a common effect of all Me-NPs studied by us up to now.…”

mentioning

confidence: 99%

Looking for Biological Protectors against Adverse Health Effects of Some Nanoparticles that Can Pollute Workplace and Ambient Air (A Summary of Authors’ Experimental Results)

Privalova¹,

Katsnelson²,

Sutunkova³

et al. 2017

JEP

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Especially high health risks associated with impacts of metallic nanoparticles (Me-NPs) and their presence in the workplace and ambient air of not only the nano-industry but also of some long-existing traditional technologies make it necessary, along with keeping respective dangerous exposures as low as possible, to look for ways of increasing the organism's resistance to them. Based on theoretical premises of such beneficial interference with toxicokinetics and toxicodynamics of Me-NPs developed by our research team and on understanding general and specific key mechanisms of different Me-NPs' toxic action, we proposed several bioprotective complexes (BPCs) comprising mainly pectin, some vitamins, glutamate, glycine, N-acetylcysteine, omega-3 PUFA, and different essential trace elements. Results of our animal experiments with different Me-NPs showed that, against the background of such BPCs' oral administration, the integral and specific toxicity of Me-NPs and even their genotoxicity can be markedly attenuated. Therefore we would recommend to further develop this vector of nano-toxicological research. KeywordsNanoparticles, Toxic metals, Bioptotectors BackgroundNanoparticles (NPs) of elemental metals and some metalloids, and even more so 845of their oxides are of special interest in the framework of health risk assessment and risk management problems. Along with engineered metallic NPs (Me-NPs), there usually exists a substantial nanoscale fraction of condensation aerosols generated as byproducts of many long existing and new technologies (steel and nonferrous metallurgies, arc-welding, laser metals treatment, etc) and thus polluting both workroom and ambient air in respective industries and adjacent areas. Other fractions of such aerosols are 8 usually presented mostly be submicron particles with dimensions above 100 nm. Examples illustrating these statements are given in Figure 1 and Figure 2.In such industries air is, as a rule, polluted by multi-component mixtures of chemically different particles of similar or dissimilar geometry. For instance, in arc-welding and alloyed steel making one usually finds different combinations of iron, chromium, nickel, manganese and silicon oxides, while in crude copper smelting and copper refining-those of copper, lead, cadmium, zinc, and arsenic oxides.In the vast nano-toxicological literature of the last decade, studies concerned with the assessment of Me-NP toxicity are quite numerous. We can refer, for example, to several works devoted to the same Me-NPs that were the sub- lot of others). However, the prevailing majority of these researchers assessed adverse effects of Me-NPs in vitro on stable cell lines. This approach features a number of well-known advantages relating, in particular, to analysis of primary toxicity mechanisms on cellular and sub-cellular levels. At the same time, any extrapolation of the results of these experiments to the organism level and even the organ-systemic level is associated with a number of uncertainties and assumptions. Moreover,...

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Glutathione Deficiency Potentiates Manganese Toxicity in Rat Striatum and Brainstem and in Pc12 Cells

Cited by 52 publications

References 0 publications

Oxidative Stress and Mitochondrial-Mediated Apoptosis in Dopaminergic Cells Exposed to Methylcyclopentadienyl Manganese Tricarbonyl

Oxidative Stress and Mitochondrial-Mediated Apoptosis in Dopaminergic Cells Exposed to Methylcyclopentadienyl Manganese Tricarbonyl

Differential Localization of Divalent Metal Transporter 1 with and without Iron Response Element in Rat PC12 and Sympathetic Neuronal Cells

Looking for Biological Protectors against Adverse Health Effects of Some Nanoparticles that Can Pollute Workplace and Ambient Air (A Summary of Authors’ Experimental Results)

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