Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on methylmercury-induced locomotor deficits and cerebellar toxicity in mice

Carvalho, Márcia C.; Franco, Jeferson Luís; Ghizoni, Heloisa; Kobus, Karoline; Nazari, Evelise Maria; Rocha, João Batista Teixeira da; Nogueira, Cristina W.; Dafre, Alcir Luiz; Müller, Yara Maria Rauh; Farina, Marcelo

doi:10.1016/j.tox.2007.07.009

Cited by 62 publications

(42 citation statements)

References 36 publications

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“…The analysis of endogenous regulators of red-ox homeostasis revealed that reduction of GPx activity was the fi rst event induced by prolonged exposure to low MeHg concentration before changes in glutathione (GSH), catalase and glutathione reductase (GR) could be observed (Farina et al 2009 ) . In agreement, GPx inhibition and lipid peroxidation were found to occur earlier than GSH and GR changes in animals prenatally exposed to MeHg (Carvalho et al 2007 ;Stringari et al 2008 ) . Probucol increased GPx activity by itself and inhibited MeHg-induced lipid peroxidation, whereas the antioxidants ascorbic acid and trolox did not (Fig.…”

Section: Effect Of Methylmercury On Cellular Red-ox Homeostasissupporting

confidence: 71%

In Vitro Models for Methylmercury Neurotoxicity: Effects on Glutamatergic Cerebellar Granule Neurons

Suñol

Rodrı́guez-Farré

2012

Methylmercury and Neurotoxicity

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Methylmercury (MeHg), a relevant persistent environmental contaminant, is widely recognized as a potent neurotoxicant in humans. The clinical features of MeHg-intoxicated people are characterized by neurological dysfunction that induces cerebellar-based ataxia, generalized extremity weakness, and sensory disturbances including speech, vision, and hearing impairment, which correlate with the loss of neurons from several areas of the brain, among them the cerebellar granule cell (CGC) layer. CGCs are glutamatergic neurons that are successfully grown in vitro. Here, we report the effects of short and long term exposure to MeHg on primary cultures of CGCs. Short exposure to micromolar concentrations of MeHg inhibits neuronal glutamate uptake and induces the release of endogenous glutamate, the increase of intracellular calcium and of oxidative stress. After continuous exposure to low MeHg concentration (in the nanomolar range) oxidative stress results in lipid peroxidation and cell death which are reduced by the glutathione peroxidase (GPx)-enhancing antioxidant probucol or by overexpressing GPx in the cells. Decreased phosphorylation and translocation of cofi lin from the cytosol to the mitochondria are also early hallmarks of MeHg-induced toxicity in cultured cerebellar granule neurons.

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Section: Effect Of Methylmercury On Cellular Red-ox Homeostasissupporting

confidence: 71%

In Vitro Models for Methylmercury Neurotoxicity: Effects on Glutamatergic Cerebellar Granule Neurons

Suñol

Rodrı́guez-Farré

2012

Methylmercury and Neurotoxicity

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“…Previous studies also showed that exposures to MeHg produce behavioral deficits related to locomotor activity and motor performance in mice (Carvalho et al, 2007;Franco et al, 2009;Stringari et al, 2006Stringari et al, , 2008 and rats Fujimura et al, 2012;Sakamoto et al, 2002). Notably, MeHginduced changes on locomotor activity and motor performance were associated with prooxidative events in the cerebellum.…”

Section: Discussionmentioning

confidence: 85%

“…(Dietrich et al, 2005;Ni et al, 2012;Farina et al, 2013). It is of interest that MeHginduced cerebellar toxicity was reported to be a result of pro-oxidative effects toward the antioxidant glutathione (GSH)-dependent system (Carvalho et al, 2007;Farina et al, 2011aFarina et al, , 2011b. Data demonstrated a significant main effect of MeHg toward cerebellar GPx activity ( Figure 3A), although L-Met exerted no significant effect and no marked MeHg by LMet interaction was detected.…”

Section: Gpx Activitymentioning

confidence: 97%

“…In contrast, oxidative stress promoted by MeHg is also related to its interaction with intracellular thiol-and selenol-containing molecules, such as glutathione (GSH) and glutathione peroxidase Franco et al, 2009). Because of the importance of the GSH-antioxidant system in protecting the CNS again oxidative stress (Dringen, 2000), MeHg-induced changes in this antioxidant system have been correlated to central oxidative damage and behavioral impairments (Carvalho et al, 2007;Dietrich et al, 2005).…”

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confidence: 99%

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Methionine Stimulates Motor Impairment And Cerebellar Mercury Deposition in Methylmercury-Exposed Mice

Zimmermann

Santos

Colle

et al. 2014

Journal of Toxicology and Environmental Health, Part A

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Methylmercury (MeHg) is a highly toxic environmental contaminant that produces neurological and developmental impairments in animals and humans. Although its neurotoxic properties have been widely reported, the molecular mechanisms by which MeHg enters the cells and exerts toxicity are not yet completely understood. Taking into account that MeHg is found mostly bound to sulfhydryl-containing molecules such as cysteine in the environment and based on the fact that the MeHg-cysteine complex (MeHg-S-Cys) can be transported via the L-type neutral amino acid carrier transport (LAT) system, the potential beneficial effects of L-methionine (L-Met, a well known LAT substrate) against MeHg (administrated as MeHg-S-Cys)-induced neurotoxicity in mice were investigated. Mice were exposed to MeHg (daily subcutaneous injections of MeHg-S-Cys, 10 mg Hg/kg) and/or L-Met (daily intraperitoneal injections, 250 mg/kg) for 10 consecutive days. After treatments, the measured hallmarks of toxicity were mostly based on behavioral parameters related to motor performance, as well as biochemical parameters related to the cerebellar antioxidant glutathione (GSH) system. MeHg significantly decreased motor activity (open-field test) and impaired motor performance (rota-rod task) compared with controls, as well as producing disturbances in the cerebellar antioxidant GSH system. Interestingly, L-Met administration did not protect against MeHg-induced behavioral and cerebellar changes, but rather increased motor impairments in animals exposed to MeHg. In agreement with this observation, cerebellar levels of mercury (Hg) were higher in animals exposed to MeHg plus L-Met compared to those only exposed to MeHg. However, this event was not observed in kidney and liver. These results are the first to demonstrate that L-Met enhances cerebellar deposition of Hg in mice exposed to MeHg and that this higher deposition may be responsible for the greater motor impairment observed in mice simultaneously exposed to MeHg and L-Met.

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“…In addition to this SOD-related research, it has been found in a number of studies that decreased GPx activity in the brains was caused by the mice being given MeHg at a concentration of 40 mg/L in drinking water for several weeks (Carvalho et al, 2007;Farina et al, 2003b;Franco et al, 2009;Glaser et al, 2010). Stringari et al (2008) reported that exposing pregnant mice to MeHg at concentrations of 1, 3, and 10 mg/L in drinking water induced a dose-dependent and long-lasting inhibitory effect on the occurrence of cerebral antioxidant enzymes, such as GPx, which is a developmental phenomenon, in their pups.…”

Section: Oxidative Stress and S-mercurationmentioning

confidence: 99%

<i>S</i>-Mercuration of cellular proteins by methylmercury and its toxicological implications

2014

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-The accumulation of methylmercury (MeHg) through the daily consumption of large predatory fish poses potential health risks. MeHg has been found to cause Minamata disease, but the full nature of MeHg toxicity remains unclear. Because of its chemical properties, MeHg covalently binds to cellular proteins through their reactive thiols, referred to as S-mercuration, resulting in the formation of protein adducts. In this review, we summarize how the S-mercuration of cellular proteins could be involved in the major mechanisms that have been suggested to underlie MeHg toxicity. Additionally, we introduce our attempts to identify cases of S-mercuration for the research to reveal the true nature of MeHg toxicity.

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Effects of 2,3-dimercapto-1-propanesulfonic acid (DMPS) on methylmercury-induced locomotor deficits and cerebellar toxicity in mice

Cited by 62 publications

References 36 publications

In Vitro Models for Methylmercury Neurotoxicity: Effects on Glutamatergic Cerebellar Granule Neurons

In Vitro Models for Methylmercury Neurotoxicity: Effects on Glutamatergic Cerebellar Granule Neurons

Methionine Stimulates Motor Impairment And Cerebellar Mercury Deposition in Methylmercury-Exposed Mice

<i>S</i>-Mercuration of cellular proteins by methylmercury and its toxicological implications

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