Role of metallothionein-III following central nervous system damage

Carrasco, Javier; Penkowa, Milena; Giralt, Mercedes; Camats, Jordi; Molinero, Amalia; Campbell, Iain L.; Palmiter, Richard D.; Hidalgo, Juan

doi:10.1016/s0969-9961(03)00015-9

Cited by 49 publications

(31 citation statements)

References 90 publications

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“…This is essentially what has also been observed in the kainic acid-induced seizure model (139). In the cryolesion model, MT-3 deficiency did not affect the inflammatory response, oxidative stress and apoptotic death (149), in sharp contrast to what is observed in MT-1&2-deficient mice (see above). Whether this indicates that MT-3 does not function effectively as an antioxidant protein in vivo in this certainly highly damaging model, or if it again highlights the limited protection afforded by this protein, remains to be established.…”

Section: Transgenic Mice Show Different Metallothionein-3 Functionssupporting

confidence: 74%

Metallothioneins and brain injury: What transgenic mice tell us

Hidalgo

2004

Environ Health Prev Med

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In rodents, the metallothionein (MT) family is composed of four members, MT-1 to MT-4. MT-1&2 are expressed in virtually all tissues including those of the Central Nervous System (CNS), while MT-3 (also called Growth Inhibitory Factor) and MT-4 are expressed prominently in the brain and in keratinizing epithelia, respectively. For the understanding of the physiological functions of these proteins in the brain, the use of transgenic mice has provided essential information. Results obtained in MT-1&2-null mice and in MT-1-overexpressing mice strongly suggest that these MT isoforms are important antioxidant, anti-inflammatory and antiapoptotic proteins in the brain. Results in MT-3-null mice show a very different pattern, with no support for MT-1&2-like functions. Rather, MT-3 could be involved in neuronal sprouting and survival. Results obtained in a model of peripheral nervous system injury also suggest that MT-3 could be involved in the control of nerve growth.

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Section: Transgenic Mice Show Different Metallothionein-3 Functionssupporting

confidence: 74%

Metallothioneins and brain injury: What transgenic mice tell us

Hidalgo

2004

Environ Health Prev Med

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“…However, unlike MT-I and MT-II, MT-III possesses several other unique properties. For example, MT-III is unlikely to be a significant factor for controlling the inflammatory response (69). MT-III, but not MT-I or MT-II, antagonizes both the neurotrophic and neurotoxic effect of amyloid ␤ peptide, which is the principal component of neuritic plaques (70,71).…”

Section: Discussionmentioning

confidence: 99%

Metallothionein-III Prevents γ-Ray-induced 8-Oxoguanine Accumulation in Normal and hOGG1-depleted Cells

Jeong

Youn

Cho

et al. 2004

Journal of Biological Chemistry

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Metallothioneins (MT) play an important biological role in preventing oxidative damage to cells. We have previously demonstrated that the efficiency of the protective effect of MT-III against the DNA degradation from oxidative damage was much higher than that of MT-I/II. As an extension of the latter investigation, this study aimed to assess the ability of MT-III to suppress 8-oxoguanine (8-oxoG), which is one of the major base lesions formed after an oxidative attack to DNA and the mutant frequency of the HPRT gene in human fibroblast GM00637 cells upon exposure to ␥-rays. We found that human MT-III expression decreased the level of 8-oxoG and mutation frequency in the ␥-irradiated cells. Using an 8-oxoguanine DNA glycosylase (OGG1)-specific siRNAs, we also found that MT-III expression resulted in the suppression of the ␥-radiation-induced 8-oxoG accumulation and mutation in the OGG1-depleted cells. Moreover, the down-regulation of MT in human neuroblastoma SKNSH cells induced by MT-specific siRNA led to a significant increase in the 8-oxoG level, after exposure to ␥-irradiation. These results suggest that under the conditions of ␥-ray oxidative stress, MT-III prevents the ␥-radiation-induced 8-oxoG accumulation and mutation in normal and hOGG1-depleted cells, and this suppression might, at least in part, contribute to the anticarcinogenic and neuroprotective role of MT-III. The metallothioneins (MT)1 are a group of intracellular metal-binding proteins of low molecular mass (6 -7 kDa) that are widely distributed in a broad range of eukaryotic species from yeast to mammals (1, 2). In both mice and humans, there are four classes of quite similar MT proteins, MT-I to MT-IV. MT-I and MT-II are widely expressed in all tissues, whereas MT-III and MT-IV are expressed mainly in the central nervous system and the squamous epithelia, respectively (3-7). Whereas much is known about the chemical properties and genetic regulation of MT, the actual physiological role of MT is largely unknown. The first recognized function of MT is the detoxification of heavy metals such as cadmium and mercury (8, 9). Subsequently, a number of cellular functions have been proposed for MT, including regulating essential metal homeostasis (10, 11), contributing to the control of cellular proliferation and apoptosis (12, 13), and protecting against radiation and oxidative damage (14, 15). The role of MT in oxidative damage has been aggressively investigated, and the vast majority of studies show that MT is a potent antioxidant that protects against various oxidative damage from reactive oxygen species (ROS) in vitro and in vivo because of their multiple cysteines. In vitro up-regulation of MT has been correlated with resistance to cytotoxicity induced by various hydroxyl radical generators, and the rate constant of MT for a reaction with hydroxyl radicals is more than 100ϫ higher than that of glutathione (16 -21). In addition, MT is 50ϫ more effective in protecting DNA from hydroxyl radicals than glutathione on a molar basis (22). In vivo, the i...

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“…The role of MT-3 in the brain was thought to be to protect and repair neurons. Recently, it has been reported that the level of MT-3 is increased by IL-3, TGF-α, and EGF and decreases by IL-6, kainite, and dexamethasone, and the level also changes in neuronal diseases such as Parkinson and prion diseases (Yu et al 2001;Carrasco et al 2003;Hozumi et al 2006;Kim et al 2008); therefore, it is thought that MT-3 also acts as a good index in the brain when a substance affects the brain.…”

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confidence: 99%

Induction of metallothionein in mouse cerebellum and cerebrum with low-dose thimerosal injection

et al. 2009

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Thimerosal, an ethyl mercury compound, is used worldwide as a vaccine preservative. We previously observed that the mercury concentration in mouse brains did not increase with the clinical dose of thimerosal injection, but the concentration increased in the brain after the injection of thimerosal with lipopolysaccharide, even if a low dose of thimerosal was administered. Thimerosal may penetrate the brain, but is undetectable when a clinical dose of thimerosal is injected; therefore, the induction of metallothionein (MT) messenger RNA (mRNA) and protein was observed in the cerebellum and cerebrum of mice after thimerosal injection, as MT is an inducible protein. MT-1 mRNA was expressed at 6 and 9 h in both the cerebrum and cerebellum, but MT-1 mRNA expression in the cerebellum was three times higher than that in the cerebrum after the injection of 12 microg/kg thimerosal. MT-2 mRNA was not expressed until 24 h in both organs. MT-3 mRNA was expressed in the cerebellum from 6 to 15 h after the injection, but not in the cerebrum until 24 h. MT-1 and MT-3 mRNAs were expressed in the cerebellum in a dose-dependent manner. Furthermore, MT-1 protein was detected from 6 to 72 h in the cerebellum after 12 microg/kg of thimerosal was injected and peaked at 10 h. MT-2 was detected in the cerebellum only at 10 h. In the cerebrum, little MT-1 protein was detected at 10 and 24 h, and there were no peaks of MT-2 protein in the cerebrum. In conclusion, MT-1 and MT-3 mRNAs but not MT-2 mRNA are easily expressed in the cerebellum rather than in the cerebrum by the injection of low-dose thimerosal. It is thought that the cerebellum is a sensitive organ against thimerosal. As a result of the present findings, in combination with the brain pathology observed in patients diagnosed with autism, the present study helps to support the possible biological plausibility for how low-dose exposure to mercury from thimerosal-containing vaccines may be associated with autism.

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Role of metallothionein-III following central nervous system damage

Cited by 49 publications

References 90 publications

Metallothioneins and brain injury: What transgenic mice tell us

Metallothioneins and brain injury: What transgenic mice tell us

Metallothionein-III Prevents γ-Ray-induced 8-Oxoguanine Accumulation in Normal and hOGG1-depleted Cells

Induction of metallothionein in mouse cerebellum and cerebrum with low-dose thimerosal injection

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