Enhanced seizures and hippocampal neurodegeneration following kainic acid‐induced seizures in metallothionein‐I + II‐deficient mice

Carrasco, Javier; Penkowa, Milena; Hadberg, Hanne; Molinero, Amalia; Hidalgo, Juan

doi:10.1046/j.1460-9568.2000.00128.x

Cited by 120 publications

(111 citation statements)

References 54 publications

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“…MT-I/II knockout mice exhibit an impaired inflammatory response (63,64), and MT-I/II deficiency potentiated the oxidative stress caused by kainic acid, a potent convulsive agent (65). Similarly, MT-I/II-null mice exhibit a delayed wound healing capacity following a focal cryolesion (66), and MT-I/II isoforms are major proteins for protecting the CNS following traumatic brain injury (67).…”

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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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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“…Thus, significant upregulation of these proteins has been observed in a number of human neurological diseases, including Alzheimer's disease (55,(79)(80)(81)(82)), Pick's disease (79), short-course Creutzfeld-Jakob disease (72), amyotrophic lateral sclerosis (83)(84)(85), and multiple sclerosis (86,87). Experiments carried out in animal models fully demonstrated the response of MT-1&2 to brain damage elicited by inflammatory factors such as lipopolysaccharides (11, 15, 24, 88), stress (62,(89)(90)(91), glutamate analogues (37,51,59,(92)(93)(94)(95), cryogenic injury (28,32,66,71), stroke/ischemia (17, [95][96][97][98], familial amyotrophic lateral sclerosis models (38,67,99,100), multiple sclerosis models (101)(102)(103), and gliotoxins (104)(105)(106).…”

Section: Transgenic Mice Show That Metallothionein-1and2 Are Essential mentioning

confidence: 99%

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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“…The primary functions of metallothioneins are to maintain homeostatic levels of essential metals and detoxify non-essential metals [16,23,30]. MT1 and MT2 protect the central nervous system from damage induced by interleukin 6, 6-aminonicotinamide, kainic acid and physical injury [4,10,33]. Studies using MT1/MT2-null mice have also shown that MT1 and MT2 protect cells from damage induced by oxidative stress [25].…”

Section: Introductionmentioning

confidence: 99%

Mercury-induced cognitive impairment in metallothionein-1/2 null mice

Eddins

Petro

Pollard

et al. 2008

Neurotoxicology and Teratology

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Metallothioneins are central for the metabolism and detoxification of transition metals. Exposure to mercury during early neurodevelopment is associated with neurocognitive impairment. Given the importance of metallothioneins in mercury detoxification, metallothioneins may be a protective factor against mercury-induced neurocognitive impairment. Deletion of the murine metallothionein-1 and metallothionein-2 genes causes choice accuracy impairments in the 8-arm radial maze. We hypothesize that deletions of metallothioneins genes will make metallothionein-null mice more vulnerable to mercury-induced cognitive impairment. We tested this hypothesis by exposing MT1/MT2-null and wildtype mice to developmental mercury (HgCl 2 ) and evaluated the resultant effects on cognitive performance on the 8-arm radial maze. During the early phase of learning metallothionein-null mice were more susceptible to mercury-induced impairment compared to wildtype. Neurochemical analysis of the frontal cortex revealed that serotonin levels were higher in metallothionein-null mice compared to wildtype mice. This effect was independent of mercury exposure. However, dopamine levels in mercury exposed metallothionein-null mice were lower compared to mercury-exposed wildtype mice. This work shows that deleting metallothioneins increase the vulnerability to developmental mercury-induced neurocognitive impairment. Metallothionein effects on monoamine transmitters may be related to this cognitive effect.

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Enhanced seizures and hippocampal neurodegeneration following kainic acid‐induced seizures in metallothionein‐I + II‐deficient mice

Cited by 120 publications

References 54 publications

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

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

Metallothioneins and brain injury: What transgenic mice tell us

Mercury-induced cognitive impairment in metallothionein-1/2 null mice

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