metallothionein and Nervous-System-Diseases

Mammalian metallothionein-2A (MT2A) has received considerable attention in recent years due to its crucial pathophysiological role in anti-oxidant, anti-apoptosis, detoxification and anti-inflammation. For many years, most studies evaluating the effects of MT2A have focused on reactive oxygen species (ROS), as second messengers that lead to oxidative stress injury of cells and tissues. Recent studies have highlighted that oxidative stress could activate mitogen-activated protein kinases (MAPKs), and MT2A, as a mediator of MAPKs, to regulate the pathogenesis of various diseases. However, the molecule mechanism of MT2A remains elusive. A deeper understanding of the functional, biochemical and molecular characteristics of MT2A would be identified, in order to bring new opportunities for oxidative stress therapy.

Topics: Animals; Cardiovascular Diseases; Humans; MAP Kinase Signaling System; Metallothionein; Neoplasms; Nervous System Diseases; Oxidative Stress

Evidence concerning a role for metallothionein (MT) in human disease is reviewed. Current knowledge of MT is juxtaposed with our understanding of the pathogenesis of disease. MT is known to modulate three fundamental processes: 1) the release of gaseous mediators such as hydroxyl radical or nitric oxide; 2) apoptosis, and 3) the binding and exchange of heavy metals such as zinc, cadmium or copper. The capability to specifically manipulate MT levels in cells and in mice is beginning to provide answers regarding how MT could impact complex disease scenarios. Associations among MT and several diseases, including cancer, circulatory and septic shock, coronary artery disease, and Alzheimer's disease have been made. Strong evidence exists that MT modulates the immune system. The primary function of MT remains unknown.

Topics: Animals; Apoptosis; Arthritis, Rheumatoid; Cadmium; Copper; Diabetes Mellitus; Free Radicals; HeLa Cells; Humans; Immune System; Metallothionein; Mice; Models, Biological; Neoplasms; Nervous System Diseases; Nitric Oxide; Protein Binding; Shock; Zinc

A symposium on the role of brain metallothioneins (MTs) in physiology and pathology was held at the 1996 Annual Society of Toxicology Meeting in Anaheim, California. The objectives of this symposium were to: (1) review the physiologic function of MTs, (2) examine the distribution of brain MTs with particular emphasis on cell-specific localization (neurons vs neuroglia), (3) discuss MT gene responsiveness upon toxic insult with metals, and (4) discuss the potential role of MTs in the etiology of neurodegenerative disorders. Dr. Cherian discussed the biochemical properties of the MTs, emphasizing structural similarities and differences between the MTs. Dr. Klaassen addressed the expression and distribution of the MTs in brains with special reference to the cell-specific localization of MTs. Dr. Aschner provided data illustrating a potential role for MTs in attenuating the cytotoxicity caused by methylmercury (MeHg) in cultured neonatal astrocytes. Dr. Palmiter discussed the properties of MT-III and the increased sensitivity of MT-III knockout mice to kainate-induced seizures. Cerebral zinc metabolism, its relationship to MT homeostasis, and its pathogenic potential in Alzheimer's disease was addressed by Dr. Bush.

Topics: Animals; Astrocytes; Brain; Cells, Cultured; Humans; Metallothionein; Methylmercury Compounds; Mice; Nerve Degeneration; Nervous System Diseases; Neuroglia; Neurons; Zinc

Cadmium (Cd) is neurotoxic metal which induces histopathological damage and oxidative stress through free radicals over production. Metallothionein (MT) is a protein able to scavenge free radicals and to chelate metals. In this study we describe the lipid peroxidation (LPO) and MT content in the brain of developing rats exposed at Cd 1 mg/kg/day intra peritoneally (i.p.) and dexamethasone (Dx) 2 mg/kg/day (i.p.) alone and combined during 5 days. At those doses, cadmium significantly increases the levels of LPO in parietal cortex, striatum and cerebellum as compared to a control group while, in the hippocampus no modifications in the LPO levels were observed. In the group treated with Cd+Dx, Dx significantly diminished the levels of LPO in parietal cortex, striatum and cerebellum. On the other hand, the MT levels showed a significant increase in all regions of the groups treated with Dx and Cd+Dx as compared with the control group. These results show that Dx treatment prevented the increase in LPO levels associated to Cd exposure, probably through the increase in MT content.

Topics: Animals; Anti-Inflammatory Agents; Brain; Brain Chemistry; Cadmium; Dexamethasone; Female; Fluorescent Dyes; Indicators and Reagents; Lipid Peroxidation; Male; Metallothionein; Nervous System Diseases; Rats; Rats, Wistar

Based on the inhibition of nitrite formation by generating superoxide from xanthine/xanthine oxidase (X/XO) reaction system, metallothionein (MT) and other sulfhydryl containing amino acids have been selected to test their abilities to scavenge superoxide radicals. Different concentrations of metallothionein and other sulfhydryl containing molecules e.g. cysteine, N-acetyl-cysteine and glutathione, were used to assess superoxide scavenging properties. Metallothionein scavenges superoxide radical in a dose-dependent manner with increasing concentrations as evidenced by the inhibition of nitrite formation. Similar abilities to scavenge superoxide radicals were shown by cysteine, N-acetyl-cysteine. Glutathione also scavenges superoxide radical in a dose-dependent manner. In vitro experiments demonstrated that metallothionein is superior in scavenging superoxide radicals compared to other sulfhydryl molecules such as cysteine, N-acetyl-cysteine and even glutathione. The data, further, suggest that metallothionein-II has a 6-fold higher capacity to scavenge superoxide radical than metallothionein-I. In addition, metallothionein-like protein was isolated from different regions of mouse brain treated with zinc. Brain metallothionein-like protein inhibits nitrite formation as demonstrated by other scavengers; however, the extent of inhibition is different by this protein isolated from different brain regions. The present study suggests that metallothioneins and metallothionein-like proteins isolated from mouse brain act as neuroprotective agents by scavenging superoxide radicals.

Topics: Acetylcysteine; Animals; Antioxidants; Brain Chemistry; Cysteine; Electrophoresis, Polyacrylamide Gel; Free Radical Scavengers; Glutathione; Male; Metallothionein; Mice; Mice, Inbred C57BL; Nervous System Diseases; Nitrites; Superoxides

As an essential substance, zinc is involved in maintaining the functions and/or the structures of at least 200 metalloenzymes that participate in numerous biochemical reactions, including the metabolism of proteins and nucleic acids. The steady-state concentration of zinc in the brain must be regulated firmly since both an excess and a deficiency of zinc have been implicated in neurological disorders including epilepsy. Zinc-binding proteins have been detected in the bovine hippocampus, cerebellum, and pineal gland. A metallothionein-like protein has been identified recently in the rat brain which resembles in some but not all aspects a hepatic metallothionein. The synthesis of this protein is stimulated following the administration of zinc and copper but not of cadmium. The zinc-stimulated protein incorporates 35S cysteine 24-fold higher than the native, unstimulated protein; is blocked by actinomycin D; produces two isoforms by ion exchange chromatography on DEAE Sephadex A 25 columns; and by high performance liquid chromatography, depicts a similar but not identical profile to zinc-stimulated hepatic metallothionein. Since the synthesis of this protein is stimulated following the administration of zinc and is depressed in the brains of zinc-deficient rats, it is postulated that the unbound pool of zinc may serve as one of the factors involved in regulating the synthesis of this protein. Since zinc in physiological concentrations stimulates a number of pyridoxal phosphate-dependent reactions and in pharmacological doses inhibits an extensive number of SH-containing enzymes and receptor sites for neurotransmitters, we postulate that the metallothionein-like protein in the brain may have function(s) associated with zinc homeostasis and perhaps events related to synaptic functions.

Topics: Animals; Carrier Proteins; Epilepsy; Humans; Metalloproteins; Metallothionein; Nerve Tissue Proteins; Nervous System Diseases; Pyridoxine; Zinc