The multipotent role of metallothionein in the nervous system


  • G. А. Ushakova Oles Honchar Dnipropetrovsk National University
  • Y. P. Kovalchuk Oles Honchar Dnipropetrovsk National University
Keywords: cadmium, zinc, metallothionein, brain, postoperative pain

Abstract

We provide a commentary on current experimental and theoretical advances and frame our consideration in terms of the possible functions of MT I+II in the nervous system. Metallothioneins (MT) are a family of small cysteine rich proteins, which since their discovery in 1957 have been implicated in a range of roles including toxic metal detoxification, protection against oxidative stress, and as a metallochaperone involved in the homeostasis of both zinc and copper. The most well studied member of the family is the mammalian metallothionein, which consists of two domains: a β-domain with 9 cysteine residues and an α-domain with 11 cysteine residues. Despite over half a century of research, the exact functions of MT in the nervous system are still unknown. Our studies have shown that the distribution of MT-I+II in the brain after prolonged intoxication, inhalation of 0.1% CdCl2 for 1 hour twice a week over 19 weeks, is dependent on the part of the brain. The metallothionein level declines more than 4 times in the hippocampus 3 weeks after continuous intoxication of 0.1% CdCl2. The level of MT-I+II in the cerebral cortex decreased by 1.5 times compared with the control group and did not change significantly in the cerebellum and thalamus/hypothalamus. The results of an experimental model of postoperative pain indicated that injection with MT-II prevents the development of postoperative hyperalgesia in response to mild alteration of physiological activity. Activation of locomotory and exploratory activity, and decrease of anxiety in rats under MT-II treatment at 100 µg/rat manifests itself on the 4th day after surgery. Our experimental data indicate the multipotent function of MT I+II in the rat brain both as a metal detoxifier and as an inhibitor of postoperative pain. 

References

Andrews, G.K., 2000. Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem. Pharmacol. 59, 95–104. >> doi:10.1016/S0006-2952(99)00301-9
Asanuma, M., Miyazaki, I., Higashi, Y., Tanaka, K., Haque, M.E., Fujita, N., Ogawa, N., 2002. Aggravation of 6-hydroxydopamine-induced dopaminergic lesions in metallo-thionein-I and -II knock-out mouse brain. Neurosci. Lett. 327, 61–65. >> doi:10.1016/S0304-3940(02)00346-4
Aschner, M., Sonnewald, U., Tan, K.H., 2002. Astrocyte modulation of neurotoxic injury. Brain Pathol. 12, 475–481.
Bremner, I., 1987. Nutritional and physiological significance of metallothionein. Experientia Suppl. 52, 81–107. >> doi:10.1007/978-3-0348-6784-9_5
Brennan, T.J., Vandermeulen, E.P., Gebhart, G.F., 1996. Characterization of a rat model of incisional pain. Pain 64(3), 493–521. >> doi:10.1016/0304-3959(95)01441-1
Chen, W.Q., Cheng, Y.Y., Li, S.T., Wang, D.L., Yu, Z., Hong, Y., 2005. Effects of zinc on the expression of metallothionein isoforms in hippocampus of stressed rats. Wei Sheng Yan Jiu 34(2), 201–204.
Danielyan, L., Tolstonog, G., Traub, P., Salvetter, J., Gleiter, C.H., Reisig, D., Gebhardt, R., Buniatian, G.H., 2007. Colocalization of glial fibrillary acidic protein, metallothionein, and MHC II in human, rat, NOD/SCID, and nude mouse skin keratinocytes and fibroblasts. J. Invest. Dermatol. 127(3), 555–563. >> doi:10.1038/sj.jid.5700575
DiSilvestro, R.A., Joseph, E., 1995. An acute phase response does not elevate rat heart metallothionein levels, nor inhibit adriamycin toxicity. Res. Commun. Mol. Pathol. Pharmacol. 88(1), 107–114.
Giralt, M., Penkowa, M., Lago, N., Molinero, A., Hidalgo, J., 2002. Metallothionein-1+2 protect the CNS after a focal brain injury. Exp. Neurol. 173, 114–128. >> doi:10.1006/exnr.2001.7772
Groten, J.P., Koeman, J.H., van Nesselrooij, J.H., 1994. Comparison of renal toxicity after long-term oral administration of cadmium chloride and cadmium-metallothionein in rats. Fundam. Appl. Toxicol. 23, 544–552. >> doi:10.1006/faat.1994.1139
Kazantzis, G., 2004. Cadmium, osteoporosis and calcium metabolism. Biometals 17(5), 493–498. >> doi:10.1023/B:BIOM.0000045727.76054.f3
Koob, A.O., Cirillo, J., Babbs, C.F., 2006. A novel open field activity detector to determine spatial and temporal movement of laboratory animals after injury and disease. J. Neurosci. Methods 157(2), 330–336. >> doi:10.1016/j.jneumeth.2006.04.020
Liu, J., Goyer, R.A., Waalkes, M.P., 2007. Toxic effects of metals. In: Klaassen, C.D., ed. Casarett and Doull’s Toxicology. The Basic Science of Poisons 7, 931–979.
Margoshes, M., Vallee, B.L., 1957. A cadmium protein from equine kidney cortex. J. Am. Chem. Soc. 79, 1813–1814. >> doi:10.1021/ja01574a064
Munoz, A., Petering, D.H., Shaw, C.F., 2000. Structure-reactivity relationships among metallothionein three-metal domains: Role of non-cysteine amino acid residues in lobster metallothionein and human metallothionein-3. Inorg. Chem. 39(26), 6114–6123. >> doi:10.1021/ic000485s
Nordberg, G.F., 2004. Cadmium and health in the 21st century – historical remarks and trends for the future. Biometals 17, 485–489.
Nordberg, G.F., Goyer, R., Nordberg, M., 1975. Comparative toxicity of cadmium-metallothionein and cadmium chloride on mouse kidney. Arch. Pathol. 99, 192–197.
Quaife, C.J., Findley, S.D., Erickson, J.C., Froelick, G.J., Kelly, E.J., Zambrowicz, B.P., Palmiter, R.D., 1994. Induction of a new metallothionein isoform (MT-IV) occurs during differentation of stratified squamous epitelia. Biochemistry 33, 7250–7259. >> doi:10.1021/bi00189a029
Radtke, F., Heuchel, R., Georgiev, O., Hergersberg, M., Gariglio, M., Dembic, Z., Schaffner, W., 1993. Cloned transcription factor MTF-1 activates the mouse metallothionein I promoter. EMBO J. 12, 1355–1362.
Simpkins, C.O., 2000. Metallothionein in human disease. Cell. Mol. Biol. 46(11), 465–488.
Sullivan, V.K., Cousins, R.J., 1997. Competitive reverse transcriptase-polymerase chain reaction shows that dietary zinc supplementation in humans increases monocyte metallo-thionein mRNA levels. J. Nutr. 127(5), 694–698.
Ushakova, G.A., Kruchinenko, O.A., 2008. Effect of chronic intoxication with cadmium on the level of metallothionein in the rat hippocampus. Neirofiziologiya / Neurophysiology 40(5–6), 426–428. >> doi:10.1007/s11062-009-9070-7
Ushakova, G.A., Kruchinenko, O.A., 2009. Peculiarities of the molecular structure and functions of metallothioneins in the central nervous system. Neirofiziologiya / Neurophysiology 41(5), 355–364. >> doi:10.1007/s11062-010-9113-0
Vander Jagt, T.A., Connor, J.A., Weiss, J.H., Shuttleworth, C.W., 2009. Intracellular Zn2+ increases contribute to the progression of excitotoxic Ca2+ increases in apical dendrites of CA1 pyramidal neurons. Neuroscience 159(1), 104–114. >> doi:10.1016/j.neuroscience.2008.11.052
Vasak, M., Hasler, D.W., 2000. Metallothioneins: New functional and structural insights. Curr. Opin. Chem. Biol. 4, 177–183. >> doi:10.1016/S1367-5931(00)00082-X
West, A.K., Stallings, R., Hildebrand, C.E., Chiu, R., Karin, M., Richards, R.I., 1990. Human metallothionein genes: Structure of the functional locus at 16q13. Genomics 8, 513–518. >> doi:10.1016/0888-7543(90)90038-V
Yajima, H., Sato, J., Giron, R., Nakamura, R., Mizumura, K., 2005. Inhibitory, facilitatory, and excitatory effects of ATP and purinergic receptor agonists on the activity of rat cutaneous nociceptors in vitro. Neurosci. Res. 51(4), 405–416. >> doi:10.1016/j.neures.2004.12.008
Published
2013-11-19
Section
Articles