Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Protective Effect of Carnosine Against Zn-Mediated Toxicity in Cortical Neuronal Cells

  • Hue, Jin-Joo (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Lee, Ah-Ram (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Lee, Yea-Eun (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Cho, Min-Hang (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Lee, Ki-Nam (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Nam, Sang-Yoon (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Yun, Young-Won (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University) ;
  • Jeong, Jae-Hwang (College of Liberal Arts) ;
  • Lee, Sang-Hwa (Department of Food and Nutrition, Seowon University) ;
  • Lee, Beom-Jun (College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University)
  • Published : 2007.03.31
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Abstract

Zinc is an endogenous transition metal that can be synaptically released during neuronal activity. However, zinc may contribute to the neuropathology associated with a variety of conditions. Carnosine expressed in glial cells can modulate the effects of zinc on neuronal excitability as a zinc chelator. We hypothesize that carnosine may protect against neurotoxicity of zinc in cortical neuronal cells. The cortical neuronal cells from newborn rats were prepared and exposed to zinc chloride and/or carnosine at various concentrations. Zinc at the doses of 0 to $500{\mu}M$ decreased neuronal cell viability in a dose-dependent manner. Additionally, at the concentrations of 100 and $200{\mu}M$, it significantly decreased cell viability in an exposed time-dependent manner (p < 0.05). Treatment with carnosine at the concentrations of 20 and $200{\mu}M$ significantly increased neuronal cell proliferation by approximately 14% and 20%, respectively, compared to the control (p < 0.05). At the concentrations of 100 and $200{\mu}M$ zinc, $20{\mu}M$ carnosine significantly increased the viability of neuronal cells by 18.3% and 12.1 %, and $200{\mu}M$ carnosine also increased it by 33.5% and 28.6%, respectively, compared to the normal control group (p < 0.01). These results suggest that carnosine at a physiologically relevant level may protect against zinc-mediated toxicity in neuronal cells as an endogenous neuroprotective agent.

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References

  1. Antonini, F.M., Petruzzi, E., Pinzani, P., Orlando, C., Poggesi, M., Serio, M., Pazzagli, M. and Masotti, G. (2002). The meat in the diet of aged subjects and the antioxidant effects of carnosine. Arch. Gerontol. Geriatr. Suppl., 8, 7-14
  2. Artero, C., Marti, E., Biffo, S., Mulatero, B., Andreone, C., Margolis, F.L. and Fasolo, A. (1991). Carnosine in the brain and olfactory system of amphibia and reptilia: a comparative study using immunocytochemical and biochemical methods. Neurosci. Lett., 130, 182-186 https://doi.org/10.1016/0304-3940(91)90392-7
  3. Bakardjiev, A. (1997). Biosynthesis of carnosine in primary cultures of rat olfactory bulb. Neurosci. Lett., 227, 115-118 https://doi.org/10.1016/S0304-3940(97)00315-7
  4. Bakardjiev, A. and Bauer, K. (1994). Transport of beta-alanine and biosynthesis of carnosine by skeletal muscle cells in primary culture. Eur. J. Biochem., 225, 617-623 https://doi.org/10.1111/j.1432-1033.1994.00617.x
  5. Baran, E.J. (2000). Metal complexes of carnosine. Biochemistry (Mosc), 65, 789-797
  6. Bauer, K., Hallermayer, K. Salnikow, J. Kleinkauf, H. and Hamprecht, B. (1982). Biosynthesis of carnosine and related peptides by glial cells in primary culture. J. Biol. Chem., 257, 3593-3597
  7. Biffo, S., Grillo, M. and Margolis, F.L. (1990). Cellular localization of carnosine-like and anserine-like immunoreactivities in rodent and avian central nervous system. Neuroscience, 35, 637-651 https://doi.org/10.1016/0306-4522(90)90335-2
  8. Boldyrev, A.A., Stvolinsky, S.L., Tyulina, O.V., Koshelev, V.B., Hori, N. and Carpenter, D.O. (1997). Biochemical and physiological evidence that carnosine is an endogenous neuroprotector against free radicals. Cell Mol. Neurobiol., 17, 259-271 https://doi.org/10.1023/A:1026374114314
  9. Boldyrev, A.A., Johnson, P., Wei, Y., Tan, Y. and Carpenter, D.O. (1999). Carnosine and taurine protect rat cerebellar granular cells from free radical damage. Neurosci. Lett., 263, 169-172 https://doi.org/10.1016/S0304-3940(99)00150-0
  10. Boldyrev, A., Bulygina, E., Leinsoo, T., Petrushanko, I., Tsubone, S. and Abe, H. (2004). Protection of neuronal cells against reactive oxygen species by carnosine and related compounds. Comp. Biochem. Physiol. B. Biochem. Mol. Biol., 137, 81-88 https://doi.org/10.1016/j.cbpc.2003.10.008
  11. Brown, C.E. and Antholine, W.E. (1979). Chelation chemistry of carnosine. Evidence that mixed complexes may occur in vivo. J. Physic. Chem., 83, 3314-3319 https://doi.org/10.1021/j100489a002
  12. Bush, A.I. and Tanzi, R.E. (2002). The galvanization of betaamyloid in Alzheimer's disease. Proc. Natl. Acad. Sci.U.S.A., 99, 7317-7319
  13. Carrard, G., Dieu, M., Raes, M., Toussaint, O. and Friguet, B. (2003). Impact of ageing on proteasome structure and function in human lymphocytes. Int. J. Biochem. Cell. Biol., 35, 728-739 https://doi.org/10.1016/S1357-2725(02)00356-4
  14. Chez, M.G., Buchanan, C.P. Aimonovitch, M.C., Becker, M., Schaefer, K., Black, C. and Komen, J. (2002). Doubleblind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders. J. Child. Neurol., 17, 833-837 https://doi.org/10.1177/08830738020170111501
  15. Cho, C.H., Luk, C.T. and Ogle, C.W. (1991). The membranestabilizing actions of zinc-carnosine (Z-103) in the stressinduced gastric ulceration in rats. Life Sci., 49, 189-194
  16. Cherny, R.A., Atwood, C.S., Xilinas, M.E., Gray, D.N., Jones, W.D., McLean, C.A., Barnham, K.J., Volitakis, I., Fraser, F.W., Kim, Y., Huang, X., Goldstein, L.E., Moir, R,D., Lim, J.T., Beyreuther, K., Zheng, H., Tanzi, R.E., Masters, C.L. and Bush, A.I. (2001). Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron, 30, 665-676 https://doi.org/10.1016/S0896-6273(01)00317-8
  17. Chvapil, M., Ryan, J.N. and Zukoski, C.F. (1972). Effect of zinc on lipid peroxidation in liver microsomes and mitochondria. Proc. Soc. Exp. Biol .Med., 141, 150-153
  18. Constantinidis, J. and Tissot, R. (1981). Role of glutamate and zinc in the hippocampal lesions of Pick's disease. Adv. Biochem. Psychopharmacol., 27, 413-422
  19. Csermely, P., Szamel, M., Resch, K. and Somogyi, J. (1988). Zinc increases the affinity of phorbol ester receptor in T lymphocytes. Biochem. Biophys. Res. Communs., 154, 578- 583 https://doi.org/10.1016/0006-291X(88)90179-9
  20. Cuajungco, M.P. and Lees, G.J. (1997). Zinc and Alzheimer's disease: is there a direct link? Brain. Res. Brain. Res.Rev., 23, 219-236 https://doi.org/10.1016/S0165-0173(97)00002-7
  21. Danscher, G., Jensen, K.B., Frederickson, C.J., Kemp, K., Andreasen, A., Juhl, S., Stoltenberg, M. and Ravid, R. (1997). Increased amount of zinc in the hippocampus and amygdala of Alzheimer's diseased brains: a proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material. J. Neurosci. Methods, 76, 53- 59 https://doi.org/10.1016/S0165-0270(97)00079-4
  22. DiDonato, M. and Sarkar. B. (1997). Copper transport and its alterations in Menkes and Wilson diseases. Biochim. Biophys. Acta, 1360, 3-16 https://doi.org/10.1016/S0925-4439(96)00064-6
  23. Donaldson, J., Pierre, T.S., Minnich, J.L. and Barbeau, A. (1973). Determination of $Na^{+}$, $K^{+}$, $Mg^{2+}$,$Cu^{2+}$, $Zn^{2+}$, and $Mn^{2+}$ in rat brain regions. Can. J. Biochem., 51, 87-92 https://doi.org/10.1139/v73-012
  24. Ferriero, D. and Marogolis, F.L. (1975). Denervation in the primary olfactory pathway of mice: II. Effects on carnosine and other amine compounds. Brain Res., 94, 75-86 https://doi.org/10.1016/0006-8993(75)90878-1
  25. Gallant, S., Kukley, M., Stvolinsky, S., Bulygina, E. and Boldyrev, A. (2000). Effect of carnosine on rats under experimental brain ischemia. Tohoku. J. Exp. Med., 191, 85-99 https://doi.org/10.1620/tjem.191.85
  26. Hipkiss, A.R. and Chana, H. (1998). Carnosine protects proteins against methylglyoxal-mediated modifications. Biochem. Biophys. Res. Commun., 248, 28-32 https://doi.org/10.1006/bbrc.1998.8806
  27. Hipkiss, A. and Brownson, C. (2000). Carnosine reacts with protein carbonyl groups: another possible role for the antiageing peptide. Biogerontol., 1, 217-223 https://doi.org/10.1023/A:1010057412184
  28. Hipkiss, A.R. (2002). Could carnosine be a naturally-occurring scavenger for acrolein and other reactive aldehydes in the brain? Neurobiol. Aging, 23, 645-646 https://doi.org/10.1016/S0197-4580(02)00006-4
  29. Hoffmann, A.M., Bakardjiev, A. and Bauer, K. (1996). Carnosine- synthesis in cultures of rat glial cells is restricted to oligodendrocytes and carnosine uptake to astrocytes. Neurosci. Lett., 215, 29-32 https://doi.org/10.1016/S0304-3940(96)12937-2
  30. Horning, M.S., Blakemore, L.J. and Trombley, P.Q. (2000). Endogenous mechanisms of neuroprotection: role of zinc, copper, and carnosine. Brain Res., 852, 56-61 https://doi.org/10.1016/S0006-8993(99)02215-5
  31. Kang, K.S., Yun, J.W. and Lee, Y.S. (2002). Protective effect of L-carnosine against 12-O-tetradecanoylphorbol-13-acetate- or hydrogen peroxide-induced apoptosis on v-myc transformed rat liver epithelial cells. Cancer Lett., 178, 53-62 https://doi.org/10.1016/S0304-3835(01)00821-7
  32. Kim, I., Kim, C.H., Kim, J.H., Lee, J., Choi, J.J., Chen, Z.A.,Lee, M.G., Chung, K.C., Hsu, C.Y. and Ahn, Y.S. (2004). Pyrrolidine dithiocarbamate and zinc inhibit proteasomedependent proteolysis. Exp. Cell Res., 298, 229-238 https://doi.org/10.1016/j.yexcr.2004.04.017
  33. Kress, Y., Gaskin, F., Brosnan, C.F. and Levine, S. (1981). Effects of zinc on the cytoskeletal proteins in the central nervous system of the rat. Brain Res., 220, 139-149 https://doi.org/10.1016/0006-8993(81)90217-1
  34. Lee, B.J., Kang, K.S., Lee, Y.S., Nam, S.W., Kim, Y.C. and Cho, M.H. (1999a). A comparison for antioxidant activity of carnosine and related compounds in several model systems. J. Toxicol. Pub. Health, 15, 297-306
  35. Lee, B.J., Lee, Y.S., Kang, K.S., Cho, M.H. and Hendricks, D.G. (1999b). Carnosine and related compounds protect against copper-induced damage of biomolecules. J. Biochem. Mol. Biol., 32, 350-357
  36. Lee, B.J., Park, J.H., Lee, Y.S., Cho, M.H., Kim, Y.C. and Hendricks, D.G. (1999c). Effect of carnosine and related compounds on glucose oxidation and protein glycation in vitro. J. Biochem. Mol. Biol., 32, 370-378
  37. Perroteau, I., Biffo, S., Tolosano, E., Tarozzo, G., Bovolin, P., Vaudry, H. and Fasolo, A. (1994). In vitro study of olfactory receptor neurones expressing the dipeptide carnosine. Neuroreport, 5, 569-572 https://doi.org/10.1097/00001756-199401000-00009
  38. Quinn, P.J., Boldyrev, A.A. and Formazuyk, V.E. (1992). Carnosine: its properties, functions and potential therapeutic applications. Mol. Aspects Med., 13, 379-444 https://doi.org/10.1016/0098-2997(92)90006-L
  39. Sassoe-Pognetto, M., Cantino, D., Panzanelli, P., Verdun, D.I., Cantogno, L., Giustetto, M., Margolis, F.L., De Biasi, S. and Fasolo, A. (1993). Presynaptic co-localization of carnosine and glutamate in olfactory neurones. Neuroreport, 5, 7-10 https://doi.org/10.1097/00001756-199310000-00001
  40. Suh, S.W., Jensen, K.B., Jensen, M.S., Silva, D.S., Kesslak, P.J., Danscher, G. and Frederickson, C.J. (2000): Histochemically- reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer's diseased brains. Brain Res., 852, 274-278 https://doi.org/10.1016/S0006-8993(99)02096-X
  41. Tabakman, R., Lazarovici, P. and Kohen, R. (2002). Neuroprotective effects of carnosine and homocarnosine on pheochromocytoma PC12 cells exposed to ischemia. J. Neurosci. Res., 68, 463-469 https://doi.org/10.1002/jnr.10228
  42. Tomonaga, S., Tachibana, T., Takagi, T., Saito, E.S., Zhang, R., Denbow, D.M. and Furuse, M. (2004). Effect of central administration of carnosine and its constituents on behaviors in chicks. Brain Res. Bull., 63, 75-82 https://doi.org/10.1016/j.brainresbull.2004.01.002
  43. Weiss, J.H., Hartley, D.M., Koh, J.Y. and Choi, D.W. (1993). AMPA receptor activation potentiates zinc neurotoxicity. Neuron, 10, 43-49 https://doi.org/10.1016/0896-6273(93)90240-R
  44. Yoshikawa, T., Naito, Y., Tanigawa, T., Yoneta, T., Yasuda, M., Ueda, S., Oyamada, H. and Kondo, M. (1991). Effect of zinc-carnosine chelate compound (Z-103), a novel antioxidant, on acute gastric mucosal injury induced by ischemia-reperfusion in rats. Free Rad. Res. Communs., 14, 289-296 https://doi.org/10.3109/10715769109088958