All Title Author
Keywords Abstract


The Molecular Mechanisms of Zinc Neurotoxicity and the Pathogenesis of Vascular Type Senile Dementia

DOI: 10.3390/ijms141122067

Keywords: Zinc, carnosine, histidine, vascular-type dementia

Full-Text   Cite this paper   Add to My Lib

Abstract:

Zinc (Zn) is an essential trace element that is abundantly present in the brain. Despite its importance in normal brain functions, excess Zn is neurotoxic and causes neurodegeneration following transient global ischemia and plays a crucial role in the pathogenesis of vascular-type dementia (VD). We have investigated the molecular mechanisms of Zn-induced neurotoxicity using immortalized hypothalamic neurons (GT1-7 cells) and found that carnosine (β-alanyl histidine) and histidine (His) inhibited Zn 2+-induced neuronal death. A DNA microarray analysis revealed that the expression of several genes, including metal-related genes (metallothionein and Zn transporter 1), endoplasmic reticulum (ER)-stress related genes ( GADD34, GADD45, and p8), and the calcium (Ca)-related gene Arc (activity-related cytoskeleton protein), were affected after Zn exposure. The co-existence of carnosine or His inhibited the expression of GADD34, p8, and Arc, although they did not influence the expression of the metal-related genes. Therefore, ER-stress and the disruption of Ca homeostasis may underlie the mechanisms of Zn-induced neurotoxicity, and carnosine might be a possible drug candidate for the treatment of VD.

References

[1]  Lee, J.M.; Grabb, M.C.; Zipfel, G.J.; Choi, D.W. Brain tissue responses to ischemia. J. Clin. Invest 2000, 106, 723–731.
[2]  De Haan, E.H.; Nys, G.M.; van Zandvoort, M.J. Cognitive function following stroke and vascular cognitive impairment. Curr. Opin. Neurol 2006, 19, 559–564.
[3]  Weiss, J.H.; Sensi, S.L.; Koh, J.Y. Zn2+: A novel ionic mediator of neural injury in brain disease. Trends Pharmacol. Sci 2000, 21, 395–401.
[4]  Kawahara, M.; Kato-Negishi, M.; Kuroda, Y. Pyruvate blocks zinc-induced neurotoxicity in immortalized hypothalamic neurons. Cell Mol. Neurobiol 2002, 22, 87–93.
[5]  Koyama, H.; Konoha, K.; Sadakane, Y.; Ohkawara, S.; Kawahara, M. Zinc neurotoxicity and the pathogenesis of vascular-type dementia: Involvement of calcium dyshomeostasis and carnosine. J. Clin. Toxicol 2011, S3, doi:10.4172/2161-0495.S3-002.
[6]  Mellon, P.L.; Windle, J.J.; Goldsmith, P.C.; Padula, C.A.; Roberts, J.L.; Weiner, R.I. Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis. Neuron 1990, 5, 1–10.
[7]  Mahesh, V.B.; Zamorano, P.; De Sevilla, L.; Lewis, D.; Brann, D.W. Characterization of ionotropic glutamate receptors in rat hypothalamus, pituitary and immortalized gonadotropin-releasing hormone (GnRH) neurons (GT1–7 cells). Neuroendocrinology 1999, 69, 397–407.
[8]  Sadakane, Y.; Konoha, K.; Kawahara, M. Protective activity of mango (Mangifera indica L.) fruit against a zinc-induced neuronal cell death is independent of its antioxidant activity. Trace Nutr. Res 2005, 22, 73–79.
[9]  Konoha, K.; Sadakane, Y.; Kawahara, M. Carnosine protects GT1–7 cells against zinc-induced neurotoxicity: A possible candidate for treatment for vascular type of dementia. Trace Nutr. Res 2006, 23, 56–62.
[10]  Sadakane, Y.; Konoha, K.; Nagata, T.; Kawahara, M. Protective activity of the extracts from Japanese eel (Anguilla japonica) against zinc-induced neuronal cell death: Carnosine and an unknown substance. Trace Nutr. Res 2007, 24, 98–105.
[11]  Sadakane, Y.; Konoha, K.; Nagata, T.; Kawahara, M. Improvement of screening for protective substances against zinc-induced neuronal cell death. Trace Nutr. Res 2008, 25, 41–45.
[12]  Kawahara, M.; Konoha, K.; Nagata, T.; Sadakane, Y. Protective substances against zinc-induced neuronal death after ischemia: Carnosine a target for drug of vascular type of dementia. Recent Pat. CNS Drug Discov 2007, 2, 145–149.
[13]  Corona, C.; Frazzini, V.; Silvestri, E.; Lattanzio, R.; La Sorda, R.; Piantelli, M.; Canzoniero, L.M.; Ciavardelli, D.; Rizzarelli, E.; Sensi, S.L. Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice. PLoS One 2011, 6, e17971.
[14]  Kawahara, M.; Koyama, H.; Nagata, T.; Sadakane, Y. Zinc, copper, and carnosine attenuate neurotoxicity of prion fragment PrP106–126. Metallomics 2011, 3, 726–734.
[15]  Hipkiss, A.R. Carnosine and its possible roles in nutrition and health. Adv. Food Nutr. Res 2009, 57, 87–154.
[16]  Hambidge, M. Human zinc deficiency. J. Nutr 2000, 130, 1344S–1349S.
[17]  Hirano, T.; Murakami, M.; Fukada, T.; Nishida, K.; Yamasaki, S.; Suzuki, T. Roles of zinc and zinc signaling in immunity: Zinc as an intracellular signaling molecule. Adv. Immunol 2008, 97, 149–176.
[18]  Prasad, A.S. Impact of the discovery of human zinc deficiency on health. J. Am. Coll. Nutr 2009, 28, 257–265.
[19]  Frederickson, C.J.; Suh, S.W.; Silva, D.; Frederickson, C.J.; Thompson, R.B. Importance of zinc in the central nervous system: The zinc-containing neuron. J. Nutr 2000, 130, 1471S–1483S.
[20]  Tamano, H.; Takeda, A. Dynamic action of neurometals at the synapse. Metallomics 2011, 3, 656–661.
[21]  Koh, J.Y.; Suh, S.W.; Gwag, B.J.; He, Y.Y.; Hsu, C.Y.; Choi, D.W. The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 1996, 272, 1013–1016.
[22]  Calderone, A.; Jover, T.; Mashiko, T.; Noh, K.M.; Tanaka, H.; Bennett, M.V.; Zukin, R.S. Late calcium EDTA rescues hippocampal CA1 neurons from global ischemia-induced death. J. Neurosci 2004, 24, 9903–9913.
[23]  Sensi, S.L.; Canzoniero, L.M.; Yu, S.P.; Ying, H.S.; Koh, J.Y.; Kerchner, G.A.; Choi, D.W. Measurement of intracellular free zinc in living cortical neurons: Routes of entry. J. Neurosci 1997, 17, 9554–9564.
[24]  Pellegrini-Giampietro, D.E.; Gorter, J.A.; Bennett, M.V.; Zukin, R.S. The GluR2 (GluR-B) hypothesis: Ca2+-permeable AMPA receptors in neurological disorders. Trends Neurosci 1997, 20, 464–470.
[25]  Plum, L.M.; Rink, L.; Haase, H. The essential toxin: Impact of zinc on human health. Int. J. Environ. Res. Public Health 2010, 7, 1342–1365.
[26]  Weiss, J.H.; Hartley, D.M.; Koh, J.Y.; Choi, D.W. AMPA receptor activation potentiates zinc neurotoxicity. Neuron 1993, 10, 43–49.
[27]  Zhu, L.; Tang, Y.; Wang, H.D.; Zhang, Z.Y.; Pan, H. Immersion autometallographic demonstration of pathological zinc accumulation in human acute neural diseases. Neurol. Sci 2012, 33, 855–861.
[28]  Adlard, P.A.; Bush, A.I. Metals and Alzheimer’s disease. J. Alzheimers. Dis 2006, 10, 145–163.
[29]  Kawahara, M.; Arispe, N.; Kuroda, Y.; Rojas, E. Alzheimer’s disease amyloid ?-protein forms Zn2+-sensitive, cation-selective channels across excised membrane patches from hypothalamic neurons. Biophys. J 1997, 73, 67–75.
[30]  Lin, H.; Bhatia, R.; Lal, R. Amyloid beta protein forms ion channels: Implications for Alzheimer’s disease pathophysiology. FASEB J 2001, 15, 2433–2444.
[31]  Leach, S.P.; Salman, M.D.; Hamar, D. Trace elements and prion diseases: A review of the interactions of copper, manganese and zinc with the prion protein. Anim. Health Res. Rev 2006, 7, 97–105.
[32]  Valentine, J.S.; Hart, P.J. Misfolded CuZnSOD and amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 2003, 100, 3617–3622.
[33]  Brewer, G.J. Recognition, diagnosis, and management of Wilson’s disease. Proc. Soc. Exp. Biol. Med 2000, 223, 39–46.
[34]  Koh, J.Y.; Choi, D.W. Zinc toxicity of cultured cortical neurons: Involvement of N-methyl-d-asparatate receptors. Neuroscience 1994, 4, 1049–1057.
[35]  Kim, A.H.; Sheline, C.T.; Tian, M.; Higashi, T.; McMahon, R.J.; Cousins, R.J.; Choi, D.W. L-type Ca2+ channel-mediated Zn2+ toxicity and modulation by ZnT-1 in PC12 cells. Brain Res 2000, 886, 99–107.
[36]  Lee, J.Y.; Kim, Y.H.; Koh, J.Y. Protection by pyruvate against transient forebrain ischemia in rats. J. Neurosci 2001, 21, RC171.
[37]  Sheline, C.T.; Behrens, M.M.; Choi, D.W. Zinc-induced cortical neuronal death: Contribution of energy failure attributable to loss of NAD(+) and inhibition of glycolysis. J. Neurosci 2000, 20, 3139–3146.
[38]  Sensi, S.L.; Ton-That, D.; Sullivan, P.G.; Jonas, E.A.; Gee, K.R.; Kaczmarek, L.K.; Weiss, J.H. Modulation of mitochondrial function by endogenous Zn2+ pools. Proc. Natl. Acad. Sci. USA 2003, 100, 6157–6162.
[39]  Kawahara, M.; Kato-Negishi, M.; Hosoda, R.; Kuroda, Y. Characterization of zinc-induced apoptosis of GT1–7 cells. Biomed. Res. Trace Elements 2002, 13, 280–281.
[40]  Konoha, K.; Sadakane, Y.; Kawahara, M. Effects of gadolinium and other metal on the neurotoxicity of immortalized hypothalamic neurons induced by zinc. Biomed. Res. Trace Elements 2004, 15, 275–277.
[41]  Kim, E.Y.; Chang, S.Y.; Chung, J.M.; Ryu, B.R.; Joo, C.K.; Moon, H.S.; Kang, K.; Yoon, S.H.; Han, P.L.; Gwag, B.J. Attenuation of Zn2+ neurotoxicity by aspirin: Role of N-type Ca2+ channel and the carboxyl acid group. Neurobiol. Dis 2001, 8, 774–783.
[42]  Kawahara, M.; Sadakane, Y.; Koyama, H.; Konoha, K.; Ohkawara, S. d-Histidine and l-histidine attenuate zinc-induced neuronal death in GT1–7 cells. Metallomics 2013, 5, 453–460.
[43]  Brown, M.K.; Naidoo, N. The endoplasmic reticulum stress response in aging and age-related diseases. Front. Physiol 2012, 3, 263.
[44]  Ferreiro, E.; Baldeiras, I.; Ferreira, I.L.; Costa, R.O.; Rego, A.C.; Pereira, C.F.; Oliveira, C.R. Mitochondrial- and endoplasmic reticulum-associated oxidative stress in Alzheimer’s disease: From pathogenesis to biomarkers. Int. J. Cell Biol 2012, 2012, doi:10.1155/2012/735206.
[45]  Roussel, B.D.; Kruppa, A.J.; Miranda, E.; Crowther, D.C.; Lomas, D.A.; Marciniak, S.J. Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol 2013, 12, 105–118.
[46]  Moskalev, A.A.; Smit-McBride, Z.; Shaposhnikov, M.V.; Plyusnina, E.N.; Zhavoronkov, A.; Budovsky, A.; Tacutu, R.; Fraifeld, V.E. Gadd45 proteins: Relevance to aging, longevity and age-related pathologies. Ageing Res. Rev 2012, 11, 51–66.
[47]  Van Prooyen, N.; Andresen, V.; Gold, H.; Bialuk, I.; Pise-Masison, C.; Franchini, G. Hijacking the T-cell communication network by the human T-cell leukemia/lymphoma virus type 1 (HTLV-1) p12 and p8 proteins. Mol. Aspects Med 2010, 31, 333–343.
[48]  Goruppi, S.; Iovanna, J.L. Stress-inducible protein p8 is involved in several physiological and pathological processes. J. Biol. Chem 2010, 285, 1577–1581.
[49]  Onoue, S.; Kumon, Y.; Igase, K.; Ohnishi, T.; Sakanaka, M. Growth arrest and DNA damage-inducible gene 153 increases transiently in the thalamus following focal cerebral infarction. Brain Res. Mol. Brain Res 2005, 134, 189–197.
[50]  Kunizuka, H.; Kinouchi, H.; Arai, S.; Izaki, K.; Mikawa, S.; Kamii, H.; Sugawara, T.; Suzuki, A.; Mizoi, K.; Yoshimoto, T. Activation of Arc gene, a dendritic immediate early gene, by middle cerebral artery occlusion in rat brain. Neuroreport 1999, 10, 1717–1722.
[51]  Rickhag, M.; Teilum, M.; Wieloch, T. Rapid and long-term induction of effector immediate early genes (BDNF, Neuritin and Arc) in peri-infarct cortex and dentate gyrus after ischemic injury in rat brain. Brain Res 2007, 1151, 203–210.
[52]  Bonfanti, L.; Peretto, P.; De Marchis, S.; Fasolo, A. Carnosine-related dipeptides in the mammalian brain. Prog. Neurobiol 1999, 59, 333–353.
[53]  De Marchis, S.; Modena, C.; Peretto, P.; Giffard, C.; Fasolo, A. Carnosine-like immunoreactivity in the central nervous system of rats during postnatal development. J. Comp. Neurol 2000, 426, 378–390.
[54]  Stuerenburg, H.J. The roles of carnosine in aging of skeletal muscle and in neuromuscular disease. Biochemistry (Mosc) 2000, 65, 862–865.

Full-Text

comments powered by Disqus