Abstract
Recent studies on mice experimentally infected with scrapie suggested that large increase in the levels of manganese ion occurs in blood and brain prior to the onset of symptoms of the prion disease, and the observed elevated manganese ion in several central nervous systems implies that the prion diseases should be considered to be one of the manganism. We have observed that oxidation of Mn(III) ion in several manganese chelates occurs in the presence of apo-transferrin, giving a di-μ-oxo bridged Mn(III/IV) species (hereafter we will call these Mn(III) and Mn(IV) ions to be labile plasma manganese ions), and at the same time facile uptake of manganese ions by apo-transferrin proceeds. This clearly shows that most manganese ions can be transported to the brain in a facile manner by transferrin under certain conditions. There are many iron-containing enzymes in the brain, and substitution of iron ion in these enzymes with other metal ions such as manganese ion results in complete or partial loss of enzymatic activity, and this is because the reactivity of the iron ion towards oxygen molecule is quite different from that of the manganese ions. Thus, the excess accumulation of the manganese ion in the brain should lead to (a) abnormality in iron metabolism, i.e., the increase of the labile plasma iron (or non-transferrin-bound iron, NTBI), which is in fact observed for the certain regions of the brain of scrapie strain infected mice; these iron ions are not transferred to transferrin, giving to the iron-deficiency state in the brain which leads to the defect of neurotransmitters such as dopamine and serotonin and (b) the abnormalities of the brain functions due to the toxicity of the labile plasma iron ions, which leads to neural cell death. Based on the above facts, and that (1) the labile plasma iron can in a facile manner produce the hydrogen peroxide and (2) the prion diseases can be elucidated by the “gain-of-function” of the prion proteins as copper(II)-containing enzyme in the presence of excess hydrogen peroxide, we have concluded that the prion diseases including both the sporadic and infected types should be elucidated by the combined toxicities due to the both labile plasma manganese and iron ions. Very recently we have succeeded in obtaining the chelate which captures both the labile plasma iron and manganese ions effectively and removes these ions without toxicity from the solution in vitro. Thus, we can hope that our new chelates should make notable contribution to the prevention and therapeutics for the prion disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, schizophrenia, and dementia, which are now in progress in Japan.
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References
Chani AC, Ferguson NM, Donnell CA, Anderson RM (2000) Nature 406:583
Beale AJ (2001) J R Soc Med 94:207
Houston F, Foster JD, Chong A, Hunter N, Bostock CJ (2000) Lancet 356:955
Cohen FE, Prusiner SB (1998) Annu Rev Biochem 67:793
Collinge J (2001) Annu Rev Neurosci 24:519
Prusiner SB (1996) Trends Biochem Sci 21:482
Caughey B (2001) Trends Biochem Sci 25:235
Brown D (2001) Trends Neurosci 24:85
Wong BS, Chen SG, Colucci M, Xie Z, Pan T, Liu T, Li R, Gambetti P, Sy MS, Brown DR (2001) J Neurochem 78:1400
Dobson AW, Erikson KM, Aschner M (2004) Ann N Y Acad Sci 1012:115
Kaiser J (2003) Science 300:926
Hesketh S, Sassoon J, Knight R, Hopkins J, Brown DR (2007) J Anim Sci 85:1596
Fernaeus S, Reis K, Bedecs K, Land T (2005) Neurosci Lett 389:133
Fernaeus S, Halldin J, Bedecs K, Land T (2005) Mol Brain Res 133:266
Nishida Y (2004) Med Hypothesis Res 1:227–245
Nishida Y (2003) Z Naturforsch 58c:752
Nishida Y (2011) Monatsh Chem 142:375
Shiraki H, Yase Y (1991) In: Vinken PI, Bruyn GW, Klawans HL (eds) Handbook of clinical neurology, vol 15, pp 273–300
Gerlach M, Schachar DB, Riederer P, Youdim MBH (1994) J Neurochem 63:793
Youdim MBH, Riederer P (1997) Sci Am 1997:52
Heilig EA, Thonpson KJ, Molina RM, Ivanov AR, Brain JD, Resnick MW (2006) Am J Physiol Lung Cell Mol Physiol 290:L1247
Abe K, Chiba Y, Nishida Y (2008) Z Naturforsch 63c:154
Nishida Y, Ito Y, Satoh T (2007) Z Naturforsch 62c:608
Sutoh Y, Nishino S, Nishida Y (2005) Chem Lett 34:140
Abragam A, Bleaney B (1970) Electron paramagnetic resonance of transition ions. Clarendon, London
Okuno T, Nishida Y (1996) Polyhedron 15:1509–1515
Que L Jr, Ho RYN (1996) Chem Rev 96:2607
Sutoh Y, Nishida Y (2005) Synth React Inorg Metal-org Nano-metal Chem 35:575
Harrison PM, Arosio P (1996) Biochem Biophys Acta 1275:161
Nishida Y (2009) TCIMAIL 141:2. http://www.tciamerica.com/tcimail/backnumber/article/141drE.pdf
Nishida Y, Takeuchi M (1987) Z Naturforsch 42b:52
Nishida Y, Nasu M, Akamatu T (1992) J Chem Soc Chem Commun 1992:94
Yamanaka K, Cleveland DW (2005) Neurology 65:1859
Alessandra G, Hider RC (2005) Br J Pharm 146:1041
Nishida Y (2007) TCIMail 135:2. http://www.tciamerica.com/tcimail/backnumber/135drE.pdf
Rakhit R, Crow JP, Lepock JR, Kondejewski LH, Cashman NR, Chakrabartty A (2004) J Biol Chem 279:15499
Abe K, Nishida Y (2008) Z Naturforsch 63c:151
Chiba Y, Sutoh Y, Nishida Y (2006) Z Naturforsch 61c:273
Sato T, Nakanishi T, Yamamoto Y, Andersen PM, Ogawa Y, Fukada K, Zhou Z, Aoike F, Sugai F, Nagano S, Hirata S, Ogawa M, Nakano R, Ohi T, Kato T, Nakagawa M, Hamasaki T, Shimizu A, Sakoda S (2005) Neurology 65:1954
Rae TD, Schmidt PJ, Pufahl RA, Culotta VC, O’Halloran TV (1999) Science 284:805
MaMahon EHM, Mange A, Nishida N, Creminon C, Casanova D, Lehmann S (2001) J Biol Chem 276:2286
Requena JR, Groth D, Legname G, Sradtman ER, Prusiner SB, Revine RL (2001) Proc Natl Acad Sci USA 98:7170
Watt NT, Taylor DR, Gillott A, Thomas DA, Perera WS, Hooper NM (2005) J Biol Chem 280:35914
Tabler BJ, Turnbull S, Fullwood NJ, German M, Allsop D (2005) Biochem Soc Trans 33:548
Tabler BJ, Agnaf OMEA, Turnbull S, German MJ, Paleologou KE, Hayashi Y, Kooper LJ, Fullwood NJ, Allsop D (2005) J Biol Chem 280:35789
Watt NT, Hopper NM (2005) Biochem Soc Trans 33:1123
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Nishida, Y. (2012). Prion diseases and manganism. In: Linert, W., Kozlowski, H. (eds) Metal Ions in Neurological Systems. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1001-0_6
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DOI: https://doi.org/10.1007/978-3-7091-1001-0_6
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