Manganese chelation therapy extends survival in a mouse model of M1000 prion disease

Marcus Brazier, Irene Volitakis, Magda Kvasnicka, Anthony White, John Underwood, Jason Green, Sen Han, Andrew Hill, Colin Masters, Steven Collins

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Abstract

Previous in vitro and in vivo investigations have suggested manganese (Mn2+) may play a role in pathogenesis through facilitating refolding of the normal cellular form of the prion protein into protease resistant, pathogenic isoforms (PrPSc), as well as the subsequent promotion of higher order aggregation of these abnormal conformers. To further explore the role of Mn2+ in pathogenesis, we undertook a number of studies, including an assessment of the disease modifying effects of chelation therapy in a well-characterized mouse model of prion disease. The di-sodium, calcium derivative of the chelator, cyclohexanediaminetetraacetic acid (Na2CaCDTA), was administered intraperitoneally to mice inoculated intra-cerebrally with either high or low-dose inocula, with treatment beginning early (shortly after inoculation) or late (at the usual mid-survival point of untreated mice). Analyses by inductively coupled plasma-mass spectrometry demonstrated brain Mn2+ levels were selectively reduced by up to 50 in treated mice compared with untreated controls, with copper, iron, zinc and cobalt levels unchanged. In mice administered high-dose inocula, none of the treatment groups displayed an increase in survival although western blot analyses of early intensively treated mice showed reduced brain PrPSc levels; mice infected using low-dose inocula however, showed a significant prolongation of survival (p = 0.002). Although our findings support a role for Mn2+ in prion disease, further studies are required to more precisely delineate the extent of pathogenic involvement.
Original languageEnglish
Pages (from-to)440 - 451
Number of pages12
JournalJournal of Neurochemistry
Volume114
Issue number2
DOIs
Publication statusPublished - 2010

Cite this

Brazier, M., Volitakis, I., Kvasnicka, M., White, A., Underwood, J., Green, J., Han, S., Hill, A., Masters, C., & Collins, S. (2010). Manganese chelation therapy extends survival in a mouse model of M1000 prion disease. Journal of Neurochemistry, 114(2), 440 - 451. https://doi.org/10.1111/j.1471-4159.2010.06771.x