Manganese chelation therapy extends survival in a mouse model of M1000 prion disease
2010
Brazier, Marcus W. | Volitakis, Irene | Kvasnicka, Magda | White, Anthony R. | Underwood, John R. | Green, Jason E. | Han, Sen | Hill, A. F. (Andrew F) | Masters, Colin L. | Collins, Steven J.
J. Neurochem. (2010) 114, 440-451. 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.
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