title: Manganese chelation therapy extends survival in a mouse model of M1000 prion disease.
abstract: Previous in vitro and in vivo investigations have suggested manganese (Mn(2+)) may play a role in pathogenesis through facilitating refolding of the normal cellular form of the prion protein into protease resistant, pathogenic isoforms (PrP(Sc)), as well as the subsequent promotion of higher order aggregation of these abnormal conformers. To further explore the role of Mn(2+) 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 (Na(2)CaCDTA), 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 Mn(2+) 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 PrP(Sc) levels; mice infected using low-dose inocula however, showed a significant prolongation of survival (p = 0.002). Although our findings support a role for Mn(2+) in prion disease, further studies are required to more precisely delineate the extent of pathogenic involvement.
authors.affiliation: Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Marcus W
authors.initials: MW
authors.lastname: Brazier
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.forename: Magda
authors.initials: M
authors.lastname: Kvasnicka
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.forename: John R
authors.initials: JR
authors.lastname: Underwood
authors.forename: Jason E
authors.initials: JE
authors.lastname: Green
authors.forename: Sen
authors.initials: S
authors.lastname: Han
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Hill
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Collins
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002614:Chelating Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008345:Manganese / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy* / Q000401:mortality
chemical_list: D002614:Chelating Agents; D018620:PrPSc Proteins; D008345:Manganese; C005390:CDTA; D004492:Edetic Acid