title: Chronic intranasal deferoxamine ameliorates motor defects and pathology in the α-synuclein rAAV Parkinson's model.
abstract: Parkinson's disease is characterized by neuronal death in the substantia nigra and the presence of intracellular inclusions of α-synuclein in the Lewy bodies. Several lines of data support a role for iron in Parkinson's disease: iron is present in Lewy bodies, iron accumulates in the dopaminergic neurons in the substantia nigra, and Parkinson's disease is correlated with polymorphisms of several genes implicated in iron metabolism. Furthermore, iron can compromise the solubility of α-synuclein through direct interaction and can induce neurotoxicity in vitro. Here, we investigate the possible neuroprotective effect of the iron chelator deferoxamine in vivo to elucidate whether iron chelation can provide meaningful therapy for Parkinson's disease. Hence, we used a Parkinson's disease animal model based on unilateral injection of a recombinant adeno-associated viral vector encoding α-synuclein in the rat midbrain. Rats were treated with a novel deferoxamine delivery approach: 6 mg of the compound was administered intranasally three times a week for 3 or 7 weeks. The behavior of the animals and histopathological changes in the brain were analyzed. Our data show that although intranasal administration of deferoxamine in rats did not protect them from dopaminergic cell death, it did decrease the number of the pathological α-synuclein formations at the terminal level. In addition, this treatment resulted in changes in the immune response and an overall partial improvement in motor behavior. Taken together, our data show that in vivo iron chelation can modulate α-synuclein-induced pathology in the central nervous system. Our data suggest that chronic administration of intranasal deferoxamine may be a valid approach to limiting the mishandling of α-synuclein in the central nervous system observed in Parkinson's disease and slowing disease progression.
authors.affiliation: CNS Disease Modeling Group, Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark. fabia.febbraro@ki.se
authors.forename: Fabia
authors.initials: F
authors.lastname: Febbraro
authors.forename: Kathrine J
authors.initials: KJ
authors.lastname: Andersen
authors.forename: Vanesa
authors.initials: V
authors.lastname: Sanchez-Guajardo
authors.forename: Noemie
authors.initials: N
authors.lastname: Tentillier
authors.forename: Marina
authors.initials: M
authors.lastname: Romero-Ramos
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002461:Cell Line, Transformed; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003676:Deferoxamine / Q000008:administration & dosage*; D003913:Dextroamphetamine; D004195:Disease Models, Animal; D005260:Female; D005552:Forelimb / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D009043:Motor Activity / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000633:toxicity; D017262:Siderophores / Q000008:administration & dosage*; D013997:Time Factors; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D003676:Deferoxamine; D003913:Dextroamphetamine; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D017262:Siderophores; D014446:Tyrosine 3-Monooxygenase; D051844:alpha-Synuclein; C067980:CD68 antigen, human; D000097382:CD68 Molecule
keywords: Dopaminergic; Iron; MHCII; Microglia; Proteinase K; Recombinant adeno-associated viral vector; T cells