title: IGF-1 intranasal administration rescues Huntington's disease phenotypes in YAC128 mice.
abstract: Huntington's disease (HD) is an autosomal dominant disease caused by an expansion of CAG repeats in the gene encoding for huntingtin. Brain metabolic dysfunction and altered Akt signaling pathways have been associated with disease progression. Nevertheless, conflicting results persist regarding the role of insulin-like growth factor-1 (IGF-1)/Akt pathway in HD. While high plasma levels of IGF-1 correlated with cognitive decline in HD patients, other data showed protective effects of IGF-1 in HD striatal neurons and R6/2 mice. Thus, in the present study, we investigated motor phenotype, peripheral and central metabolic profile, and striatal and cortical signaling pathways in YAC128 mice subjected to intranasal administration of recombinant human IGF-1 (rhIGF-1) for 2 weeks, in order to promote IGF-1 delivery to the brain. We show that IGF-1 supplementation enhances IGF-1 cortical levels and improves motor activity and both peripheral and central metabolic abnormalities in YAC128 mice. Moreover, decreased Akt activation in HD mice brain was ameliorated following IGF-1 administration. Upregulation of Akt following rhIGF-1 treatment occurred concomitantly with increased phosphorylation of mutant huntingtin on Ser421. These data suggest that intranasal administration of rhIGF-1 ameliorates HD-associated glucose metabolic brain abnormalities and mice phenotype.
authors.affiliation: CNC-Center for Neuroscience and Cell Biology and Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Lopes
authors.forename: Márcio
authors.initials: M
authors.lastname: Ribeiro
authors.forename: Ana I
authors.initials: AI
authors.lastname: Duarte
authors.forename: Sandrine
authors.initials: S
authors.lastname: Humbert
authors.forename: Frederic
authors.initials: F
authors.lastname: Saudou
authors.forename: Luís
authors.initials: L
authors.lastname: Pereira de Almeida
authors.forename: Michael
authors.initials: M
authors.lastname: Hayden
authors.forename: A Cristina
authors.initials: AC
authors.lastname: Rego
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010641:Phenotype
chemical_list: D007334:Insulin-Like Growth Factor I