title: FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of Huntington disease.
abstract: Huntington disease (HD) is a genetic neurodegenerative disorder for which there is currently no cure and no way to stop or even slow the brain changes it causes. In the present study, we aimed to investigate whether FTY720, the first approved oral therapy for multiple sclerosis, may be effective in HD models and eventually constitute an alternative therapeutic approach for the treatment of the disease. Here, we utilized preclinical target validation paradigms and examined the in vivo efficacy of chronic administration of FTY720 in R6/2 HD mouse model. Our findings indicate that FTY720 improved motor function, prolonged survival and reduced brain atrophy in R6/2 mice. The beneficial effect of FTY720 administration was associated with a significant strengthening of neuronal activity and connectivity and, with reduction of mutant huntingtin aggregates, and it was also paralleled by increased phosphorylation of mutant huntingtin at serine 13/16 residues that are predicted to attenuate protein toxicity.
authors.affiliation: IRCCS Neuromed, 86077 Pozzilli (IS), Italy.
authors.forename: Alba
authors.initials: A
authors.lastname: Di Pardo
authors.forename: Enrico
authors.initials: E
authors.lastname: Amico
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Favellato
authors.forename: Roberta
authors.initials: R
authors.lastname: Castrataro
authors.forename: Sergio
authors.initials: S
authors.lastname: Fucile
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Squitieri
authors.forename: Vittorio
authors.initials: V
authors.lastname: Maglione
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011409:Propylene Glycols / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000099157:Sphingosine Kinase
chemical_list: D000068876:Fingolimod Hydrochloride; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D013110:Sphingosine; D000099157:Sphingosine Kinase