title: Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of α-synucleinopathy.
abstract: The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA. Fluoxetine administration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine administration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine administration on myelin and serotonin markers were also examined. Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders.
authors.affiliation: Department of Neurosciences, University of California, San Diego, CA, USA.
authors.forename: Kiren
authors.initials: K
authors.lastname: Ubhi
authors.forename: Chandra
authors.initials: C
authors.lastname: Inglis
authors.forename: Michael
authors.initials: M
authors.lastname: Mante
authors.forename: Christina
authors.initials: C
authors.lastname: Patrick
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.forename: Verena
authors.initials: V
authors.lastname: May
authors.forename: Juergen
authors.initials: J
authors.lastname: Winkler
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005473:Fluoxetine / Q000494:pharmacology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009048:Motor Skills / Q000187:drug effects*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D005473:Fluoxetine; D051100:Glial Cell Line-Derived Neurotrophic Factor; D017367:Selective Serotonin Reuptake Inhibitors; D051844:alpha-Synuclein; C495040:Gdnf protein, mouse