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 adminstration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine adminstration 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 adminstration 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.

Orcinol glucoside produces antidepressant effects by blocking the behavioural and neuronal deficits caused by chronic stress

“…Moreover, in a transgenic mouse model of α-synucleinopathy, chronic administration of fluoxetine increased the expression of BDNF and p-ERK in wholebrain homogenates above the level observed in nontransgenic mice (Ubhi et al, 2012). Additionally, reboxetine, a selective norepinephrine reuptake inhibitor (NRI), is reported to upregulate the expression of BDNF in the prefrontal cortex of CUMS rats above control levels (First et al, 2012).…”

Glial A30P alpha-synuclein pathology segregates neurogenesis from anxiety-related behavior in conditional transgenic mice

“…Recent studies show that treatment with antidepressant/anxiolytic drugs increased hippocampal neurogenesis in α-syn tg mice (Kohl et al, 2012; Ubhi et al, 2012). An increase in anxiety behavior observed in our mice correlates with the detected accumulation of α-syn in forebrain areas, especially the OB and HC.…”

Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials

“…Primary antibody incubation was followed by biotinylated secondary incubation (1:100, Vector Laboratories), Avidin-Biotin Complex (1:200, ABC Elite, Vector Laboratories) and developed by incubation with diaminobenzidine. Sections were analyzed with a bright field digital B50 Olympus microscope; serial digital images were analyzed with the Image J program (NIH) to determine counts and levels of immunoreactivity [7,77,78]. For immunofluorescence analyses, primary antibody binding was detected using a FITC-tagged secondary antibody or the Tyramide Signal Amplification ™ -Direct (Red) system (1:100, NEN Life Sciences).…”