title: Noradrenergic and serotonergic neurochemistry arising from intranasal inoculation with α-synuclein aggregates which incite parkinsonian-like symptoms.
abstract: Alpha-synuclein (α-syn) toxic aggregates delivered by the nasal vector have been shown to modify the neurochemistry of dopamine (DA) which is associated with parkinsonian-like motor symptoms. The aim was therefore to study the intranasal effects of α-syn oligomers, fibrils or their combination on the motor behavior of aged mice in relation to possible noradrenergic and serotonergic correlates. In vitro generated α-syn oligomers and fibrils were verified using atomic force microscopy and the thioflavin T binding assay. Levels of noradrenaline (NA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were detected using HPLC with electrochemical detection in the substantia nigra (SN) and striatum. The oligomers or fibrils administered alone or in a 50:50 combination (total dose of 0.48 mg/kg) were given intranasally for 14 days and "open-field" behaviour was tested on days 0, 15 and 28 of the protocol, at which time brain structures were sampled. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e. 14 days after treatment completion) induced hypokinesia and immobility whilst the aggregate combination additionally produced rigidity. The α-Syn oligomer/fibril mixture also instigated PD-like motor symptoms which correlated heterochronically with elevated NA levels in the striatum but then later in the SN while intranasal fibrils alone augmented 5-HT and 5-HIAA nigral concentrations throughout the protocol. In contrast, α-syn oligomers displayed a delayed serotonin upsurge in the SN. Neurodegenerative and/or actions on neurotransmitter transporters (such as NET, SERT and VMAT2) are discussed as being implicated in these α-syn amyloid induced neurochemical and motoric disturbances.
authors.affiliation: P. K. Anokhin Institute of Normal Physiology RAMS, Moscow, Russia.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Gruden
authors.affiliation: Institute of General Pathology and Pathophysiology RAMS, Moscow, Russia.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Davydova
authors.affiliation: Institute of Pharmacology RAMS, Moscow, Russia.
authors.forename: Victor B
authors.initials: VB
authors.lastname: Narkevich
authors.affiliation: Institute of General Pathology and Pathophysiology RAMS, Moscow, Russia.
authors.forename: Valentina G
authors.initials: VG
authors.lastname: Fomina
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, SE-90187, Sweden.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of Pharmacology RAMS, Moscow, Russia.
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Kudrin
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, SE-90187, Sweden.
authors.forename: Ludmilla A
authors.initials: LA
authors.lastname: Morozova-Roche
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, UK. Electronic address: sewell@cardiff.ac.uk.
authors.forename: Robert D E
authors.initials: RD
authors.lastname: Sewell
mesh_terms: D000281:Administration, Intranasal; D000682:Amyloid / Q000008:administration & dosage*; D000818:Animals; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D017072:Neostriatum / Q000737:chemistry*; D009638:Norepinephrine / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000503:physiopathology; D066329:Protein Aggregates; D012701:Serotonin / Q000378:metabolism*; D013378:Substantia Nigra / Q000737:chemistry*; D051844:alpha-Synuclein / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000682:Amyloid; D066329:Protein Aggregates; D051844:alpha-Synuclein; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D009638:Norepinephrine
keywords: 5-HT; Behavior; Metabolism; Noradrenaline; Rodent model; α-synuclein oligomers & fibrils