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: Marina A Gruden, Tatiana V Davydova, Victor B Narkevich, Valentina G Fomina, Chao Wang, Vladimir S Kudrin, Ludmilla A Morozova-Roche, Robert D E Sewell
• Journal: Behavioural brain research (Behav Brain Res) Vol. 279 Pg. 191-201 (Feb 15 2015) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 25446742 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Amyloid
• Protein Aggregates
• alpha-Synuclein
• Serotonin
• Hydroxyindoleacetic Acid
• Norepinephrine

Topics

• Administration, Intranasal
• Amyloid (administration & dosage)
• Animals
• Hydroxyindoleacetic Acid (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Motor Activity
• Neostriatum (chemistry)
• Norepinephrine (metabolism)
• Parkinsonian Disorders (metabolism, physiopathology)
• Protein Aggregates
• Serotonin (metabolism)
• Substantia Nigra (chemistry)
• alpha-Synuclein (administration & dosage, chemistry)