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.

α‐Synuclein Oligomers: A Study in Diversity

“…αSn monomer concentration is important for its aggregation, where a higher concentration aggregates faster. This is also visible in the table, where αSn incubation is done, either at low concentrations for a longer period (up to 7 days), or at higher concentrations for a shorter time (<24 hrs) . The different conditions result in a heterogeneous group of αSOs.…”

“…Despite the sparse evidence for αSO seeding ability, one study reported that αSOs, in contrast to fibrils, were able to spread pathology in vivo following injection in the olfactory bulb . In contrast, another group reported that αSOs were indeed able to spread pathology in vivo following injection in the brain, but fibril injection was more effective and also resulted in motor deficits, in contrast to αSOs ,…”

Synthetic Peptides Affect the Expression of &lt;i&gt;Gdnf&lt;/i&gt; and Gdnf Receptors in Rats with 6-OHDA-Induced PD-Like Parkinsonism

“…We analyzed levels of DA, NA, and 5-HT in the left and right striatum of all rats. To validate the 6-OHDA-induced lesion, the content of monoamines in these samples (nmol/g of tissue) was measured using HPLC with electrochemical detection, as described elsewhere [34] [35].…”

Intranasal delivery of dopamine to the striatum using glycol chitosan/sulfobutylether-β-cyclodextrin based nanoparticles

“…In fact, more recently many authors have investigated the effects of DA or L-Dopa intranasally applied [11][12][13][14][15][16][17]. Moreover, the intranasal administration has been used by different authors to test the prion-like spreading of pathological a-synuclein in the brain [18][19][20][21]. In particular, it has been reported that nasal administration of a-syn amyloidogenic species produce dopaminergic but also non-dopaminergic parkinsonian neurochemical alterations as well as behavioral deficits indicated by rigidity and reduced locomotor activity [18][19][20].…”

“…Moreover, the intranasal administration has been used by different authors to test the prion-like spreading of pathological a-synuclein in the brain [18][19][20][21]. In particular, it has been reported that nasal administration of a-syn amyloidogenic species produce dopaminergic but also non-dopaminergic parkinsonian neurochemical alterations as well as behavioral deficits indicated by rigidity and reduced locomotor activity [18][19][20]. In this respect, it has been demonstrated that there is a final common pathway linking olfactory neuroepithelial receptor cells with axonal projections of the olfactory bulb and these networks are connected to centrifugal neuronal afferents from the substantia nigra dopamine nuclei [22].…”