Intranasal administration of alpha-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates.

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder in which both alpha-synuclein (α-syn) and dopamine (DA) have a critical role. Our previous studies instigated a novel PD model based on nasal inoculation with α-syn aggregates which expressed parkinsonian-like behavioral and immunological features. The current study in mice substantiated the robustness of the amyloid nasal vector model by examining behavioral consequences with respect to DA-ergic neurochemical corollaries. In vitro generated α-syn oligomers and fibrils were characterized using atomic force microscopy and the thioflavin T binding assay. These toxic oligomers or fibrils administered alone (0.48 mg/kg) or their 50:50 combination (total dose of 0.48 mg/kg) were given intranasally for 14 days and "open-field" behavior was tested on days 0, 15 and 28 of the protocol. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e., 14 days after treatment completion) induced rigidity, hypokinesia and immobility. This was accompanied by elevated nigral but not striatal DA, DOPAC and HVA concentrations in response to dual administration of α-syn oligomers plus fibrils but not the oligomers by themselves. α-Syn fibrils intensified not only the hypokinesia and immobility 14 days post treatment, but also reduced vertical rearing and enhanced DA levels in the substantia nigra. Only nigral DA turnover (DOPAC/DA but not HVA/DA ratio) was augmented in response to fibril treatment but there were no changes in the striatum. Compilation of these novel behavioral and neurochemical findings substantiate the validity of the α-syn nasal vector model for investigating parkinsonian-like symptoms.

• 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. 263 Pg. 158-68 (Apr 15 2014) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 24480422 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Amyloid
• Protein Aggregates
• alpha-Synuclein
• 3,4-Dihydroxyphenylacetic Acid
• 3-methoxytyramine
• Dopamine
• Homovanillic Acid

Topics

• 3,4-Dihydroxyphenylacetic Acid (metabolism)
• Administration, Intranasal
• Amyloid (administration & dosage)
• Animals
• Corpus Striatum (metabolism)
• Disease Models, Animal
• Dopamine (analogs & derivatives, metabolism)
• Homovanillic Acid (metabolism)
• Hypokinesia (etiology, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Motor Activity (physiology)
• Muscle Rigidity (etiology, physiopathology)
• Parkinsonian Disorders (complications, physiopathology)
• Protein Aggregates
• Substantia Nigra (metabolism)
• alpha-Synuclein (administration & dosage, chemistry)