Intranasal administration of alpha-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates.
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.
P.K. Anokhin Institute of Normal Physiology, Russian Academy of Medical Science, Moscow, Russia.
Marina A
MA
Gruden
Institute of General Pathology and Pathophysiology, Russian Academy of Medical Science, Moscow, Russia.
Tatiana V
TV
Davydova
Institute of Pharmacology, Russian Academy of Medical Science, Moscow, Russia.
Victor B
VB
Narkevich
Institute of General Pathology and Pathophysiology, Russian Academy of Medical Science, Moscow, Russia.
Valentina G
VG
Fomina
Department of Medical Biochemistry and Biophysics, Umeå University, Umeå SE-90187, Sweden.
Chao
C
Wang
Institute of Pharmacology, Russian Academy of Medical Science, Moscow, Russia.
Vladimir S
VS
Kudrin
Department of Medical Biochemistry and Biophysics, Umeå University, Umeå SE-90187, Sweden.
Ludmilla A
LA
Morozova-Roche
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK. Electronic address: sewell@cardiff.ac.uk.
Robert D E
RD
Sewell
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000281:Administration, Intranasal; D000682:Amyloid / Q000008:administration & dosage*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D018476:Hypokinesia / Q000209:etiology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology; D009127:Muscle Rigidity / Q000209:etiology / Q000503:physiopathology; D020734:Parkinsonian Disorders / Q000150:complications / Q000503:physiopathology*; D066329:Protein Aggregates; D013378:Substantia Nigra / Q000378:metabolism*; D051844:alpha-Synuclein / Q000008:administration & dosage* / Q000737:chemistry
D000682:Amyloid; D066329:Protein Aggregates; D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; C001746:3-methoxytyramine; D004298:Dopamine; D006719:Homovanillic Acid
Behavior; Dopamine neurochemistry; Fibrils; Rodent model; α-synuclein oligomers