title: Neuronal nicotinic receptor agonists ameliorate spontaneous motor asymmetries and motor discoordination in a unilateral mouse model of Parkinson's disease.
abstract: The degeneration of the nigrostriatal dopamine (DA) system underlies the motor deficits in Parkinson's disease (PD). In recent years, epidemiological reports that smokers have lower incidences of PD have brought attention to the nicotinic acetylcholine system as a potential target for novel therapeutics. Nicotine, an agonist of neuronal nicotinic receptors (NNRs), modulates functions relevant to PD via stimulation of dopaminergic transmission in the nigrostriatal pathway, particularly via activation of α6β2* and α4β2* NNRs. Recently, reduced support of DA neurons by neurotrophic growth factors has been described in PD. Fibroblast growth factor (FGF) is critical for the development and protection of adult DA neurons. In FGF-2 knockout mice and the related th-fgfr1(tk-) mouse model there is heightened sensitivity to DA neuronal oxidative neurotoxin 6-hydroxydopamine (6-OHDA). In the present study, FGF-deficient transgenic mice th-fgfr1(tk-) were used to analyze the effects of novel full (TC-8831) and partial (TC-8581) agonists of β2-containing nicotinic receptors on impaired motor behavior following unilateral 6-OHDA lesions. The lesions generated spontaneous (drug-naïve) turning asymmetries that correlated exponentially with the depletion of DA biomarkers in the lesioned striata. These mice also exhibited a reduced capacity to remain on the accelerating rotarod. Oral administration of TC-8831, an NNR agonist with high specificity for β2 subunits and a full agonist at producing DA release from striatal synaptosomes, attenuated unidirectional turning and improved motor coordination. In contrast, partial β2 NNR agonist TC-8581 had no effect on behaviors in this model. This study demonstrates the potential of NNR targeting-compounds to facilitate motor function in PD.
authors.affiliation: Department of Pathology and Anatomical Sciences, State University of New York, Buffalo, 206 Farber Hall, 1300 University Blvd., University at Buffalo, NY 14214-3005, USA. Electronic address: ajk22@buffalo.edu.
authors.forename: Aaron
authors.initials: A
authors.lastname: Kucinski
authors.forename: Scott
authors.initials: S
authors.lastname: Wersinger
authors.forename: Ewa K
authors.initials: EK
authors.lastname: Stachowiak
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Corso
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Parry
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.forename: Kristen
authors.initials: K
authors.lastname: Jordan
authors.forename: Sharon
authors.initials: S
authors.lastname: Letchworth
authors.forename: Merouane
authors.initials: M
authors.lastname: Bencherif
authors.forename: Michal K
authors.initials: MK
authors.lastname: Stachowiak
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001522:Behavior, Animal; D002460:Cell Line; D003521:Cyclopropanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010300:Parkinson Disease / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000502:physiology*
chemical_list: D053961:Azabicyclo Compounds; D003521:Cyclopropanes; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C000588808:TC-8581; C588225:TC-8831; D004298:Dopamine
keywords: FGF receptor-1; Nicotinic acetylcholine receptor; Parkinson's disease therapy; Unilateral 6-OHDA mouse model; α4β2; α6β2