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BN82451 attenuates L-dopa-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease.
Neuropharmacology. 2011 Mar; 60(4):692-700.N

Abstract

The development of L-dopa-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson's disease (PD). This study aimed to assess the effect of the multitargeting molecule BN82451 on LID and to measure striatal mRNA expression of several genes in a rat model of PD. Rats were administered two unilateral injections of 6-OHDA in the striatum. After four weeks, the animals started a chronic daily treatment with increasing doses of L-dopa over a further four-week period. Over the course of L-dopa treatment, the rats developed abnormal involuntary movements (AIMs) classified as locomotive, axial, orolingual and forelimb dyskinesia. In animals rendered dyskinetic by L-dopa, administration of BN82451 at doses ranging from 1 to 10 mg/kg p.o. attenuated the severity of fully-established AIMs in a dose-related manner. This anti-dyskinetic effect could be achieved with lower doses of BN82451 administered sub chronically vs. acute single treatment. The improvement of AIMs is not due to a reduction in the general motor activity of dyskinetic rats. BN82451 treatment significantly reversed the overexpression of c-Fos, FosB and Arc mRNA associated with the dyskinesiogenic action of L-dopa. A significant correlation between the degree of overexpression of c-Fos, FosB and Arc mRNA and the dyskinesiogenic action of L-dopa was observed. The data demonstrate that BN82451 effectively attenuates LID and the associated molecular alterations in an animal model of PD and may represent a treatment option for managing dyskinesia.

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Authors+Show Affiliations

Spinnewyn B
Ipsen Innovation, Neurology, Les Ulis, France.
Mautino G
No affiliation info available
Marin JG
No affiliation info available
Rocher MN
No affiliation info available
Grandoulier AS
No affiliation info available
Ferrandis E
No affiliation info available
Auguet M
No affiliation info available
Chabrier PE
No affiliation info available

MeSH

AnimalsArea Under CurveBehavior, AnimalChromatography, High Pressure LiquidCorpus StriatumDose-Response Relationship, DrugDyskinesia, Drug-InducedGene ExpressionLevodopaMaleNeuroprotective AgentsOxidopamineParkinsonian DisordersRNA, MessengerRatsRats, Sprague-DawleyReverse Transcriptase Polymerase Chain ReactionThiazoles

Pub Type(s)

Journal Article

Language

eng

PubMed ID

21129389

Citation

Spinnewyn, Brigitte, et al. "BN82451 Attenuates L-dopa-induced Dyskinesia in 6-OHDA-lesioned Rat Model of Parkinson's Disease." Neuropharmacology, vol. 60, no. 4, 2011, pp. 692-700.
Spinnewyn B, Mautino G, Marin JG, et al. BN82451 attenuates L-dopa-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease. Neuropharmacology. 2011;60(4):692-700.
Spinnewyn, B., Mautino, G., Marin, J. G., Rocher, M. N., Grandoulier, A. S., Ferrandis, E., Auguet, M., & Chabrier, P. E. (2011). BN82451 attenuates L-dopa-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease. Neuropharmacology, 60(4), 692-700. https://doi.org/10.1016/j.neuropharm.2010.11.019
Spinnewyn B, et al. BN82451 Attenuates L-dopa-induced Dyskinesia in 6-OHDA-lesioned Rat Model of Parkinson's Disease. Neuropharmacology. 2011;60(4):692-700. PubMed PMID: 21129389.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BN82451 attenuates L-dopa-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease. AU - Spinnewyn,Brigitte, AU - Mautino,Gisele, AU - Marin,Jean-Gregoire, AU - Rocher,Marie Noëlle, AU - Grandoulier,Anne Sophie, AU - Ferrandis,Eric, AU - Auguet,Michel, AU - Chabrier,Pierre-Etienne, Y1 - 2010/12/01/ PY - 2010/03/31/received PY - 2010/11/22/revised PY - 2010/11/23/accepted PY - 2010/12/7/entrez PY - 2010/12/7/pubmed PY - 2011/5/13/medline SP - 692 EP - 700 JF - Neuropharmacology JO - Neuropharmacology VL - 60 IS - 4 N2 - The development of L-dopa-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson's disease (PD). This study aimed to assess the effect of the multitargeting molecule BN82451 on LID and to measure striatal mRNA expression of several genes in a rat model of PD. Rats were administered two unilateral injections of 6-OHDA in the striatum. After four weeks, the animals started a chronic daily treatment with increasing doses of L-dopa over a further four-week period. Over the course of L-dopa treatment, the rats developed abnormal involuntary movements (AIMs) classified as locomotive, axial, orolingual and forelimb dyskinesia. In animals rendered dyskinetic by L-dopa, administration of BN82451 at doses ranging from 1 to 10 mg/kg p.o. attenuated the severity of fully-established AIMs in a dose-related manner. This anti-dyskinetic effect could be achieved with lower doses of BN82451 administered sub chronically vs. acute single treatment. The improvement of AIMs is not due to a reduction in the general motor activity of dyskinetic rats. BN82451 treatment significantly reversed the overexpression of c-Fos, FosB and Arc mRNA associated with the dyskinesiogenic action of L-dopa. A significant correlation between the degree of overexpression of c-Fos, FosB and Arc mRNA and the dyskinesiogenic action of L-dopa was observed. The data demonstrate that BN82451 effectively attenuates LID and the associated molecular alterations in an animal model of PD and may represent a treatment option for managing dyskinesia. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/21129389/BN82451_attenuates_L_dopa_induced_dyskinesia_in_6_OHDA_lesioned_rat_model_of_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(10)00318-7 DB - PRIME DP - Unbound Medicine ER -