title: An improved model to investigate the efficacy of antidyskinetic agents in hemiparkinsonian rats.
abstract: A number of experimental models of L-DOPA-induced dyskinesia have been proposed, but these models result in a low to medium rate of dyskinetic animals with mild to severe symptoms. The objective of this study was to combine a model of 6-OHDA-induced parkinsonism and of L-DOPA-induced dyskinesia in rats to establish a reliable preclinical model. Two stereotaxic injections of 6-OHDA were administered in the left striatum. This model led to 90-100% of rats with a marked contralateral circling behaviour, significant limb use asymmetry (20%), a decrease in ipsilateral striatal dopamine content (70%) and degeneration of dopamine neurons in the substantia nigra (70%). Chronic treatment with L-DOPA was administered for 35 days and consisted of three phases with incremental daily doses. The third phase resulted in 83-90% of rats developing severe abnormal involuntary movements (AIMs) which included limb and locomotive dyskinesia, axial dystonia and orolingual dyskinesia. Reproducibility of the model, criteria of strict blinding, placebo-controlled design, randomization of study subjects and pretrial determination of sample size were used to measure efficacy of amantadine and istradefylline and to validate the protocol design. Acute or subchronic post-treatment with amantadine reduced the severity of dyskinesia while istradefylline punctually attenuated AIMs. Our experimental conditions using gradual development of dyskinesia induced by increasing doses of L-DOPA resulted in a reliable model of L-DOPA-induced dyskinesia with a high rate of dyskinetic rats.
authors.affiliation: Ipsen Innovation, 5 Avenue du Canada, 91940 Les Ulis, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Spinnewyn
authors.forename: Christelle
authors.initials: C
authors.lastname: Charnet
authors.forename: Sylvie
authors.initials: S
authors.lastname: Cornet
authors.forename: Véronique
authors.initials: V
authors.lastname: Roubert
authors.forename: Pierre-Etienne
authors.initials: PE
authors.lastname: Chabrier
authors.forename: Michel
authors.initials: M
authors.lastname: Auguet
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology / Q000633:toxicity; D000547:Amantadine / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal; D001545:Benserazide / Q000494:pharmacology; D001681:Biological Assay; D003342:Corpus Striatum; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology / Q000633:toxicity; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007980:Levodopa / Q000009:adverse effects / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D010919:Placebos; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D011897:Random Allocation; D051381:Rats; D015203:Reproducibility of Results; D012399:Rotation; D018401:Sample Size; D016037:Single-Blind Method; D013565:Sympatholytics / Q000633:toxicity
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D010919:Placebos; D011687:Purines; D013565:Sympatholytics; C111599:istradefylline; D007980:Levodopa; D001545:Benserazide; D016627:Oxidopamine; D000547:Amantadine; D004298:Dopamine