Pardoprunox reverses motor deficits but induces only mild dyskinesia in MPTP-treated common marmosets.
Long-acting full dopamine D(2) agonists produce less dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates and in Parkinson's disease than effective antiparkinsonian doses of levodopa. They do not however, prevent priming for dyskinesia expression on subsequent levodopa exposure. In contrast, the effects of partial D(2) receptor agonists on dyskinesia are unclear. We now examine the ability of the partial D(2) agonist pardoprunox (SLV308) to improve motor function and its propensity to prime for dyskinesia in drug naïve, MPTP-treated common marmosets. Previously, drug naïve, MPTP-treated common marmosets were treated with equivalent doses of either pardoprunox (SLV308) (0.1 mg/kg po), ropinirole (0.18 mg/kg po), or levodopa (10 mg/kg po BID) for 28 days. All treatments induced a similar reduction of motor disability. Dyskinesia induced by levodopa was of greater intensity than that following administration of either pardoprunox (SLV308) or ropinirole. Administration of pardoprunox (SLV308) resulted in dyskinesia that was less intense and of shorter duration than either ropinirole or levodopa. At the end of drug treatment, acute challenge with levodopa resulted in the expression of marked dyskinesia in animals that had previously received chronic levodopa or ropinirole treatment. However, animals previously treated with pardoprunox (SLV308) showed only mild dyskinesia in response to the levodopa challenge. These results suggest that the partial D(2) agonist pardoprunox (SLV308) is less likely to prime for dyskinesia or to lead to the expression of dyskinesia than either levodopa or full dopamine agonists.
Johnston
Louisa Clare
LC
Neurodegenerative Diseases Research Centre, School of Health and Biomedical Sciences, King's College, London, UK.
Jackson
Michael John
MJ
Rose
Sarah
S
McCreary
Andrew Christopher
AC
Jenner
Peter
P
D000704:Analysis of Variance; D000818:Animals; D000977:Antiparasitic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D001583:Benzoxazoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D002144:Callithrix; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020820:Dyskinesias / Q000209:etiology; D005260:Female; D008124:Locomotion / Q000187:drug effects; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D013997:Time Factors
D000977:Antiparasitic Agents; D001583:Benzoxazoles; D010879:Piperazines; C480679:pardoprunox