Effects of piclozotan (SUN N4057), a partial serotonin 1A receptor agonist, on motor complications induced by repeated administration of levodopa in parkinsonian rats.
Serotonin 1A receptor agonists have attracted much interest recently as potential therapeutic agents for levodopa-induced motor complications, such as dyskinesia and motor fluctuations. The effects of piclozotan (SUN N4057) on a rat model of advanced Parkinson's disease were investigated. Parkinsonian rats, unilaterally 6-hydroxydopamine-lesioned rats, were administered levodopa for 8 to 9 weeks. Based on the results of rotational behavior and forelimb hyperkinesia in Week 5, the rats were allocated to three treatment groups (saline and two dosing rates of piclozotan set at 0.018 and 0.036 mg/kg/h). Piclozotan was administered via continuous subcutaneous infusion using an osmotic pump for 3 to 4 weeks. At Week 7 of repeated levodopa dosing, the effects of piclozotan on levodopa-induced behavior were evaluated. In addition, extracellular levels of levodopa-derived dopamine in the striatum were measured using microdialysis in Weeks 8 to 9 after completion of the respective behavioral studies. Chronic treatment with levodopa-induced forelimb hyperkinesia and shortened the duration of rotational behavior. Piclozotan (0.018 and 0.036 mg/kg/h, plasma concentrations 5.3±0.7 and 14.3±2.9 ng/ml) reduced levodopa-induced forelimb hyperkinesia by 55% and 69%, respectively, at 1h relative to the control. Piclozotan (0.036 mg/kg/h) significantly lengthened the duration of rotational behavior by 26% versus the control and attenuated the increase in striatal levodopa-derived extracellular dopamine levels. These findings suggest that piclozotan, a serotonin 1A agonist, can improve motor complications in patients with advanced Parkinson's disease.
Tani
Yoshihiro
Y
Biomedical Research Laboratories, Asubio Pharma Co., Ltd., 1-1-1, Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8513, Japan. tani.yoshihiro.fu@asubio.co.jp
Ogata
Atsuto
A
Koyama
Makoto
M
Inoue
Teruyoshi
T
D000818:Animals; D000978:Antiparkinson Agents / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D001545:Benserazide / Q000633:toxicity; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D054333:Drug Partial Agonism; D004409:Dyskinesia, Drug-Induced / Q000097:blood / Q000188:drug therapy*; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D007980:Levodopa / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D010077:Oxazepines / Q000097:blood / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000097:blood / Q000627:therapeutic use*
D000978:Antiparkinson Agents; D015259:Dopamine Agents; D004338:Drug Combinations; D010077:Oxazepines; D058825:Serotonin 5-HT1 Receptor Agonists; C005177:benserazide, levodopa drug combination; D044282:Receptor, Serotonin, 5-HT1A; D007980:Levodopa; D001545:Benserazide; C510463:Piclozotan; D004298:Dopamine