L-stepholidine reduced L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson's disease.
L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) remains a challenge in Parkinson's disease (PD) drug therapy. In the present study, we examined the effect of L-stepholidine (L-SPD), a known dual dopamine receptor agent, on LID in 6-hydroxydopamine (6-OHDA)-lesioned PD rat model. Daily administration of L-DOPA to PD rats for 22 days induced steady expression of LID, co-administration of L-SPD with L-DOPA significantly ameliorated LID without compromising the therapeutic potency of L-DOPA, indicating that L-SPD attenuated LID development. L-SPD alone elicited stable contralateral rotational behavior without inducing significant dyskinesia. Acute administration of L-SPD to rats with established LID produced significant relief of dyskinesia; this effect was mimicked by D(2) receptor antagonist haloperidol, but blunted by 5-HT(1A) receptor antagonist WAY100635. Furthermore, the mRNA level of 5-HT(1A) decreased significantly on 6-OHDA-lesioned striata, whereas chronic L-SPD treatment restored 5-HT(1A) receptor mRNA level on the lesioned striata. The present data demonstrated that L-SPD elicited antidyskinesia effects via both dopamine (D(2) receptor antagonistic activity) and nondopamine (5-HT(1A) agonistic activity) mechanisms.
Mo
Jiao
J
State Key Laboratory of Drug Research, Department of Neuropharmacology, Shanghai Institute of Material Medica, Chinese Academy of Sciences, Shanghai, China.
Zhang
Hai
H
Yu
Lei-Ping
LP
Sun
Pei-Hua
PH
Jin
Guo-Zhang
GZ
Zhen
Xuechu
X
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000493:pharmacokinetics; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001552:Benzazepines / Q000008:administration & dosage; D001599:Berberine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016466:CHO Cells; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004347:Drug Interactions; D020820:Dyskinesias / Q000188:drug therapy* / Q000209:etiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics; D014162:Transfection; D014316:Tritium / Q000493:pharmacokinetics
D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D001552:Benzazepines; D015259:Dopamine Agents; D012333:RNA, Messenger; C534628:SCH 23390; D017366:Serotonin Receptor Agonists; D001599:Berberine; C010513:stepholidine; D014316:Tritium; D044282:Receptor, Serotonin, 5-HT1A; D007980:Levodopa; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D016627:Oxidopamine