title: Intranigral administration of substance P receptor antagonist attenuated levodopa-induced dyskinesia in a rat model of Parkinson's disease.
abstract: Levodopa (L-dopa) remains the most effective drug in the treatment of Parkinson's disease (PD). However, L-dopa-induced dyskinesia (LID) has hindered its use for PD patients. The mechanisms of LID are not fully understood. Substance P (SP) receptor antagonist has been shown to reduce parkinsonism in animal models of PD, and ameliorate LID in PD rats. But the concrete mechanism is not fully understood. To address this issue, we produced a rat model of PD using 6-hydroxydompamine (6-OHDA) injections, and valid PD rats were intranigrally administrated with different doses of SP receptor antagonist LY303870 (5 nmol/day, 10 nmol/day and 20 nmol/day) following L-dopa (6 mg/kg/day, i.p.) plus benserazide (12 mg/kg/day, i.p.) for 23 days. We found that nigral SP levels were increased on days 3, 7 and 14 and decreased on day 21 after 6-hydroxydompamine lesions. But nigral SP levels kept increasing after repeated L-dopa administration in PD rats. Intranigral administration of low and moderate LY303870 reduced abnormal involuntary movements (AIMs) while improving motor deficits in PD rats treated with L-dopa plus benserazide. Microdialysis revealed that LY303870 (10 nmol/day) treatment attenuated the increase of striatal dopamine and the reduction of γ-aminobutyric acid in ventromedial thalamus of PD rats primed with L-dopa. Additionally, LY303870 (10 nmol/day) treatment prior to L-dopa administration reduced the phosphorylated levels of dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein of 32 kDa at Thr 34 and extracellular signal-regulated kinases 1/2 as well as the levels of activity-regulated cytoskeleton-associated protein and Penk in L-dopa-primed PD rats. Taken together, these data showed that low and moderate SP receptor antagonists LY303870 could ameliorate LID via neurokinin 1 receptor without affecting therapeutic effect of L-dopa.
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Neurology, Xuzhou Central Hospital, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, China.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Ultrasound, The Affiliated Hospital of Xuzhou Medical College, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, China.
authors.forename: Shenyang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, China.
authors.forename: Zunsheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zu
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, China. Electronic address: cuiguiyun-js@163.com.
authors.forename: Guiyun
authors.initials: G
authors.lastname: Cui
authors.affiliation: Department of Neurology, The Affiliated Hospital of Xuzhou Medical College, China. Electronic address: huafang@xzmc.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001058:Apomorphine / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D005786:Gene Expression Regulation / Q000187:drug effects; D007211:Indoles / Q000627:therapeutic use*; D007980:Levodopa / Q000009:adverse effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D010880:Piperidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: C096759:1-(N-(2-methoxybenzyl)acetylamino)-3-(1H-indol-3-yl)-2-(N-(2-(4-(piperidin-1-yl)piperidin-1-yl)acetyl)amino)propane; D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D007980:Levodopa; D016627:Oxidopamine; D001058:Apomorphine; D004298:Dopamine
keywords: Dopamine; Levodopa induced dyskinesia; Neurokinin 1 receptor; Parkinson's disease; Protein kinase A; Substance P