Intranigral administration of substance P receptor antagonist attenuated levodopa-induced dyskinesia in a rat model of Parkinson's disease

• Published in: Experimental neurology 2015-09, Vol.271, p.168-174
• Main Authors: Yang, Xinxin, Zhao, Hui, Shi, Hongjuan, Wang, Xiaoying, Zhang, Shenyang, Zhang, Zunsheng, Zu, Jie, Zhang, Wei, Shen, Xia, Cui, Guiyun, Hua, Fang
• Format: Article
• Language: English
• Subjects: Adrenergic Agents - toxicity; Animals; Antiparkinson Agents - adverse effects; Apomorphine - pharmacology; Disease Models, Animal; Dopamine; Dopamine - metabolism; Dopamine Agonists - pharmacology; Drug Administration Schedule; Dyskinesia, Drug-Induced - drug therapy; Gene Expression Regulation - drug effects; Indoles - therapeutic use; Levodopa - adverse effects; Levodopa induced dyskinesia; Male; MAP Kinase Signaling System - drug effects; Motor Activity - drug effects; Neurokinin 1 receptor; Neurokinin-1 Receptor Antagonists - therapeutic use; Oxidopamine - toxicity; Parkinson Disease - drug therapy; Parkinson Disease - etiology; Parkinson Disease - pathology; Parkinson's disease; Piperidines - therapeutic use; Protein kinase A; Rats; Rats, Sprague-Dawley; Substance P; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Time Factors
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2015.05.007

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 (5nmol/day, 10nmol/day and 20nmol/day) following l-dopa (6mg/kg/day, i.p.) plus benserazide (12mg/kg/day, i.p.) for 23days. 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 (10nmol/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 (10nmol/day) treatment prior to l-dopa administration reduced the phosphorylated levels of dopamine- and cyclic adenosine monophosphate-regulated phosphoprotein of 32kDa 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. •Nigral SP levels were increased in levodopa-primed PD rats.•SPA reduced LID without affecting anti-parkinsonian effect of levodopa in PD rats.•SPA attenuated striatal DA efflux and GABA reduction in VMTh of dykinetic rats.•SPA reduced p-DARPP-32, p-ERK1/2, Arc and Penk levels in dyskinetic rats.