Neuropsychiatric Disease and Treatment (Jul 2018)
The abnormal activation of D1R/Shp-2 complex involved in levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned Parkinson’s rats
Abstract
Na Wu, Ying Wan, Lu Song, Chen Qi, Zhenguo Liu, Jing Gan Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China Background: Levodopa-induced dyskinesia (LID) is a troublesome problem in the treatment of Parkinson’s disease (PD). The mechanisms of LID are still mysterious. Recently, the interaction between Shp-2 and D1 dopamine receptor (D1R) has been identified to be indispensable in the D1R-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation and the occurrence of LID. However, the role of Shp-2 in the D1R-mediated signaling pathway of dyskinetic rat models is not fully clear. We designed this study with the purpose of exploring the role of D1R/Shp-2 complex in the D1R-mediated signaling pathway in the occurrence of LID.Materials and methods: The 6-hydroxydopamine (6-OHDA) was injected unilaterally to produce the rat models of PD. Successful PD rat models were randomly divided into three groups to receive the treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) + benserazide, L-DOPA + benserazide + D1R antagonist (SCH23390) or D1R agonist (SKF38393). Abnormal involuntary movements were assessed in different groups during the treatment. The interaction between D1R and Shp-2 was confirmed in the sham and LID rats through the methods of coimmunoprecipitation. In addition, the levels of p-Shp-2, p-ERK1/2 and p-mTOR were determined by Western blot in different groups.Results: After the treatment with L-DOPA + benserazide for 22 days, PD rats presented with dyskinesia. D1R agonist, SKF38393, induced similar involuntary movements in PD rats. In contrast, the dyskinetic movements were not induced by coadministration of L-DOPA + D1R antagonist (SCH23390). The interaction between D1R and Shp-2 in the normal rats was kept stable after the long-term use of L-DOPA. Moreover, we found that the pulsatile levodopa administration induced hyperphosphorylation of Shp-2, ERK1/2 and mTOR, while the coadministration of L-DOPA and D1R antagonist, SCH23390, did not induce the hyperphosphorylation of these proteins.Conclusion: These data verified the existence of D1R/Shp-2 complex and its crucial role in the D1R-mediated signaling pathway in dyskinetic rats. Focus on the D1R/Shp-2 complex might be a potential treatment of LID in the future. Keywords: Parkinson’s disease, dyskinesia, levodopa, D1 receptors, Shp-2
