The abnormal activation of D1R/Shp-2 complex involved in levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned Parkinson’s rats

Abstract

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

Acknowledgments

The study was supported by the National Key R&D Program of China (2017YFC1310300, 2016YFC1306600), Projects of National Science Foundation of China (81400925, 81471148, 81671273, 81771211, 81703852), Projects of the Shanghai Committee of Science and Technology (17401901000) and SHSMU-ION Research Center for Brain Disorders (2015NKX007).

Disclosure

The authors report no conflicts of interest in this work.