2. Academic Validation
  3. Amphiregulin blockade decreases the levodopa-induced dyskinesia in a 6-hydroxydopamine Parkinson's disease mouse model

Amphiregulin blockade decreases the levodopa-induced dyskinesia in a 6-hydroxydopamine Parkinson's disease mouse model

  • CNS Neurosci Ther. 2023 Apr 26. doi: 10.1111/cns.14229.
Piniel Alphayo Kambey 1 2,  Wen Ya Liu 1,  Jiao Wu 1,  Chuanxi Tang 1,  Wokuheleza Buberwa 3,  Adonira Saro 4,  Alphonce M K Nyalali 5,  Dianshuai Gao 1
Affiliations

Affiliations

  • 1 Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, China.
  • 2 Organization of African Academic Doctors (OAAD), Nairobi, Kenya.
  • 3 Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 4 Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, China.
  • 5 Department of Neurosurgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
PMID: 37101388 DOI: 10.1111/cns.14229
Abstract

Background: Levodopa (L-DOPA) is considered the most reliable drug for treating Parkinson's disease (PD) clinical symptoms. Regrettably, long-term L-DOPA therapy results in the emergence of drug-induced abnormal involuntary movements (AIMs) in most PD patients. The mechanisms underlying motor fluctuations and dyskinesia induced by L-DOPA (LID) are still perplexing.

Methods: Here, we first performed the analysis on the microarray data set (GSE55096) from the gene expression omnibus (GEO) repository and identified the differentially expressed genes (DEGs) using linear models for microarray analysis (Limma) R packages from the Bioconductor project. 12 genes (Nr4a2, Areg, Tinf2, Ptgs2, Pdlim1, Tes, Irf6, Tgfb1, Serpinb2, Lipg, Creb3l1, Lypd1) were found to be upregulated. Six genes were validated on quantitative polymerase chain reaction and subsequently, Amphiregulin (Areg) was selected (based on log2 fold change) for further experiments to unravel its involvement in LID. Areg LV_shRNA was used to knock down Areg to explore its therapeutic role in the LID model.

Results: Western blotting and immunofluorescence results show that AREG is significantly expressed in the LID group relative to the control. Dyskinetic movements in LID mice were alleviated by Areg knockdown, and the protein expression of delta FOSB, the commonly attributable protein in LID, was decreased. Moreover, Areg knockdown reduced the protein expression of P-ERK. In order to ascertain whether the inhibition of the ERK pathway (a common pathway known to mediate levodopa-induced dyskinesia) could also impede Areg, the Animals were injected with an ERK Inhibitor (PD98059). Afterward, the AIMs, AREG, and ERK protein expression were measured relative to the control group. A group treated with ERK Inhibitor had a significant decrease of AREG and phosphorylated ERK protein expression relative to the control group.

Conclusion: Taken together, our results indicate unequivocal involvement of Areg in levodopa-induced dyskinesia, thus a target for therapy development.

Keywords

Amphiregulin; Parkinson's disease; dyskinesia; levodopa.

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