氨丁二酸阻断可减少 6-羟多巴胺帕金森病小鼠模型中左旋多巴诱导的运动障碍。
Amphiregulin blockade decreases the levodopa-induced dyskinesia in a 6-hydroxydopamine Parkinson's disease mouse model.
机构信息
Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, China.
Organization of African Academic Doctors (OAAD), Nairobi, Kenya.
出版信息
CNS Neurosci Ther. 2023 Oct;29(10):2925-2939. doi: 10.1111/cns.14229. Epub 2023 Apr 26.
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.
背景
左旋多巴（L-DOPA）被认为是治疗帕金森病（PD）临床症状最可靠的药物。遗憾的是，长期的 L-DOPA 治疗会导致大多数 PD 患者出现药物诱导的异常不自主运动（AIMs）。L-DOPA（LID）引起的运动波动和运动障碍的机制仍然令人费解。
方法
在这里，我们首先对来自基因表达综合数据库（GEO）的微阵列数据集（GSE55096）进行了分析，使用 Bioconductor 项目中的线性模型进行微阵列分析（Limma）R 包来识别差异表达基因（DEGs）。发现 12 个基因（Nr4a2、Areg、Tinf2、Ptgs2、Pdlim1、Tes、Irf6、Tgfb1、Serpinb2、Lipg、Creb3l1、Lypd1）上调。6 个基因在定量聚合酶链反应中得到验证，随后基于 log2 倍变化选择 Amphiregulin（Areg）进行进一步实验，以揭示其在 LID 中的作用。使用 Areg LV_shRNA 敲低 Areg 以探索其在 LID 模型中的治疗作用。
结果
Western blot 和免疫荧光结果显示，AREG 在 LID 组相对于对照组显著表达。Areg 敲低减轻了 LID 小鼠的运动障碍，并且共同归因于 LID 的蛋白 delta FOSB 的蛋白表达减少。此外，Areg 敲低降低了 P-ERK 的蛋白表达。为了确定抑制 ERK 通路（一种已知介导左旋多巴诱导运动障碍的共同通路）是否也能抑制 Areg，向动物注射了 ERK 抑制剂（PD98059）。随后，与对照组相比，测量了 AIMs、AREG 和 ERK 蛋白表达。与对照组相比，用 ERK 抑制剂处理的一组 AREG 和磷酸化 ERK 蛋白表达显著降低。
结论
综上所述，我们的结果表明 Areg 明确参与了左旋多巴诱导的运动障碍，因此是治疗开发的靶点。
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