National Research Council of Italy (CNR), Neuroscience Institute - Cagliari, C/o Department of Biomedical Sciences, Cittadella Universitaria di Monserrato, 09042, Monserrato, CA, Italy.
Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cittadella Universitaria di Monserrato, 09042, Monserrato, CA, Italy.
Neuropharmacology. 2021 Sep 15;196:108693. doi: 10.1016/j.neuropharm.2021.108693. Epub 2021 Jul 3.
Several lines of evidence have strongly implicated neuroinflammation in Parkinson's disease (PD) progression and l-dopa-induced dyskinesia. The present study investigated whether early subchronic pretreatment with the serotonin 5-HT receptor agonist eltoprazine plus the adenosine A receptor antagonist preladenant counteracted l-dopa-induced abnormal involuntary movements (AIMs, index of dyskinesia), and neuroinflammation, in unilateral 6-hydroxydopamine(6-OHDA)-lesioned rat model of PD. The immunoreactivity of glial fibrillary acidic protein (GFAP), and the colocalization of ionized calcium binding adaptor molecule-1 (IBA-1), with interleukin (IL)-1β, tumor-necrosis-factor-α (TNF-α) and IL-10 were evaluated in the denervated caudate-putamen (CPu) and substantia nigra pars-compacta (SNc). The combined subchronic pretreatment with l-dopa plus eltoprazine and preladenant reduced AIMs induced by acute l-dopa challenge in these rats and decreased GFAP and IBA-1 immunoreactivity induced by the drug in both CPu and SNc, with reduction in IL-1β in IBA-1-positive cells in both CPu and SNc, and in TNF-α in IBA-1-positive cells in SNc. Moreover, a significant increase in IL-10 in IBA-1-positive cells was observed in SNc. Evaluation of immediate early-gene zif-268 (index of neuronal activation) after l-dopa challenge, showed an increase in its expression in denervated CPu of rats pretreated with l-dopa or l-dopa plus preladenant compared with vehicle, whereas rats pretreated with eltoprazine, with or without preladenant, had lower zif-268 expression. Finally, tyrosine hydroxylase and dopamine transporter examined to evaluate neurodegeneration, showed a significant equal decrease in all experimental groups. The present findings suggest that combination of l-dopa with eltoprazine and preladenant may be promising therapeutic strategy for delaying the onset of dyskinesia, preserving l-dopa efficacy and reducing neuroinflammation markers in nigrostriatal system of 6-OHDA-lesioned rats.
有几条证据强烈表明神经炎症参与了帕金森病（PD）的进展和左旋多巴诱导的运动障碍。本研究旨在探讨早期亚慢性预处理 5-羟色胺 5-HT 受体激动剂埃替拉嗪加腺苷 A 受体拮抗剂普莱登南是否能对抗单侧 6-羟多巴胺（6-OHDA）损伤 PD 大鼠模型中左旋多巴诱导的异常不自主运动（AIM，运动障碍的指标）和神经炎症。在去神经的尾壳核（CPu）和黑质致密部（SNc）中评估了胶质纤维酸性蛋白（GFAP）的免疫反应性，以及离子钙结合衔接蛋白-1（IBA-1）与白细胞介素（IL）-1β、肿瘤坏死因子-α（TNF-α）和 IL-10 的共定位。联合亚慢性预处理左旋多巴加埃替拉嗪和普莱登南可减少这些大鼠急性左旋多巴挑战引起的 AIM，并减少 CPu 和 SNc 中药物引起的 GFAP 和 IBA-1 免疫反应性，同时减少 CPu 和 SNc 中 IBA-1 阳性细胞中的 IL-1β，以及 SNc 中 IBA-1 阳性细胞中的 TNF-α。此外，在 SNc 中还观察到 IBA-1 阳性细胞中 IL-10 显著增加。在左旋多巴挑战后，对即刻早期基因 zif-268（神经元激活指标）进行评估，结果表明与载体相比，预先用左旋多巴或左旋多巴加普莱登南预处理的大鼠去神经 CPu 中 zif-268 的表达增加，而用埃替拉嗪预处理的大鼠，无论是否加用普莱登南，zif-268 的表达均较低。最后，检查酪氨酸羟化酶和多巴胺转运体以评估神经退行性变，发现所有实验组的表达均明显下降。这些发现表明，左旋多巴与埃替拉嗪和普莱登南联合使用可能是一种有前途的治疗策略，可延迟运动障碍的发生，保持左旋多巴的疗效，并减少 6-OHDA 损伤大鼠黑质纹状体系统的神经炎症标志物。
