<br>分子伴侣 Sigma1R 在帕金森病 6-OHDA 模型中介导阿福巴唑的神经保护作用。,Scientific Reports

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分子伴侣 Sigma1R 在帕金森病 6-OHDA 模型中介导阿福巴唑的神经保护作用。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-11-19 , DOI: 10.1038/s41598-019-53413-w
Mikhail V Voronin ₁ , Ilya A Kadnikov ₁ , Dmitry N Voronkov ₂ , Sergey B Seredenin ₁

Affiliation

帕金森病 (PD) 是一种进行性神经退行性疾病，治疗选择有限。因此，迫切需要确定治疗靶点。先前的研究表明，sigma-1 伴侣 (Sigma1R) 的配体激活可促进神经保护。在 6-羟基多巴胺 (6-OHDA) 诱导的帕金森病模型中，多靶点药物阿福巴唑（5-乙氧基-2-[2-(吗啉代)-乙硫基]苯并咪唑二盐酸盐）可与 Sigma1Rs 相互作用并防止纹状体多巴胺减少。本研究的目的是阐明 Sigma1Rs 在阿福巴唑药理活性中的作用。使用 ICR 小鼠，我们发现给予阿福巴唑（2.5 mg/kg，腹腔注射）或 Sigma1R PRE-084 选择性激动剂（1.0 mg/kg，腹腔注射）超过 14 天可以使运动功能障碍正常化，并防止 6-OHDA- 中多巴胺的减少。受损的纹状体。阿福巴唑给药还可以防止黑质中 TH + 神经元的损失。预先施用选择性 Sigma1R 拮抗剂 BD-1047（3.0 mg/kg，腹腔注射）可消除阿福巴唑或 PRE-084 的活性，这一点通过转棒试验和纹状体多巴胺含量分析确定。目前的研究证明了Sigma1Rs在帕金森病6-OHDA模型中阿福巴唑神经保护作用中的贡献，并定义了Sigma1R激动剂在临床中的治疗前景。

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Chaperone Sigma1R mediates the neuroprotective action of afobazole in the 6-OHDA model of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease with limited treatment options. Therefore, the identification of therapeutic targets is urgently needed. Previous studies have shown that the ligand activation of the sigma-1 chaperone (Sigma1R) promotes neuroprotection. The multitarget drug afobazole (5-ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was shown to interact with Sigma1Rs and prevent decreases in striatal dopamine in the 6-hydroxydopamine (6-OHDA)-induced parkinsonism model. The aim of the present study was to elucidate the role of Sigma1Rs in afobazole pharmacological activity. Using ICR mice we found that administration of afobazole (2.5 mg/kg, i.p.) or selective agonist of Sigma1R PRE-084 (1.0 mg/kg, i.p.) over 14 days normalizes motor disfunction and prevents decreases in dopamine in the 6-OHDA-lesioned striatum. Afobazole administration also prevents the loss of TH + neurons in the substantia nigra. The pre-administration of selective Sigma1R antagonist BD-1047 (3.0 mg/kg, i.p.) abolishes the activity of either afobazole or PRE-084, as determined using the rotarod test and the analysis of striatal dopamine content. The current study demonstrates the contribution of Sigma1Rs in the neuroprotective effect of afobazole in the 6-OHDA model of Parkinson's disease and defines the therapeutic perspective of Sigma1R agonists in the clinic.

更新日期：2019-11-19

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