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Apomorphine Reduces A53T α-Synuclein-Induced Microglial Reactivity Through Activation of NRF2 Signalling Pathway
Cellular and Molecular Neurobiology ( IF 3.6 ) Pub Date : 2021-08-20 , DOI: 10.1007/s10571-021-01131-1
Tony Heurtaux 1, 2, 3 , Melanie Kirchmeyer 1, 2 , Eric Koncina 1, 2 , Paul Felten 1, 2 , Lorraine Richart 1, 3, 4 , Oihane Uriarte Huarte 1, 3, 5 , Herve Schohn 6 , Michel Mittelbronn 1, 2, 3, 4, 5, 7
Affiliation  

The chiral molecule, apomorphine, is currently used for the treatment of Parkinson’s disease (PD). As a potent dopamine receptor agonist, this lipophilic compound is especially effective for treating motor fluctuations in advanced PD patients. In addition to its receptor-mediated actions, apomorphine has also antioxidant and free radical scavenger activities. Neuroinflammation, oxidative stress, and microglia reactivity have emerged as central players in PD. Thus, modulating microglia activation in PD may be a valid therapeutic strategy. We previously reported that murine microglia are strongly activated upon exposure to A53T mutant α-synuclein. The present study was designed to investigate whether apomorphine enantiomers could modulate this A53T-induced microglial activation. Taken together, the results provided evidence that apomorphine enantiomers decrease A53T-induced microgliosis, through the activation of the NRF2 signalling pathway, leading to a lower pro-inflammatory state and restoring the phagocytic activity. Suppressing NRF2 recruitment (trigonelline exposure) or silencing specifically Nfe2l2 gene (siRNA treatment) abolished or strongly decreased the anti-inflammatory activity of apomorphine. In conclusion, apomorphine, which is already used in PD patients to mimic dopamine activity, may also be suitable to decrease α-synuclein-induced microglial reactivity.



中文翻译:

阿扑吗啡通过激活 NRF2 信号通路降低 A53T α-突触核蛋白诱导的小胶质细胞反应性

手性分子阿扑吗啡目前用于治疗帕金森病 (PD)。作为一种有效的多巴胺受体激动剂,这种亲脂性化合物对治疗晚期 PD 患者的运动波动特别有效。除了其受体介导的作用外,阿扑吗啡还具有抗氧化和自由基清除剂活性。神经炎症、氧化应激和小胶质细胞反应性已成为 PD 的核心参与者。因此,调节 PD 中的小胶质细胞活化可能是一种有效的治疗策略。我们之前报道过小鼠小胶质细胞在暴露于 A53T 突变体 α-突触核蛋白后会被强烈激活。本研究旨在调查阿扑吗啡对映异构体是否可以调节这种 A53T 诱导的小胶质细胞活化。综合起来,结果提供了证据,表明阿扑吗啡对映异构体通过激活 NRF2 信号通路减少 A53T 诱导的小胶质细胞增生,从而降低促炎状态并恢复吞噬活性。抑制 NRF2 募集(葫芦巴碱暴露)或特异性沉默Nfe2l2基因(siRNA 处理)消除或强烈降低阿扑吗啡的抗炎活性。总之,已经在 PD 患者中用于模拟多巴胺活性的阿扑吗啡也可能适用于降低 α-突触核蛋白诱导的小胶质细胞反应性。

更新日期:2021-08-20
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