香豆素曼尼希碱衍生物LZJ17治疗帕金森病的药效学和机制研究
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摘要
目的:观察香豆素曼尼希碱衍生物LZJ17对单胺氧化酶B(monoamine oxidase B,MAO-B)和神经炎症的抑制活性,以及对帕金森病(Parkinson's disease,PD)模型小鼠的神经保护作用。方法:用脂多糖(lipopolysaccharides,LPS)刺激BV2细胞,观察培养基中一氧化氮(nitric oxide,NO)的释放量,以评估LZJ17对神经炎症的影响,并在体外实验中检测LZJ17对MAO-B活性的抑制作用。然后在MPTP诱发的亚急性帕金森病小鼠模型中通过运动行为学测试、免疫组化及Western Blot实验观察LZJ17的神经保护作用。结果:在体外研究中,LZJ17表现出较好的抑制MAO-B和神经炎症的活性。在MPTP小鼠亚急性帕金森病模型中,LZJ17可明显提高小鼠的掉落潜伏期和酪氨酸羟化酶(tyrosine hydroxylase,TH)阳性神经元的数目。同时LZJ17也可明显抑制小鼠脑内MAO-B的活性并减少炎症蛋白i NOS和COX-2的表达。结论:LZJ17能够明显改善MPTP诱导的运动障碍,保护TH阳性神经元,机制研究显示LZJ17这种保护作用与其同时抑制MAO-B活性和神经炎症有关。
Objective: To investigate the inhibitory effects of coumarin mannich base derivative LZJ17 on monoamine oxidase B( MAO-B) and neuroinflammation,as well as the therapeutic effects of LZJ17 on experimental Parkinson's disease( PD) mouse model induced by MPTP. Methods: BV2 cell line was challenged by lipopolysaccharide( LPS) and nitric oxide( NO) was quantified to reflect the anti-inflammatory effect of LZJ17. The inhibitory effect of LZJ17 on MAO-B was determined in in vitro studies. Then a sub-acute PD mouse model was developed by injection of MPTP. Behavioral test,tyrosine hydroxylase( TH) immunohistochemistry and Western Blot experiments were performed to observe the efficacy of LZJ17 on PD mouse model. Results: In the in vitro studies,LZJ17 exhibited good MAO-B inhibitory effect and anti-inflammatory effect. In the sub-acute PD mouse model induced by MPTP,LZJ17 significantly increased the latency and the number of TH-positive neurons. It was also shown that LZJ17 reduced MAO-B activity and the expression of i NOS and COX-2 in vivo. Conclusion: LZJ17 could attenuate MPTP-induced dyskinesia and protect TH-positive neurons. Mechanism studies have shown that the protective effectof LZJ17 may be associated with its MAO-B and neuroinflammation inhibitory activities.
Objective: To investigate the inhibitory effects of coumarin mannich base derivative LZJ17 on monoamine oxidase B( MAO-B) and neuroinflammation,as well as the therapeutic effects of LZJ17 on experimental Parkinson's disease( PD) mouse model induced by MPTP. Methods: BV2 cell line was challenged by lipopolysaccharide( LPS) and nitric oxide( NO) was quantified to reflect the anti-inflammatory effect of LZJ17. The inhibitory effect of LZJ17 on MAO-B was determined in in vitro studies. Then a sub-acute PD mouse model was developed by injection of MPTP. Behavioral test,tyrosine hydroxylase( TH) immunohistochemistry and Western Blot experiments were performed to observe the efficacy of LZJ17 on PD mouse model. Results: In the in vitro studies,LZJ17 exhibited good MAO-B inhibitory effect and anti-inflammatory effect. In the sub-acute PD mouse model induced by MPTP,LZJ17 significantly increased the latency and the number of TH-positive neurons. It was also shown that LZJ17 reduced MAO-B activity and the expression of i NOS and COX-2 in vivo. Conclusion: LZJ17 could attenuate MPTP-induced dyskinesia and protect TH-positive neurons. Mechanism studies have shown that the protective effectof LZJ17 may be associated with its MAO-B and neuroinflammation inhibitory activities.
引文
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[15] LULL ME,BLOCK ML. Microglial activation and chronic neurodegeneration[J]. Neurotherapeutics,2010,7(4):354-365.
[16] WANG QQ,LIU YJ,ZHOU JW. Neuroinflammation in Parkinson's disease and its potential as therapeutic target[J]. Transl Neurodegener,2015,4(1):19.
[2] BOBELA W,AEBISCHER P,SCHNEIDER B. Alphal-synuclein as a mediator in the interplay between aging and Parkinson's disease[J]. Biomolecules,2015,5(4):2675-2700.
[3] ZEUNER KE,SCHAFFER E,HOPFNER F,et al. Progress of pharmacological approaches in Parkinson's disease[J]. Clin Pharmacol Ther,2019,105(5):1106-1120.
[4] CACABELOS R. Parkinson's disease:from pathogenesis to pharmacogenomics[J]. Int J Mol Sci,2017,18(3):551.
[5] TEO KC,HO SL. Monoamine oxidase-B(MAO-B)inhibitors:implications for disease-modification in Parkinson's disease[J].Transl Neurodegener,2013,2(1):19.
[6] FINBERG JPM. Inhibitors of MAO-B and COMT:their effects on brain dopamine levels and uses in Parkinson's disease[J]. J Neural Transm,2019,126(4):433-448.
[7] KEMPURAJ D,THANGAVEL R,SELVAKUMAR GP,et al.Brain and peripheral atypical inflammatory mediators potentiate neuroinflammation and neurodegeneration[J]. Front Cell Neurosci,2017,11:216.
[8] SKALICKA-WOZNIAK K,ORHAN IE,CORDELL GA,et al.Implication of coumarins towards central nervous system disorders[J]. Pharm Res,2016,103:188-203.
[9] SAKTHIVEL KM,GURUVAYOORAPPAN C. Acacia ferruginea inhibits inflammation by regulating inflammatory i NOS and COX-2[J]. J Immunotoxicol,2016,13(1):127-135.
[10]严芳,王宇卉.帕金森病心血管自主神经功能障碍的病理生理学及其治疗[J].世界临床药物,2018,39(7):458-463.
[11]梁瑶,张蕾,曾灶昌.新型抗帕金森病药物沙芬酰胺[J].中国新药杂志,2018,27(14):1603-1606.
[12] CHAN HH,TSE MK,KUMAR S,et al. A novel selective MAO-B inhibitor with neuroprotective and anti-Parkinsonian properties[J]. Eur J Pharmacol,2018,818:254-262.
[13] MALLAJOSYULA JK,KAUR D,CHINTA SJ,et al. MAO-B elevation in mouse brain astrocytes results in Parkinson's pathology[J]. PLoS One,2008,3(2):e1616
[14] YOUDIM,MBH,EDMONDSON D,TIPTON KF. The therapeutic potential of monoamine oxidase inhibitors[J]. Nat Rev Neurosci,2006,7(4):295-309.
[15] LULL ME,BLOCK ML. Microglial activation and chronic neurodegeneration[J]. Neurotherapeutics,2010,7(4):354-365.
[16] WANG QQ,LIU YJ,ZHOU JW. Neuroinflammation in Parkinson's disease and its potential as therapeutic target[J]. Transl Neurodegener,2015,4(1):19.