钩藤中主要的四环素类生物碱钩藤碱激活PI3-K/Akt/GSK3β/MEF2D信号通路对MPP+细胞毒性的保护作用。

PubMed ID
G H
发表日期 2018年月

原始出处 药理学前沿
Frontiers in pharmacology
作者 Hu  Shengquan  Mak  Shinghung  Zuo  Xialin  Li  Haitao  Wang  Yuqiang  Han  Yifan 

文献标题 钩藤中主要的四环素类生物碱钩藤碱激活PI3-K/Akt/GSK3β/MEF2D信号通路对MPP+细胞毒性的保护作用。
Neuroprotection Against MPP+-Induced Cytotoxicity Through the Activation of PI3-K/Akt/GSK3β/MEF2D Signaling Pathway by Rhynchophylline, the Major Tetracyclic Oxindole Alkaloid Isolated From Uncaria rhynchophylla.
Neuroprotection Against MPP+-Induced Cytotoxicity Through the Activation of PI3-K/Akt/GSK3β/MEF2D Signaling Pathway by Rhynchophylline, the Major Tetracyclic Oxindole Alkaloid Isolated From Uncaria rhynchophylla.

文献摘要

钩藤碱是钩藤中一种主要的四环素类生物碱,广泛应用于防治惊厥和高血压。然而,关于钩藤碱对帕金森病(Parkinson'sdisease,PD)的神经保护作用的证据仍然很少,PD是一种神经退行性疾病,目前尚无有效的治疗方法。在本研究中,钩藤碱的神经保护分子机制进行了研究与帕金森病相关的细胞模型。结果表明,钩藤碱(10-50μM)能显著抑制1-甲基-4-苯基吡啶离子(MPP+)对原代小脑颗粒神经元的神经毒性作用,其作用机制可通过提高细胞活力和逆转Bax/Bcl-2比值失调的蛋白表达来证实。非常令人鼓舞的是,我们通过荧光素酶报告基因分析发现,钩藤碱在基础和病理条件下都能显著增强转录因子心肌细胞增强因子2D(MEF2D)的活性,并逆转MPP+对MEF2D的抑制作用。此外,通过药理学抑制PI3激酶或短发夹RNA介导的MEF2D基因下调,从而消除了钩藤碱的保护作用。此外,Western-blot分析显示钩藤碱可增强PI3-K/Akt以减弱MPP+损伤引起的GSK3β(MEF2D抑制剂)。综上所述,钩藤碱通过激活PI3-K/Akt/GSK3β级联反应来刺激MEF2D,从而抑制MPP+引发的神经毒性。钩藤碱是一种新型的MEF2D增强子,有可能成为进一步预防PD临床前研究的候选药物。


Rhynchophylline is a major tetracyclic oxindole alkaloid in Uncaria rhynchophylla, which has been extensively used as traditional herb medicine for the prevention of convulsions and hypertension. However, there is still little evidence about the neuroprotective effects of rhynchophylline for Parkinson's disease (PD), a neurodegenerative condition currently without any effective cure. In this present study, the neuroprotective molecular mechanisms of rhynchophylline were investigated in a cellular model associated with PD. It is shown that rhynchophylline (10-50 μM) greatly prevented neurotoxicity caused by 1-methyl-4-phenylpyridinium ion (MPP+) in primary cerebellar granule neurons, as evidenced by the promotion of cell viability as well as the reversal of dysregulated protein expression of Bax/Bcl-2 ratio. Very encouragingly, we found that rhynchophylline markedly enhanced the activity of the transcription factor myocyte enhancer factor 2D (MEF2D) at both basal and pathological conditions using luciferase reporter gene assay, and reversed the inhibition of MEF2D caused by MPP+. Additionally, pharmacological inhibition of PI3-Kinase or short hairpin RNA-mediated gene down-regulation of MEF2D abrogated the protection provided by rhynchophylline. Furthermore, Western blot analysis revealed that rhynchophylline could potentiate PI3-K/Akt to attenuate GSK3β (the MEF2D inhibitor) in response to MPP+ insult. In conclusion, rhynchophylline inhibits MPP+-triggered neurotoxicity by stimulating MEF2D via activating PI3-K/Akt/GSK3β cascade. Rhynchophylline is served as a novel MEF2D enhancer and might be a potential candidate for further preclinical study in the prevention of PD.

Rhynchophylline is a major tetracyclic oxindole alkaloid in Uncaria rhynchophylla, which has been extensively used as traditional herb medicine for the prevention of convulsions and hypertension. However, there is still little evidence about the neuroprotective effects of rhynchophylline for Parkinson's disease (PD), a neurodegenerative condition currently without any effective cure. In this present study, the neuroprotective molecular mechanisms of rhynchophylline were investigated in a cellular model associated with PD. It is shown that rhynchophylline (10-50 μM) greatly prevented neurotoxicity caused by 1-methyl-4-phenylpyridinium ion (MPP+) in primary cerebellar granule neurons, as evidenced by the promotion of cell viability as well as the reversal of dysregulated protein expression of Bax/Bcl-2 ratio. Very encouragingly, we found that rhynchophylline markedly enhanced the activity of the transcription factor myocyte enhancer factor 2D (MEF2D) at both basal and pathological conditions using luciferase reporter gene assay, and reversed the inhibition of MEF2D caused by MPP+. Additionally, pharmacological inhibition of PI3-Kinase or short hairpin RNA-mediated gene down-regulation of MEF2D abrogated the protection provided by rhynchophylline. Furthermore, Western blot analysis revealed that rhynchophylline could potentiate PI3-K/Akt to attenuate GSK3β (the MEF2D inhibitor) in response to MPP+ insult. In conclusion, rhynchophylline inhibits MPP+-triggered neurotoxicity by stimulating MEF2D via activating PI3-K/Akt/GSK3β cascade. Rhynchophylline is served as a novel MEF2D enhancer and might be a potential candidate for further preclinical study in the prevention of PD.


获取全文 10.3389/fphar.2018.00768