The orphan nuclear receptor Nurr1 agonist amodiaquine mediates neuroprotective effects in 6-OHDA Parkinson's disease animal model by enhancing the phosphorylation of P38 mitogen-activated kinase but not PI3K/AKT signaling pathway
The orphan nuclear receptor Nurr1 agonist amodiaquine mediates neuroprotective effects in 6-OHDA Parkinson's disease animal model by enhancing the phosphorylation of P38 mitogen-activated kinase but not PI3K/AKT signaling pathway
复制标题
DOI：
10.1007/s11011-021-00670-2
复制
发表时间：
2021-01-28
影响因子：
3.6
通讯作者：
Gao，Dianshuai
中科院分区：
文献类型：
--
作者：
Kambey，Piniel Alphayo;Ma，Chengcheng;Gao，Dianshuai
近年来的研究表明，黑质孤儿核受体Nurr1基因的缺陷或表达改变与帕金森病的发病机制有关。为了证实能够复制Nurr1效果的治疗修饰性疾病，研究人员发现，阿莫地喹和Nurr1具有相同的化学支架，这表明了一种至关重要的结构-活性关系。有趣的是，阿莫地喹通过与其配体结合域（LBD）的物理相互作用刺激Nurr1的转录功能。然而，阿莫地喹激活Nurr1产生保护作用的信号通路仍有待阐明。我们首先证明了阿莫地喹治疗改善了6-OHDA帕金森病小鼠模型的行为缺陷，并促进了酪氨酸羟化酶（TH）和多巴胺转运蛋白（DAT） mRNA对多巴胺能神经元的保护；致密黑质中酪氨酸羟化酶（TH）蛋白表达水平及免疫反应性。随后，我们使用抑制剂来确定阿莫地喹对Akt和P38 Mapk作为神经保护的关键信号通路的影响。Wortmannin （Akt Inhibitor）诱导Akt mRNA显著降低；然而，阿莫地喹治疗组与对照组之间没有统计学差异，提示阿莫地喹可能不是Akt的活性刺激物。Western blot分析证实，与对照组相比，阿莫地喹组磷酸化Akt显著降低。同样，我们发现阿莫地喹显著增加磷酸化P38 Mapk的水平。当P38 Mapk被SB203580 （P38-Mapk Inhibitor）抑制时，P38 Mapk总量显著降低，而磷酸化的P38 Mapk未显著降低，酪氨酸羟化酶显著升高。这些结果共同表明，阿莫地喹可以通过磷酸化P38 Mapk增加酪氨酸羟化酶的表达，同时负调控磷酸化Akt的蛋白表达。
Recent studies implicate the defects or altered expression of the orphan nuclear receptor Nurr1 gene in the substantia nigra in Parkinson’s disease pathogenesis. In an attempt to corroborate the treatment-modifying disease that would replicate the effect of Nurr1, it has been found that amodiaquine and Nurr1 had the same chemical scaffolding, indicating a crucial structure-activity relationship. Interestingly, amodiaquine stimulate the transcriptional function of Nurr1 by physical interaction with its ligand-binding domain (LBD). However, the signaling route by which Nurr1 is activated by amodiaquine to cause the protective effect remains to be elucidated. We first demonstrated that amodiaquine treatment ameliorated behavioural deficits in 6-OHDA Parkinson’s disease mouse model, and it promoted dopaminergic neurons protection signified by Tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA; Tyrosine hydroxylase (TH) protein expression level and the immunoreactivity in the substantia nigra compacta. Subsequently, we used inhibitors to ascertain the effect of amodiaquine on Akt and P38 Mapk as crucial signaling pathways for neuroprotection. Wortmannin (Akt Inhibitor) induced a significant reduction of Akt mRNA; however, there was no statistical difference between the amodiaquine-treated group and the control group suggesting that amodiaquine may not be the active stimulant of Akt. Western blot analysis confirmed that the phosphorylated Akt decreased significantly in the amodiaquine group compared to the control group. In the same vein, we found that amodiaquine substantially increased the level of phosphorylated P38 Mapk. When P38 Mapk inhibited by SB203580 (P38-Mapk Inhibitor), the total P38 Mapk but not the phosphorylated P38 Mapk decreased significantly, while tyrosine hydroxylase significantly increased. These results collectively suggest that amodiaquine can augment tyrosine hydroxylase expression via phosphorylated P38 Mapk while negatively regulating the phosphorylated Akt in protein expression.