Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China.
Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China; Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.
Neuropharmacology. 2017 Nov;126:12-24. doi: 10.1016/j.neuropharm.2017.08.014. Epub 2017 Aug 12.
We have previously demonstrated the unexpected neuroprotection of the anti-cancer agent SU4312 in cellular models associated with Parkinson's disease (PD). However, the precise mechanisms underlying its neuroprotection are still unknown, and the effects of SU4312 on rodent models of PD have not been characterized. In the current study, we found that the protection of SU4312 against 1-methyl-4-phenylpyridinium ion (MPP)-induced neurotoxicity in PC12 cells was achieved through the activation of transcription factor myocyte enhancer factor 2D (MEF2D), as evidenced by the fact that SU4312 stimulated myocyte enhancer factor 2 (MEF2) transcriptional activity and prevented the inhibition of MEF2D protein expression caused by MPP, and that short hairpin RNA (ShRNA)-mediated knockdown of MEF2D significantly abolished the neuroprotection of SU4312. Additionally, Western blotting analysis revealed that SU4312 potentiated pro-survival PI3-K/Akt pathway to down-regulate MEF2D inhibitor glycogen synthase kinase-3beta (GSK3β). Furthermore, using the in vivo PD model of C57BL/6 mice insulted with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we found that intragastrical administration of SU4312 (0.2 and 1 mg/kg) greatly ameliorated Parkinsonian motor defects, and restored protein levels of MEF2D, phosphorylated-Ser473-Akt and phosphorylated-Ser9-GSK3β. Meanwhile, SU4312 effectively reversed the decrease in protein expression of tyrosine hydroxylase in substantia nigra pars compacta dopaminergic neurons, inhibited oxidative stress, maintained mitochondrial biogenesis and partially prevented the depletion of dopamine and its metabolites. Very encouragingly, SU4312 was able to selectively inhibit monoamine oxidase-B (MAO-B) activity both in vitro and in vivo, with an IC value of 0.2 μM. These findings suggest that SU4312 provides therapeutic benefits in cellular and animal models of PD, possibly through multiple mechanisms including enhancement of MEF2D through the activation of PI3-K/Akt pathway, maintenance of mitochondrial biogenesis and inhibition of MAO-B activity. SU4312 thus may be an effective drug candidate for the prevention or even modification of the pathological processes of PD.
我们之前已经证明了抗癌药物 SU4312 在与帕金森病（PD）相关的细胞模型中具有出人意料的神经保护作用。然而，其神经保护的确切机制仍不清楚，并且 SU4312 对 PD 啮齿动物模型的影响尚未得到描述。在本研究中，我们发现 SU4312 通过激活转录因子肌细胞增强因子 2D（MEF2D）来抵抗 1-甲基-4-苯基吡啶鎓（MPP）诱导的 PC12 细胞神经毒性，这是因为 SU4312 刺激肌细胞增强因子 2（MEF2）转录活性并防止 MPP 引起的 MEF2D 蛋白表达抑制，短发夹 RNA（shRNA）介导的 MEF2D 敲低显着消除了 SU4312 的神经保护作用。此外，Western blot 分析显示，SU4312 增强了促生存的 PI3-K/Akt 途径，以下调 MEF2D 抑制剂糖原合酶激酶-3β（GSK3β）。此外，我们使用 C57BL/6 小鼠 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的体内 PD 模型发现，给予 SU4312（0.2 和 1mg/kg）灌胃可大大改善帕金森运动缺陷，并恢复 MEF2D、磷酸化-Ser473-Akt 和磷酸化-Ser9-GSK3β 的蛋白水平。同时，SU4312 有效逆转了黑质致密部多巴胺能神经元酪氨酸羟化酶蛋白表达的下降，抑制了氧化应激，维持了线粒体生物发生，并部分阻止了多巴胺及其代谢物的耗竭。非常令人鼓舞的是，SU4312 能够在体外和体内选择性抑制单胺氧化酶-B（MAO-B）的活性，IC 值为 0.2μM。这些发现表明，SU4312 在 PD 的细胞和动物模型中提供了治疗益处，可能通过多种机制，包括通过激活 PI3-K/Akt 途径增强 MEF2D、维持线粒体生物发生和抑制 MAO-B 活性。因此，SU4312 可能是预防甚至改变 PD 病理过程的有效药物候选物。
