The anti-cancer agent SU4312 unexpectedly protects against MPP plus -induced neurotoxicity via selective and direct inhibition of neuronal NOS
The anti-cancer agent SU4312 unexpectedly protects against MPP plus -induced neurotoxicity via selective and direct inhibition of neuronal NOS
复制标题
抗癌剂 SU4312 通过选择性和直接抑制神经元 NOS 出人意料地防止 MPP 加诱导的神经毒性
DOI：
10.1111/bph.12004
复制
发表时间：
2013-03-01
影响因子：
7.3
通讯作者：
Han, Yifan
中科院分区：
文献类型：
--
作者：
Cui, Wei;Zhang, Zaijun;Han, Yifan
背景与目的SU 4312是一种有效的选择性血管内皮生长因子受体2（VEGFR-2）抑制剂，用于治疗肿瘤。最近的研究表明，SU 4312也可用于治疗神经退行性疾病。在这项研究中，我们评估了SU 4312对1-甲基-4-苯基吡啶离子（MPP+）诱导的神经毒性的神经保护作用，并进一步探讨了潜在的机制。实验方法用MPP+处理的神经元和1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）处理的斑马鱼研究SU 4312的神经保护作用。在体外测定NOS活性，以检查SU 4312和NOS亚型之间的直接相互作用。关键结果SU 4312出乎意料地阻止MPP+诱导的神经元凋亡在体外和减少MPTP诱导的多巴胺能神经元的损失，减少酪氨酸羟化酶的mRNA表达和斑马鱼游泳行为受损。相比之下，PTK 787/ZK 222584（一种经过充分研究的VEGFR-2抑制剂）未能预防神经毒性，表明SU 4312的神经保护作用与其抗血管生成作用无关。此外，SU 4312表现出非竞争性抑制纯化的神经元型NOS（nNOS）的IC 50值为19.0 M，但表现出很少或没有影响诱导型和内皮型NOS。分子对接模拟表明，SU 4312和血红素组的活性中心的nNOS之间的相互作用。结论与意义SU 4312对MPP+具有神经保护作用，其机制至少部分是通过选择性和直接抑制nNOS而实现的。由于SU 4312可以到达大鼠的大脑，我们的研究也为进一步开发SU 4312治疗神经退行性疾病，特别是与NO介导的神经毒性相关的疾病提供了支持。
Background and Purpose SU4312, a potent and selective inhibitor of VEGF receptor-2 (VEGFR-2), has been designed to treat cancer. Recent studies have suggested that SU4312 can also be useful in treating neurodegenerative disorders. In this study, we assessed neuroprotection by SU4312 against 1-methyl-4-phenylpyridinium ion (MPP+)-induced neurotoxicity and further explored the underlying mechanisms. Experimental Approach MPP+-treated neurons and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated zebrafish were used to study neuroprotection by SU4312. NOS activity was assayed in vitro to examine direct interactions between SU4312 and NOS isoforms. Key Results SU4312 unexpectedly prevented MPP+-induced neuronal apoptosis in vitro and decreased MPTP-induced loss of dopaminergic neurons, reduced expression of mRNA for tyrosine hydroxylase and impaired swimming behaviour in zebrafish. In contrast, PTK787/ZK222584, a well-studied VEGFR-2 inhibitor, failed to prevent neurotoxicity, suggesting that the neuroprotective actions of SU4312 were independent of its anti-angiogenic action. Furthermore, SU4312 exhibited non-competitive inhibition of purified neuronal NOS (nNOS) with an IC50 value of 19.0M but showed little or no effects on inducible and endothelial NOS. Molecular docking simulations suggested an interaction between SU4312 and the haem group within the active centre of nNOS. Conclusions and Implication SU4312 exhibited neuroprotection against MPP+ at least partly via selective and direct inhibition of nNOS. Because SU4312 could reach the brain in rats, our study also offered a support for further development of SU4312 to treat neurodegenerative disorders, particularly those associated with NO-mediated neurotoxicity.