Department of Neurology, Affiliated Hospital of Xiangnan University, Chenzhou, China.
Department of Cardiovascular, Chenzhou NO.1 People's Hospital, Chenzhou, China.
Cell Biochem Funct. 2020 Dec;38(8):1025-1035. doi: 10.1002/cbf.3534. Epub 2020 May 31.
Parkinson's disease (PD) is a neurodegenerative disease which results in damage in neuronal cells. Insulin-like growth factor (IGF)-1 was previously reported to play a role of neuroprotection in some diseases. Nitric oxide (NO) can also regulate neuronal cells. However, the mechanisms underlying IGF-1 and NO in PD still need to be elucidated. In present study, we explored the interaction between IGF-1 and inducible Nitric-Oxide Synthase (iNOS) in PD progression. We firstly constructed PD models by methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or MPP treatment. Then RT-qPCR revealed that IGF-1 expression was downregulated while iNOS expression was upregulated in MPTP model. Moreover, IGF-1 elevation or iNOS depletion enhanced cell viability and blocked cell apoptosis. Rescue assay disclosed iNOS overexpression reversed the effect on viability and apoptosis mediated by IGF-1 upregulation. Furthermore, IGF-1 was identified to positively regulate miR-302b-5p which could target iNOS. MiR-302b-5p could abolish the inhibitory function IGF-1 exerted on cell apoptosis and iNOS could counteract miR-302b-5p upregulation-triggered inhibition on cell apoptosis as well. Besides, we observed the deficiency of miR-302b-5p improved the lesioned neurobehavior of MPTP-treated mice. To sum up, present study proved that miR-302b-5p enhanced the neuroprotective effect of IGF-1 in MPTP-induced PD by regulating iNOS, recommending a novel therapeutic target for PD treatment. SIGNIFICANCE OF THE STUDY: In this study, we mainly explored that IGF-1 was decreased while iNOS was boosted in MPTP-induced PD mice model; IGF-1 suppressed while iNOS promoted MPP -induced toxicity and apoptosis in SH-SY5Y cells; miR-302b-5p ehanhced the neuroprotective effect of IGF-1 via targeting Inos; deficiency of miR-302b-5p improved the lesioned neurobehavior of MPTP-treated mice.
帕金森病（PD）是一种神经退行性疾病，导致神经元细胞损伤。胰岛素样生长因子（IGF）-1 先前被报道在某些疾病中发挥神经保护作用。一氧化氮（NO）也可以调节神经元细胞。然而，IGF-1 和 NO 在 PD 中的作用机制仍需阐明。在本研究中，我们探讨了 IGF-1 和诱导型一氧化氮合酶（iNOS）在 PD 进展中的相互作用。我们首先通过甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）或 MPP 处理构建 PD 模型。然后 RT-qPCR 显示，MPTP 模型中 IGF-1 表达下调，iNOS 表达上调。此外，IGF-1 升高或 iNOS 耗竭增强细胞活力并阻断细胞凋亡。挽救实验显示，iNOS 过表达逆转了 IGF-1 上调介导的细胞活力和凋亡的影响。此外，IGF-1 被鉴定为正向调节 miR-302b-5p，其可以靶向 iNOS。miR-302b-5p 可以消除 IGF-1 对细胞凋亡的抑制作用，而 iNOS 可以抵消 miR-302b-5p 上调触发的细胞凋亡抑制作用。此外，我们观察到 miR-302b-5p 的缺乏改善了 MPTP 处理小鼠的神经行为损伤。总之，本研究证明 miR-302b-5p 通过调节 iNOS 增强了 IGF-1 在 MPTP 诱导的 PD 中的神经保护作用，为 PD 治疗提供了新的治疗靶点。
这项研究的意义在于，我们主要探索了在 MPTP 诱导的 PD 小鼠模型中，IGF-1 减少而 iNOS 增加；IGF-1 抑制而 iNOS 促进 MPP 诱导的 SH-SY5Y 细胞毒性和凋亡；miR-302b-5p 通过靶向 Inos 增强 IGF-1 的神经保护作用；miR-302b-5p 的缺乏改善了 MPTP 处理小鼠的神经行为损伤。
