Feng Chien-Wei, Chen Nan-Fu, Chan Te-Fu, Chen Wu-Fu
Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan.
Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807377, Taiwan.
Parkinsons Dis. 2020 Dec 29;2020:8814236. doi: 10.1155/2020/8814236. eCollection 2020.
Parkinson's disease (PD) is one of the most widespread neurodegenerative diseases. However, the currently available treatments could only relieve symptoms. Novel therapeutic targets are urgently needed. Several previous studies mentioned that protein tyrosine phosphatase 1B (PTP1B) acted as a negative regulator of the insulin signal pathway and played a significant role in the inflammation process. However, few studies have investigated the role of PTP1B in the central nervous system. Our study showed that suramin, an inhibitor of PTP1B, could improve neuronal damage. It could significantly attenuate the interferon-gamma-induced upregulation of proinflammatory cytokines, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B). It enhanced M2 type microglia markers, such as arginase-1 and Ym-1 in BV2 murine microglial cells. PTP1B inhibition also reversed 6-hydroxydopamine- (6-OHDA-) induced downregulation of phospho-cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) in SH-SY5Y cells. Besides, we knocked down and overexpressed PTP1B in the SH-SY5Y cells to confirm its role in neuroprotection. We also verified the effect of suramin in the zebrafish PD model. Treatment with suramin could significantly reverse 6-OHDA-induced locomotor deficits and improved tyrosine hydroxylase (TH) via attenuating endoplasmic reticulum (ER) stress biomarkers. These results support that PTP1B could potentially regulate PD via antineuroinflammation and antiapoptotic pathways.
帕金森病（PD）是最常见的神经退行性疾病之一。然而，目前可用的治疗方法只能缓解症状。迫切需要新的治疗靶点。先前的几项研究提到，蛋白酪氨酸磷酸酶1B（PTP1B）作为胰岛素信号通路的负调节因子，在炎症过程中发挥重要作用。然而，很少有研究调查PTP1B在中枢神经系统中的作用。我们的研究表明，PTP1B抑制剂苏拉明可以改善神经元损伤。它可以显著减弱干扰素-γ诱导的促炎细胞因子的上调，包括诱导型一氧化氮合酶（iNOS）、环氧化酶-2（COX-2）和活化B细胞核因子κB（NF-κB）。它增强了BV2小鼠小胶质细胞中M2型小胶质细胞标志物，如精氨酸酶-1和Ym-1。抑制PTP1B还可逆转6-羟基多巴胺（6-OHDA）诱导的SH-SY5Y细胞中磷酸化环磷酸腺苷反应元件结合蛋白（p-CREB）和脑源性神经营养因子（BDNF）的下调。此外，我们在SH-SY5Y细胞中敲低和过表达PTP1B以确认其在神经保护中的作用。我们还验证了苏拉明在斑马鱼PD模型中的作用。苏拉明治疗可通过减弱内质网（ER）应激生物标志物显著逆转6-OHDA诱导的运动缺陷并改善酪氨酸羟化酶（TH）。这些结果支持PTP1B可能通过抗神经炎症和抗凋亡途径潜在地调节PD。
