College of Life and Health Sciences, Northeastern University, No.195, Chuangxin Road, Hunnan District, Shenyang 110169, China.
College of Life and Health Sciences, Northeastern University, No.195, Chuangxin Road, Hunnan District, Shenyang 110169, China; Institute of Health Sciences, Key Laboratory of Medical Cell Biology of Ministry of Education, China Medical University, Shenyang 110122, China; Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, BMC A10, 22184 Lund, Sweden.
Redox Biol. 2019 Feb;21:101090. doi: 10.1016/j.redox.2018.101090. Epub 2018 Dec 21.
Brain iron accumulation is common in patients with Parkinson's disease (PD). Iron chelators have been investigated for their ability to prevent neurodegenerative diseases with features of iron overload. Given the non-trivial side effects of classical iron chelators, lactoferrin (Lf), a multifunctional iron-binding globular glycoprotein, was screened to identify novel neuroprotective pathways against dopaminergic neuronal impairment. We found that Lf substantially ameliorated PD-like motor dysfunction in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. We further showed that Lf could alleviate MPTP-triggered apoptosis of DA neurons, neuroinflammation, and histological alterations. As expected, we also found that Lf suppressed MPTP-induced excessive iron accumulation and the upregulation of divalent metal transporter (DMT1) and transferrin receptor (TFR), which is the main intracellular iron regulation protein, and subsequently improved the activity of several antioxidant enzymes. We probed further and determined that the neuroprotection provided by Lf was involved in the upregulated levels of brain-derived neurotrophic factor (BDNF), hypoxia-inducible factor 1α (HIF-1α) and its downstream protein, accompanied by the activation of extracellular regulated protein kinases (ERK) and cAMP response element binding protein (CREB), as well as decreased phosphorylation of c-Jun N-terminal kinase (JNK) and mitogen activated protein kinase (MAPK)/P38 kinase in vitro and in vivo. Our findings suggest that Lf may be an alternative safe drug in ameliorating MPTP-induced brain abnormalities and movement disorder.
脑铁积累在帕金森病（PD）患者中很常见。铁螯合剂已被研究用于预防具有铁过载特征的神经退行性疾病。鉴于经典铁螯合剂的非微不足道的副作用，乳铁蛋白（Lf），一种多功能的铁结合球蛋白，被筛选以鉴定针对多巴胺能神经元损伤的新的神经保护途径。我们发现 Lf 可显著改善亚急性 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠模型中的 PD 样运动功能障碍。我们进一步表明，Lf 可以减轻 MPTP 引发的 DA 神经元凋亡、神经炎症和组织学改变。正如预期的那样，我们还发现 Lf 抑制了 MPTP 诱导的过度铁积累以及二价金属转运蛋白（DMT1）和转铁蛋白受体（TFR）的上调，TFR 是主要的细胞内铁调节蛋白，随后改善了几种抗氧化酶的活性。我们进一步研究确定，Lf 提供的神经保护作用涉及脑源性神经营养因子（BDNF）、缺氧诱导因子 1α（HIF-1α）及其下游蛋白水平的上调，伴随着细胞外调节蛋白激酶（ERK）和 cAMP 反应元件结合蛋白（CREB）的激活，以及 c-Jun N 末端激酶（JNK）和丝裂原激活蛋白激酶（MAPK）/P38 激酶的磷酸化减少在体外和体内。我们的研究结果表明，Lf 可能是一种改善 MPTP 诱导的大脑异常和运动障碍的替代安全药物。
