PMID- 30593976 OWN - NLM STAT- MEDLINE DCOM- 20190401 LR - 20200309 IS - 2213-2317 (Electronic) IS - 2213-2317 (Linking) VI - 21 DP - 2019 Feb TI - Lactoferrin ameliorates dopaminergic neurodegeneration and motor deficits in MPTP-treated mice. PG - 101090 LID - S2213-2317(18)31208-4 [pii] LID - 10.1016/j.redox.2018.101090 [doi] LID - 101090 AB - 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 1alpha (HIF-1alpha) 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. CI - Copyright (c) 2018 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Xu, Shuang-Feng AU - Xu SF AD - College of Life and Health Sciences, Northeastern University, No.195, Chuangxin Road, Hunnan District, Shenyang 110169, China. FAU - Zhang, Yan-Hui AU - Zhang YH AD - College of Life and Health Sciences, Northeastern University, No.195, Chuangxin Road, Hunnan District, Shenyang 110169, China. FAU - Wang, Shan AU - Wang S AD - College of Life and Health Sciences, Northeastern University, No.195, Chuangxin Road, Hunnan District, Shenyang 110169, China. FAU - Pang, Zhong-Qiu AU - Pang ZQ AD - College of Life and Health Sciences, Northeastern University, No.195, Chuangxin Road, Hunnan District, Shenyang 110169, China. FAU - Fan, Yong-Gang AU - Fan YG AD - College of Life and Health Sciences, Northeastern University, No.195, Chuangxin Road, Hunnan District, Shenyang 110169, China. FAU - Li, Jia-Yi AU - Li JY AD - 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. FAU - Wang, Zhan-You AU - Wang ZY AD - 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. Electronic address: wangzy@mail.neu.edu.cn. FAU - Guo, Chuang AU - Guo C AD - College of Life and Health Sciences, Northeastern University, No.195, Chuangxin Road, Hunnan District, Shenyang 110169, China. Electronic address: guoc@mail.neu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181221 PL - Netherlands TA - Redox Biol JT - Redox biology JID - 101605639 RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Neuroprotective Agents) RN - 0 (Reactive Oxygen Species) RN - 9P21XSP91P (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) RN - E1UOL152H7 (Iron) RN - EC 3.4.21.- (Lactoferrin) SB - IM MH - 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/adverse effects MH - Animals MH - Apoptosis/drug effects MH - Behavior, Animal/drug effects MH - Cell Line MH - Disease Models, Animal MH - Dopaminergic Neurons/*drug effects/*metabolism/pathology MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism MH - Iron/metabolism MH - Lactoferrin/*pharmacology MH - MAP Kinase Signaling System MH - Male MH - Mice MH - Motor Disorders/drug therapy/etiology/metabolism/physiopathology MH - Neurodegenerative Diseases/drug therapy/etiology/metabolism/physiopathology MH - Neuroglia/drug effects/metabolism MH - Neuroprotective Agents/*pharmacology MH - Reactive Oxygen Species/metabolism PMC - PMC6307097 OTO - NOTNLM OT - Iron chelators OT - Lactoferrin OT - Motor dysfunction OT - Parkinson's disease EDAT- 2018/12/30 06:00 MHDA- 2019/04/02 06:00 PMCR- 2018/12/21 CRDT- 2018/12/30 06:00 PHST- 2018/12/10 00:00 [received] PHST- 2018/12/17 00:00 [revised] PHST- 2018/12/19 00:00 [accepted] PHST- 2018/12/30 06:00 [pubmed] PHST- 2019/04/02 06:00 [medline] PHST- 2018/12/30 06:00 [entrez] PHST- 2018/12/21 00:00 [pmc-release] AID - S2213-2317(18)31208-4 [pii] AID - 101090 [pii] AID - 10.1016/j.redox.2018.101090 [doi] PST - ppublish SO - Redox Biol. 2019 Feb;21:101090. doi: 10.1016/j.redox.2018.101090. Epub 2018 Dec 21.