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Lactoferrin ameliorates dopaminergic neurodegeneration and motor deficits in MPTP-treated mice

Xu, Shuang Feng; Zhang, Yan Hui; Wang, Shan; Pang, Zhong Qiu; Fan, Yong Gang; Li, Jia Yi LU ; Wang, Zhan You and Guo, Chuang (2019) In Redox Biology 21.
Abstract

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,... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Iron chelators, Lactoferrin, Motor dysfunction, Parkinson's disease
in
Redox Biology
volume
21
publisher
Elsevier
external identifiers
  • scopus:85059039459
ISSN
2213-2317
DOI
10.1016/j.redox.2018.101090
language
English
LU publication?
yes
id
2087bce3-b769-4ef1-9b77-eb2b0f76bb97
date added to LUP
2019-01-02 13:03:04
date last changed
2019-02-20 11:41:14
@article{2087bce3-b769-4ef1-9b77-eb2b0f76bb97,
  abstract     = {<p>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.</p>},
  articleno    = {101090},
  author       = {Xu, Shuang Feng and Zhang, Yan Hui and Wang, Shan and Pang, Zhong Qiu and Fan, Yong Gang and Li, Jia Yi and Wang, Zhan You and Guo, Chuang},
  issn         = {2213-2317},
  keyword      = {Iron chelators,Lactoferrin,Motor dysfunction,Parkinson's disease},
  language     = {eng},
  month        = {02},
  publisher    = {Elsevier},
  series       = {Redox Biology},
  title        = {Lactoferrin ameliorates dopaminergic neurodegeneration and motor deficits in MPTP-treated mice},
  url          = {http://dx.doi.org/10.1016/j.redox.2018.101090},
  volume       = {21},
  year         = {2019},
}