title: Deferoxamine-mediated up-regulation of HIF-1α prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice.
abstract: Accumulating evidence suggests that an abnormal accumulation of iron in the substantia nigra (SN) is one of the defining characteristics of Parkinson's disease (PD). Accordingly, the potential neuroprotection of Fe chelators is widely acknowledged for the treatment of PD. Although desferrioxamine (DFO), an iron chelator widely used in clinical settings, has been reported to improve motor deficits and dopaminergic neuronal survival in animal models of PD, DFO has poor penetration to cross the blood-brain barrier and elicits side effects. We evaluated whether an intranasal administration of DFO improves the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of dopaminergic neurons in the nigrostriatal axis and investigated the molecular mechanisms of intranasal DFO treatment in preventing MPTP-induced neurodegeneration. Treatment with DFO efficiently alleviated behavioral deficits, increased the survival of tyrosine hydroxylase (TH)-positive neurons, and decreased the action of astrocytes in the SN and striatum in an MPTP-induced PD mouse model. Interestingly, we found that DFO up-regulated the expression of HIF-1α protein, TH, vascular endothelial growth factor (VEGF), and growth associated protein 43 (GAP43) and down-regulated the expression of α-synuclein, divalent metal transporter with iron-responsive element (DMT1+IRE), and transferrin receptor (TFR). This was accompanied by a decrease in iron-positive cells in the SN and striatum of the DFO-treated group. We further revealed that DFO treatment significantly inhibited the MPTP-induced phosphorylation of the c-Jun N-terminal kinase (JNK) and differentially enhanced the phosphorylation of extracellular regulated protein kinases (ERK) and mitogen-activated protein kinase (MAPK)/P38 kinase. Additionally, the effects of DFO on increasing the Bcl-2/Bax ratio were further validated in vitro and in vivo. In SH-SY5Y cells, the DFO-mediated up-regulation of HIF-1α occurred via the activation of the ERK and P38MAPK signaling pathway. Collectively, the present data suggest that intranasal DFO treatment is effective in reversing MPTP-induced brain abnormalities and that HIF-1-pathway activation is a potential therapy target for the attenuation of neurodegeneration.
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
authors.forename: Chuang
authors.initials: C
authors.lastname: Guo
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Hao
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Yang
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chai
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Gao
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
authors.forename: Man-Li
authors.initials: ML
authors.lastname: Zhong
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. Electronic address: jiayili@mail.neu.edu.cn.
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Li
authors.affiliation: Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. Electronic address: wangzy@mail.neu.edu.cn.
authors.forename: Zhan-You
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects*; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020267:MPTP Poisoning / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D014446:Tyrosine 3-Monooxygenase; D020929:Mitogen-Activated Protein Kinase Kinases; D003676:Deferoxamine
keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Deferoxamine; Hypoxia inducible factor; Iron; Parkinson's disease; Tyrosine hydroxylase