PMID- 26996132 OWN - NLM STAT- MEDLINE DCOM- 20170428 LR - 20180218 IS - 1090-2430 (Electronic) IS - 0014-4886 (Linking) VI - 280 DP - 2016 Jun TI - Deferoxamine-mediated up-regulation of HIF-1alpha prevents dopaminergic neuronal death via the activation of MAPK family proteins in MPTP-treated mice. PG - 13-23 LID - S0014-4886(16)30059-0 [pii] LID - 10.1016/j.expneurol.2016.03.016 [doi] AB - 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-1alpha protein, TH, vascular endothelial growth factor (VEGF), and growth associated protein 43 (GAP43) and down-regulated the expression of alpha-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-1alpha 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. CI - Copyright (c) 2016 Elsevier Inc. All rights reserved. FAU - Guo, Chuang AU - Guo C AD - Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. FAU - Hao, Li-Juan AU - Hao LJ AD - Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. FAU - Yang, Zhao-Hui AU - Yang ZH AD - Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. FAU - Chai, Rui AU - Chai R AD - Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. FAU - Zhang, Shuai AU - Zhang S AD - Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. FAU - Gu, Yu AU - Gu Y AD - Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. FAU - Gao, Hui-Ling AU - Gao HL AD - Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. FAU - Zhong, Man-Li AU - Zhong ML AD - Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. FAU - Wang, Tao AU - Wang T AD - Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. FAU - Li, Jia-Yi AU - Li JY AD - Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. Electronic address: jiayili@mail.neu.edu.cn. FAU - Wang, Zhan-You AU - Wang ZY AD - Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China. Electronic address: wangzy@mail.neu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160318 PL - United States TA - Exp Neurol JT - Experimental neurology JID - 0370712 RN - 0 (Hif1a protein, mouse) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (bcl-2-Associated X Protein) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - J06Y7MXW4D (Deferoxamine) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Cell Death/drug effects MH - Cell Line, Tumor MH - Deferoxamine/*pharmacology/therapeutic use MH - Disease Models, Animal MH - Dopaminergic Neurons/*drug effects MH - Exploratory Behavior/drug effects MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism MH - MPTP Poisoning/chemically induced/drug therapy/*physiopathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mitogen-Activated Protein Kinase Kinases/*metabolism MH - Neuroblastoma/pathology MH - Proto-Oncogene Proteins c-bcl-2/metabolism MH - Signal Transduction/drug effects MH - Time Factors MH - Tyrosine 3-Monooxygenase/metabolism MH - Up-Regulation/*drug effects MH - bcl-2-Associated X Protein/metabolism OTO - NOTNLM OT - 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine OT - Deferoxamine OT - Hypoxia inducible factor OT - Iron OT - Parkinson's disease OT - Tyrosine hydroxylase EDAT- 2016/03/22 06:00 MHDA- 2017/04/30 06:00 CRDT- 2016/03/22 06:00 PHST- 2015/10/15 00:00 [received] PHST- 2016/01/26 00:00 [revised] PHST- 2016/03/15 00:00 [accepted] PHST- 2016/03/22 06:00 [entrez] PHST- 2016/03/22 06:00 [pubmed] PHST- 2017/04/30 06:00 [medline] AID - S0014-4886(16)30059-0 [pii] AID - 10.1016/j.expneurol.2016.03.016 [doi] PST - ppublish SO - Exp Neurol. 2016 Jun;280:13-23. doi: 10.1016/j.expneurol.2016.03.016. Epub 2016 Mar 18.