Over-expressed human divalent metal transporter 1 is involved in iron accumulation in MES23.5 cells

Xu, Huamin; Jiang, Hong; Wang, Jun; Luo, Bing; Xie, Junxia

doi:10.1016/j.neuint.2007.10.019

Cited by 29 publications

(19 citation statements)

References 48 publications

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“…Similar to previous studies, divalent metal transporter-1 was observed to be up-regulated by MPTP (59) and this increase was sustained even in the presence of DHB (data not shown). Recent studies suggest that overexpression of divalent metal transporter-1 alone is associated with intracellular iron accumulation (60) and MPTP-induced apoptosis (61), however, these detrimental effects appear to be overridden by other HIF-related events in our system.…”

Section: Discussionmentioning

confidence: 92%

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Lee

Rajagopalan

Siddiq

et al. 2009

Journal of Biological Chemistry

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Hypoxia-inducible factor (HIF) plays an important role in cell survival by regulating iron, antioxidant defense, and mitochondrial function. Pharmacological inhibitors of the iron-dependent enzyme class prolyl hydroxylases (PHD), which target ␣ subunits of HIF proteins for degradation, have recently been demonstrated to alleviate neurodegeneration associated with stroke and hypoxic-ischemic injuries. Here we report that inhibition of PHD by 3,4-dihydroxybenzoate (DHB) protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic cell loss and up-regulates HIF-1␣ within these neurons. Elevations in mRNA and protein levels of HIF-dependent genes heme oxygenase-1 (Ho-1) and manganese superoxide dismutase (Mnsod) following DHB pretreatment alone are also maintained in the presence of MPTP. MPTP-induced reductions in ferroportin and elevations in nigral and striatal iron levels were reverted to levels comparable with that of untreated controls with DHB pretreatment. Reductions in pyruvate dehydrogenase mRNA and activity resulting from MPTP were also found to be attenuated by DHB. In vitro, the HIF pathway was activated in N27 cells grown at 3% oxygen treated with either PHD inhibitors or an iron chelator. Concordant with our in vivo data, the MPP ؉ -elicited increase in total iron as well as decreases in cell viability were attenuated in the presence of DHB. Taken together, these data suggest that protection against MPTP neurotoxicity may be mediated by alterations in iron homeostasis and defense against oxidative stress and mitochondrial dysfunction brought about by cellular HIF-1␣ induction. This study provides novel data extending the possible therapeutic utility of HIF induction to a Parkinson disease model of neurodegeneration, which may prove beneficial not only in this disorder itself but also in other diseases associated with metal-induced oxidative stress.Parkinson disease (PD) 2 is a neurodegenerative disorder primarily associated with loss of dopaminergic (DAergic) neurons of the pars compacta region of the substantia nigra (SNpc). Dopaminergic neurons are particularly prone to oxidative damage due to high levels of inherent reactive oxygen species that are produced during dopamine synthesis or its breakdown by monoamine oxidases or autoxidation to quinones (1-3). Importantly, iron bound to neuromelanin within DAergic neurons can subsequently react with metabolically liberated hydrogen peroxide through the Fenton reaction to produce extremely toxic hydroxyl radicals. If not properly buffered, hydroxyl radicals can stimulate protein oxidation and lipid peroxidation, which is thought to contribute to macromolecular injury and neuronal death. Iron is the most abundant metal in the brain and some degree of accessible reactive iron is necessary for brain viability as it serves as a cofactor in DNA, RNA, and protein synthesis and for heme and non-heme enzymes involved in both mitochondrial respiration and neurotransmitter synthesis (4). Although iron deficiencies early in life ...

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Section: Discussionmentioning

confidence: 92%

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Lee

Rajagopalan

Siddiq

et al. 2009

Journal of Biological Chemistry

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“…Cell Culture MES23.5 cells were offered by Dr. Wei-dong Le (Baylor College of Medicine, TX, USA) and cultured as previously described (Xu et al 2008;Zhang et al 2008). For experiments, cells were seeded at a density of 1×10 5 per square centimeter in the plastic flasks or plates.…”

Section: Methodsmentioning

confidence: 99%

“…Nuclear morphological changes were detected using the method described before (Xu et al 2008;Zhang et al 2008). MES23.5 cells were seeded on sterile cover glasses placed in a six-well plate at a density of 1.0×10 4 cells per square centimeter.…”

Section: Hoechst 33258 Stainingmentioning

confidence: 99%

Ghrelin Antagonized 1-Methyl-4-Phenylpyridinium (MPP+)-Induced Apoptosis in MES23.5 Cells

et al. 2008

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Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) acting to stimulate growth hormone release. In the previous study, we have observed the neuroprotective effects of ghrelin on dopaminergic neurons in vivo in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine -treated Parkinson's disease mice. In order to illustrate the underlying mechanisms, in the present study, we conducted our experiment in vitro in 1-methyl-4-phenylpyridinium (MPP(+))-treated MES23.5 cells that could express GHS-R1a. Ten- to 1,000-micromol/L MPP(+) treatment caused decreased cell viability, with increased lactate dehydrogenase leakage. A 200-micromol/L MPP(+) treatment was chosen to do the further experiments. MES23.5 cells treated with 200 micromol/L MPP(+) showed decreased mitochondrial transmembrane potential, an elevated level of reactive oxidative species production and activation of caspase-3. Additionally, these cells also showed apoptotic morphological changes. Pretreatment with different doses of ghrelin (10(-12)-10(-7) mol/L) could abolish the MPP(+)-induced apoptotic changes in a dose-dependent manner. These results suggested that ghrelin could antagonize MPP(+)-induced apoptosis in MES23.5 cells. The protective effects of ghrelin involved the restoration of mitochondria function.

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“…Nuclear morphology was detected using the method previously described from our laboratory (Xu et al, 2008;Zhang et al, 2008). MES23.5 cells were seeded on glass coverslips in 24-well plates and incubated with zinc as described above for 1, 2, 4, 8, 16, and 24 hr.…”

Section: Hoechst 33258 Stainingmentioning

confidence: 99%

Potassium channels are involved in zinc‐induced apoptosis in MES23.5 cells

Shi

Song

Jiang

et al. 2008

J of Neuroscience Research

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There is evidence that zinc may be involved in the pathogenesis of Parkinson's disease by an apoptotic pathway. However, the mechanisms underlying zinc-induced apoptosis are unknown. Previous studies showed that 6-hydroxydopamine (6-OHDA)-enhanced potassium channels are involved in apoptosis of dopaminergic neurons. Our study was designed to test whether zinc-induced apoptosis was mediated by potassium channels. First we demonstrated cell apoptosis with zinc treatment by Hoechst staining assay. The results showed that 13.38% +/- 0.6% of MES23.5 cells were apoptotic after 24 hr of incubation with 60 microM zinc sulfate. Then we observed that the tyrosine hydroxylase (TH) protein expression and the dopamine content decreased, as detected by Western blots and high-performance liquid chromatography-electrochemical detection (HPLC-ECD). We further elucidated the mechanism of cell apoptosis by using whole-cell patch clamp recording. The data demonstrated that MES23.5 cells exhibited a tetraethylammonium (TEA)-sensitive outward K(+) current with delayed rectifier characteristics. Increases of K(+) current density were recorded following the treatment with 60 microM zinc for 4-8 hr. After incubation with 20 mM TEA, the zinc-induced enhancement of K(+) currents was fully blocked. Furthermore, incubation with TEA blocked zinc-mediated caspase-3 activation and cell apoptosis. These data suggest that zinc-induced apoptosis of MES23.5 dopaminergic cells may due to the enhancement of TEA-sensitive K(+) channel activity.

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Over-expressed human divalent metal transporter 1 is involved in iron accumulation in MES23.5 cells

Cited by 29 publications

References 48 publications

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Ghrelin Antagonized 1-Methyl-4-Phenylpyridinium (MPP+)-Induced Apoptosis in MES23.5 Cells

Potassium channels are involved in zinc‐induced apoptosis in MES23.5 cells

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