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Mysregulation of iron in Parkinson’s disease and its relation to the dopaminergic cell death

Mysregulation of iron in Parkinson’s disease and its relati...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： hong jiang,jun-xia xie~* state key discipline:physiology(in incubation),department of physiology,qingdao university

＜正＞Objective Iron plays a key role in Parkinson’s disease（PD） and elevated iron levels in the substantia nigra（SN） participate in neuronal death in *** the mechanisms underlying the increased iron are still unknown,some iron transport proteins may be *** nigral iron accumulation could be a result of either increased import or decreased *** investigated the role of iron import transporter divalent metal transporter 1（DMT1） and iron export transporter ferroportinl（FP1） in PD *** Expression of DMT1 and FP1 was identified by immunohistochemisty and western *** transfection,small interferring RNA and calcein-induced iron uptake were used to determine the funtion of DMT1 and *** We first observed DMT1 with the iron responsive element（ERE,DMT1+IRE） but not DMT1 without IRE（DMT 1-IRE） was up-regulated and FP1 down-regulated in vivo in the SN of 6-hydroxydopamine（6-OHDA）- induced PD rats,suggesting increased DMT1+IRE and decreased FP1 expression might account for the nigral iron accumulation in PD *** was father confirmed by our in vitro study in 6-OHDA-treated MES23.5 *** iron regulatory protein（IRP） 1 and IRP2 expression were observed,while silencing of IRPs dramatically diminished 6-OHDA-induced DMT1+IRE up-regulation and FP1 *** with N-acetyl-L-cysteine could fully suppress IRPs up-regulations by inhibiting 6-OHDA-induced oxidative *** Our data gave the direct evidence that DMT1+IRE up-regulation and FP1 down-regulation accounted for 6-OHDA-induced iron accumulation in an IRE/IRP-dependent manner,which was initiated by 6-OHDA-induced intracellular oxidative *** intracellular iron thus resulted in aggravated oxidative *** anti-oxidants,such as Rg1 and curcumin,showed neuroprotective effects. This study might support the use of anti-oxidants in the treatment of PD from a quite new angle,which could inhibit iron accumulation by regulating DMT1 and FP1 e

关键词： iron Parkinson’s disease divalent metal transporter 1 ferroportin 1 iron responsive element anti-oxidants

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Ferroportinl but not hephaestin was involved in the 6-hydroxydopamine induced iron accumulation in MES23.5 dopaminergic cells

Ferroportinl but not hephaestin was involved in the 6-hydrox...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Ning SONG,jun WANG,hong jiang,jun-xia xie~* state key discipline:physiology(in incubation),department of physiology,qingdao university,qingdao,266071

＜正＞Objective Iron accumulation in the substantia nigra was thought to play an important role in the pathogenesis of Parkinson’s disease（PD）.Our in vivo experiments suggested that iron transporters ferroportinl（FP1） and hephaestin （HP） might account for the nigral iron accumulation in 6-hydroxydopamine（6-OHDA） lesioned PD *** present study is to explore the mechanisms underlying FP1 and HP mis-regulation in MES23.5 dopaminergic *** Realtime PCR and western blots were applied to detect FP1,HP,ferritin and iron regulatory protein（IRP） *** interfering RNA was applied for gene *** cytometry was applied to determine iron induced oxidative stress. Results Both FP1 and HP were down-regulated,followed by the decreased iron efflux in 6-OHDA treated MES23.5 cells. FP1 showed a dose-dependent up-regulation while HP showed no response in MES23.5 cells overloaded with ferric ammonium citrate,indicating that down-regulation of FP1 and HP was not due to the increased intracellular iron content. In 6-OHDA treated cells,both IRP1 and IRP2 were up-regulated,and silencing of IRPs in MES23.5 cells dramatically abolished 6-OHDA-induced FP1 down-regulation and even reversed HP *** of FP1 but not HP would lead to the intracellular iron accumulation in MES23.5 *** Down-regulations of both FP1 and HP by 6-OHDA were ***1 but not HP was involved in the 6-OHDA induced iron accumulation in MES23.5 cells.

关键词： ferroportinl hephaestin 6-hydroxydopamine iron Parkinson’s disease

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Protective effects of curcumin on 6-OHDA-induced Parkinson’s disease rat model

Protective effects of curcumin on 6-OHDA-induced Parkinson’...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Xi-Xun DU,jun WANG,hong jiang,jun-xia xie~* state key discipline:physiology(in incubation),department of physiology,qingdao university,qingdao 266071, China

＜正＞Objective Curcumin is a well-defined *** has a neuroprotective effect due to its free radical scavenging, iron-chelating and anti-inflammatory actions in different *** the mechanism of its protective effects on dopaminergic neurons is still not *** HPLC-ECD was used to determine the content of DA and its metabolites:3,4- dihydroxyphenylacetic acid（DOPAC）,homovanillic acid（HVA） in striatum（Str）.Immunohistochemistry assay was used to detect the numbers of dopaminergic ***’s iron-staining to detect the iron levels in substantia nigra（SN）.Results （1） After 6-OHDA lesions,the DA and its metabolite DOPAC contents in the Str decreased compared with that of control, while the HVA level was not *** the curcumin treatment group,the DA and its metabolites contents increased compared with that of 6-OHDA treatment group.（2） The number of tyrosine hydroxylase（TH） positive neurons in the SN decreased after 6-OHDA lesions compared with that of control *** significantly inhibited 6-OHDA-induced decrease of the numbers of TH positive neurons.（3） The number of iron-staining cells increased in the SN decreased after 6-OHDA lesions compared with that of control *** significantly inhibited 6-OHDA-induced increase of the numbers of iron-staining *** Curcumin could significantly reduce the toxic effects of 6-OHDA on dopaminergic neurons in rat SN via its iron-chelating property.

关键词： curcumin Parkinson’s disease 6-hydroxydopamine iron

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Ceruloplasmin is involved in the nigral iron accumulation of 6-OHDA lesioned rats

Ceruloplasmin is involved in the nigral iron accumulation of...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： jun WANG hong jiang jun-xia xie~* state key discipline:physiology(in incubation) department of physiology qingdao university qingdao 266071

＜正＞Objective Elevated iron levels in the substantia nigra participate in neuronal death in Parkinson’s disease（PD）. While the mechanisms underlying the increased iron are still ***（CP） is a ferroxidase that converts highly toxic ferrous iron to its non-toxic ferric form,which cooperated with ferroportinl（FP1） facilitating the export of iron from reticuloendothelial system and other peripheral *** previous study showed that decreased expression of FP1 in the substantia nigra can account for the increased iron *** elucidate if the abnormal expression of CP is also involved in the nigral iron accumulation,here,we investigated CP expression in the substantia nigra of rats lesioned by 6- hydroxydopamine（6-OHDA）.Methods Immunofluorescence,immunohistochemistry and RT-PCR were used to observe the expression of ***（1） Using immunofluorescence,we showed mat FP1 and CP colocalized in the rat substantia nigra.（2） By immunohistochemistry,we observed that one day after 6-OHDA lesion,the expression of CP decreased compared with the *** rats began showing rotation behavior induced by apomorphine,usually after six weeks since 6-OHDA lesion,they are considered PD *** these PD models,a further decrease was observed.（3） RT-PCR showed that the mRNA level of CP decreased one day after 6-OHDA lesion compared with the control,and further decrease was also observed in the PD model *** These results show that FP1 and CP colocalize in the rat brain,indicating the coordinated actions of the two proteins in the iron export from neural cells;and suggest that decreased expression of CP in the substantia nigra is involved in the nigral iron accumulation of 6-OHDA lesioned rats.

关键词： 6-hydroxydopamine Ceruloplasmin iron Parkinson’s disease

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Ghrelin protects MES23.5 cells against 1-Methyl-4-phenylpyridinium ioninduced cytotoxicity

Ghrelin protects MES23.5 cells against 1-Methyl-4-phenylpyri...

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中国神经科学学会第四次会员代表大会暨第八届全国学术会议

作者： Li LIU,Hua-Min XU,hong jiang,jun WANG,Ning SONG,jun-xia xie~* state key disciplines:physiology(in incubation),department of physiology,qingdao university,qingdao 266071

Objective 1-Methyl-4-phenylpyridinium ion(MPP) has been widely used as a cellular model of Parkinson’s disease(PD),because it can elevate intracellular reactive oxygen species level and apoptotic death,eliciting a severe PD- like ***,a 28-amino acid peptide,is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R).Our previous data showed that ghrelin could protect dopaminergic neurons against 1 -methyl-4-phenyl-1,2,3,6- tetrahydropyridine(MPTP)-induced neurotoxicity in *** the present study,MPP-treated MES23.5 cells which could express GHS-R were used to further explore the underlying molecular mechanisms of this protective *** The MDA level was measured by MDA Assay ***-PCR and western-blots were adopted to detect the changes of catalase, SOD1,caspase-3 protein expression,and Bax/Bcl-2 ***(1) Ghrelin could suppress MPPMnduced lipid peroxidation in MES23.5 cells.(2) Ghrelin promoted the expression of endogenous antioxidant defense components including CAT and SOD 1.(3) Ghrelin could attenuate MPP-induced up-regulation of Bax/Bcl-2 ratio and the activation of *** Our results suggest that the protective effects of ghrelin on MPP-induced cytotoxicity may be ascribed to its anti-oxidative properties,anti-apoptotic activity via inducing expression of SOD1 and catalase,and regulation of Bcl-2 and Bax expression.

关键词： oxidative stress Parkinson’s disease ghrelin MPP+

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Nifedipine reduces iron overload-induced dopamine neuron degeneration by inhibition of iron accumulation in the substantia nigra of rats

Nifedipine reduces iron overload-induced dopamine neuron deg...

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中国生理学会第23届全国会员代表大会暨生理学学术大会

作者： Ze-Gang MA,hong jiang,jun-xia xie~* department of physiology,Shandong Provincial key Laboratory of Pathogenesis and Prevention of Neurological Disorders and state key disciplines:physiology,Medical College of qingdao university,qingdao,266071

＜正＞The effects of nifedipine on iron overload-induced neurodegeneration in the substantia nigra（SN）-striatum system were *** high performance liquid chromatography-electrochemical detection（HPLC-ECD）,tyrosine hydroxylase（TH） immunohistochemistry and inductive coupled plasma emission spectrometer detection,we measured the dopamine neuron degeneration and iron content in the SN of rats overloaded with iron dextran,and assessed the effects of treatment with *** results showed that the dopamine content in the striatum decreased after iron dextran treatment,which could be restored by *** dextran overload increased iron content in the SN and reduced the numbers of TH-positive *** with nifedipine prevented the increase of iron content and restored the numbers of TH-positive neurons to control *** results suggested that the protective effects of nifedipine on the toxicity of iron-overload could be attributed to the nifedipine-suppressed iron toxicity.

关键词： Nifedipine Iron Dopamine neuron

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The effects of intranigral injection of ghrelin on haloperidol- induced catalepsy in rats

The effects of intranigral injection of ghrelin on haloperid...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Li-Min SHI,hong jiang,jun-xia xie~* department of physiology,Shandong Provincial key Laboratory of Pathogenesis and Prevention of Neurological Disorders and state key disciplines:physiology,Medical College of qingdao university,qingdao 266071,China

＜正＞Objective Ghrelin,a natural ligand for the growth hormone secretagogue receptor la（GHS-Rla）, is mainly secreted from stomach with small amounts produced in the *** expression of GHS-Rla in the dopaminergic neurons of substantia nigra（SN）indicates that SN might be a target site of *** previously reported that ghrelin could protect dopaminergic neurons through GHS-Rla against neurotoxicity by inhibiting apoptosis,attenuating oxidative stress and enhancing the cell ***,the role of ghrelin in motor coordination is largely *** present study aims to explore the effects of intranigral injection of ghrelin on haloperidol-induced catalepsy in *** Cannula-embedding technique,intranigral injection,postural and bar test were ***（1）Unilateral microinjection of ghrelin（1000 nmol/L）into the SN induced a contralateral dystonic posturing in the haloperidol-induced catalepsy *** the control group,saline injection into the SN did not cause any fixed deviated posturing in the haloperidol-induced catalepsy rats.（2）Microinjection of 1000 nmol/L ghrelin into the SN was able to attenuate the descent latency in the presence of systemic haloperidol administration. Conclusion Ghrelin is capable of attenuating haloperidol-induced catalepsy and regulating the motor function of SN.

关键词： ghrelin substantia nigra dopaminergic neuron haloperidol catalepsy

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Up-regulation of DMTl+IRE and down-regulation of FPl are involved in 6-hydroxydopamine-induced neurotoxicity

Up-regulation of DMTl+IRE and down-regulation of FPl are inv...

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第十七届国际生物物理大会;第十二届中国生物物理大会

作者： hong jiang 1.department of physiology,Shandong Provincial key Laboratory of Pathogenesis and Prevention of Neurological Disorders and state key disciplines:physiology,Medical College of qingdao university, qingdao,266071,China

Iron plays a key role in Parkinson's disease(PD) and elevated iron levels in the substantia nigra(SN) participate in neuronal death in *** the mechanisms underlying the increased iron are still *** investigated the role of iron import transporter divalent metal transporter 1(DMTl) and iron export transporter ferroportinl(FP1) in PD *** observed DMT1+IRE but not DMT1-IRE up-regulated and FP1

关键词： IRE Up-regulation of DMTl+IRE and down-regulation of FPl are involved in 6-hydroxydopamine-induced neurotoxicity

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Iron transporters mis-regulation contributes to the nigral iron accumulation in Parkinson's disease

Iron transporters mis-regulation contributes to the nigral i...

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中国生理学会第十一届张锡钧基金全国青年优秀生理学学术论文交流及评奖会议

作者： Ning Song,hong jiang,jun Wang,junxia xie (department of physiology,Shandong Provincial key Laboratory of Pathogenesis and Prevention of Neurological Disorders and state key disciplines:physiology,Medical College of qingdao university, qingdao,266071)

Iron plays a key role in Parkinson’s disease(PD).The reasons underlying the high iron content found in the substantia nigra(SN) of PD are largely *** observed in the SN of 6-hydroxydopamine(6-OHDA)-induced PD rats,ferroportinl(FPN1) and hephaestin(HP) were down-regulated,and divalent metal transporter 1 with the iron responsive element(IRE,DMT1+IRE) was up-regulated,suggesting these iron transporters misregulation might account for nigral iron

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Alpha-synuclein aggregation is involved in the iron toxicity to SK-N-SH neuroblastoma cells

Alpha-synuclein aggregation is involved in the iron toxicity...

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中国生理学会第23届全国会员代表大会暨生理学学术大会

作者： hong jiang~*,Qing HE,Wen-Jing LI,Ning SONG,jun-xia xie~* department of physiology,Shandong Provincial key Laboratory of Pathogenesis and Prevention of Neurological Disorders and state key disciplines:physiology,Medical College of qingdao university,qingdao 266071,China

＜正＞Increased nigral iron levels and intracytoplasmic Lewy bodies（LBs） in the degenerating neurons are found in Parkinson’s disease（PD）.Whether LBs formation is involved in the toxicity of iron is largely *** the present study,the enhanced toxicity of alpha-synuclein aggregates was confirmed in cells with ferrous iron treatment and conversely,alpha-synuclein knockdown could exert protective effects against ferrous iron induced cell *** showed a novel study that down-regulation of nuclear factor E2-related factor 2（Nrf2） and heme oxygenase-1（HO-1） might contribute to iron-induced alpha-synuclein aggregation in SK-N-SH neuroblastoma *** iron induced time-course regulation of Nrf2 and *** high ferrous iron conditions,alpha-synuclein over-expression led to more greatly down-regulation of Nrf2 and HO-1 levels,accompanied by more alpha-synuclein aggragates,while alpha-synuclein knockdown brought Nrf2 and HO-1 to the basal levels in cells with almost none alpha-synuclein *** further demonstrated that increased HO-1 expression could promote alpha-synuclein mRNA *** also showed that the predicated iron responsive element（IRE） in the 5’-UTR of alpha-synuclein is a functional *** is probably important for the post-transcriptional regulation of *** these together,our results provide a novel pathway that ferrous iron induces alpha-synuclein aggregation and exerts neurotoxicity by inhibiting Nrf2/ HO-1 and IRP-IRE binding,proposing a vicious cycle of iron accumulation,alpha-synuclein aggregation and HO-1 disturbance in PD.

关键词： Parkinson’s disease Lewy body alpha-synuclein iron iron responsive element

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