Altered regulation of iron transport and storage in Parkinson's disease

Parkinson's disease (PD) is characterized by the death of dopaminergic neurons in the substantia nigra. This neuronal degeneration is associated with a strong microglial activation and iron accumulation in the affected brain structures. The increased iron content may result from an increased iron penetration into the brain parenchyma due to a higher expression of lactoferrin and lactoferrin receptors at the level of the blood vessels and dopaminergic neurons in the substantia nigra in PD. Iron may also accumulate in microglial cells after phagocytosis of dopaminergic neurons. These effects may be reinforced by a lack of up-regulation of the iron storage protein ferritin, as suggested by an absence of change in iron regulatory protein 1 (IRP-1) control of ferritin mRNA translation in PD. Thus, a dysregulation of the labile iron pool may participate in the degenerative process affecting dopaminergic neurons in PD.     

Iron induces degeneration of nigrostriatal neurons.

Parkinson's-diseased (PD) brains have been reported to contain increased quantities of iron within the zona compacta of the substantia nigra (SN). To test whether excess iron in the SN could cause a PD-like loss of dopaminergic neurons, various concentrations of iron were infused unilaterally within the SN of adult male rats. At 1-2 months post-infusion, examination of thionine and iron stained brain sections from animals infused with low concentration iron revealed: (1) iron diffusion limited to and concentrated within the infused SN and (2) a selective degeneration of neurons within zona compacta of SN. Infusion of higher iron concentrations induced near complete neuronal losses in zona compacta, as well as neuronal degeneration within zona reticularis and areas immediately adjacent to the SN. Striatal dopamine and its catabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were reduced in a dose-dependent fashion, with over 80% depletions observed at the highest iron concentration infused. These data indicated that neurons within zona compacta of SN are sensitive to infusions of low iron concentrations. The data support the notion that iron in zona compacta of the SN could act as an endotoxin in the pathogenesis of PD.     

百草枯对小鼠黑质多巴胺能神经元的选择性损害

目的:探讨百草枯对黑质部多巴胺能神经元的损害是否具有选择性。方法:用口服百草枯的途径,建立小鼠帕金森病模型;应用原位杂交技术观察DAT和VMAT2在不同脑区的mRNA表达水平并测定两者的比值,采用细胞计数观察百草枯干预后多巴胺能神经元的损害。结果:在黑质部DATmRNA和VMAT2mRNA的比值最高;在红核和下丘脑室旁核区域DATmRNA与VMAT2mRNA的比值和黑质部相比较低(P<0·01)。百草枯干预后黑质部的多巴胺能神经元减少37·7%;红核和下丘脑室旁核区的多巴胺能神经元分别减少12·2%和13·1%。结论:百草枯对黑质部多巴胺能神经元的损害具有相对选择性,其原因可能与黑质部DATmRNA和VMAT2mRNA的比值高有关。     

Sequestration of iron by Lewy bodies in Parkinson’s disease

Central to the oxidative stress hypothesis of Parkinson’s disease (PD) pathogenesis is the ability of iron to generate hydroxyl radicals via the Fenton reaction, and the consistent demonstration of iron elevation in the pars compacta region of the substantia nigra. However, uncertainty exists as to whether the excess iron exists in a state suitable for redox chemistry. Here, using a method we developed that detects redox-active iron in situ, we were able to demonstrate strong labeling of Lewy bodies in substantia nigra pars compacta neurons in PD. In contrast, cortical Lewy bodies in cases of Lewy body variant of Alzheimer’s disease were unstained. While the presence of elevated iron in PD substantiates the oxidative stress hypothesis, one must remember that these are viable neurons, indicating that Lewy bodies may act to sequester iron in PD brains in a protective, rather than degenerative, mechanism. The absence of redox-active iron in neocortical Lewy bodies highlights a fundamental difference between cortical and brain stem Lewy bodies. Received: 9 February 2000 / Revised: 31 March 2000 / Accepted: 2 April 2000     

骨髓基质细胞移植治疗帕金森病河猴的实验研究

目的 探讨以骨髓基质细胞(BMSCs)为供体移植治疗帕金森病(PD)模型恒河猴的可行性.方法 应用立体定向手术毁损单侧黑质建立恒河猴PD模型,采用加拿大评分和单光子发射计算机断层成像术(SPECT)分别观察恒河猴行为学和大脑黑质多巴胺转运蛋白(DAT)的变化,免疫荧光双标染色检测恒河猴黑质移植侧和正常侧BMSCs的分化状态.结果 移植BMSCs后恒河猴的PD综合征症状逐渐加重;SPECT检测显示恒河猴移植BMSCs前后黑质双侧DAT无明显变化,但免疫荧光显示移植后BMSCs分化为多巴胺(DA)能神经元的比例高达25%.结论 BMSCs无法作为有效的移植供体治疗PD,其可行性尚需进一步研究.     

Parkinson's disease: pathological mechanisms and actions of piribedil

The cause of the degeneration of dopamine-containing cells in the zona compacta of the substantia nigra in Parkinson's disease remains unknown. The ability of the selective nigral toxin 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) (via its metabolite MPP⁺) to destroy nigral dopamine cells selectively by inhibiting complex I of the mitochondrial energy chain may provide a clue. Indeed, recent studies of post-mortem brain tissue have suggested the presence of an on-going toxic process in the substantia nigra in Parkinson's disease leading to excess lipid peroxidation. This appears also to involve a disruption of mitochondrial function since mitochondrial superoxide dismutase activity is increased and there is impairment of complex I. These changes may in turn relate to a selective increase in the total iron content of substantia nigra coupled to a generalised decrease in brain ferritin content. Piribedil is used in the symptomatic treatment of Parkinson's disease and is particularly effective against tremor. Piribedil (and its metabolites) acts as a dopamine D-2 receptor agonist. However, in our studies in contrast to other dopamine agonists, in vivo piribedil interacts with dopamine receptors in the substantia nigra and nucleus accumbens but not those in the striatum. In patients with Parkinson's disease the beneficial effects of piribedil may be limited by nausea and drowsiness. Indeed, in MPTP-treated primates piribedil reverses motor deficits but marked side-effects occur. However, pre-treatment with the peripheral dopamine receptor antagonist domperidone prevents the unwanted effects and piribedil produces a profound and longer-lasting reversal of all components of the motor syndrome. These results suggest that combined with domperidone piribedil could be used as an effective monotherapy in the treatment of Parkinson's disease.     

脑内高铁在帕金森病病因中的作用

对帕金森病的病理研究发现黑质内存在氧化应激状态是由于铁在黑质致密带多巴胺能神经元内选择性堆积的结果。实验已证实铁负载引起卢的氧化应激导致的生化变化与帕金森病黑质内的改变是一致的,黑质内注射铁可选择性损伤多巴胺能神经元,模拟帕金森病的生化及行为改变,最近对6-羟基多巴的神经毒性与其能从铁蛋白中释放铁的有关研究,更加证实了铁诱导产生氧自由基参与黑质纹状体多巴胺能神经元变性,对铁鳌合剂去铁胺的研究也证实了这一观点。     

Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN). It has been suggested that microglial inflammation augments the progression of PD. Neuromelanin (NM), a complex polymer pigment found in catecholaminergic neurons, has sparked interest because of the suggestion that NM is involved in cell death in Parkinson's disease, possibly via microglia activation. To further investigate the possible role of NM in the pathogenesis of PD, we conducted in vivo experiments to find out whether microglial cells become activated after injection of human neuromelanin (NM) into (1) the cerebral cortex or (2) the substantia nigra to monitor in this PD-relevant model both microglial activation and possible neurodegeneration. In this study, adult male Wistar rats received an intracerebral injection of either NM, bacterial lipopolysaccharide (LPS, positive control), phosphate-buffered saline (PBS, negative control) or colloidal gold suspension (negative particular control). After different survival times (1, 8 or 12 weeks), brain slices from the cerebral cortex or substantia nigra (SN, 1 week) were stained with Iba-1 and/or GFAP antibody to monitor microglial and astrocytic reaction, and with tyrosine hydroxylase (TH) to monitor dopaminergic cell survival (SN group only). The injection of LPS induced a strong inflammatory response in the cortex as well in the substantia nigra. Similar results could be obtained after NM injection, while the injection of PBS or gold suspension showed only moderate or no glial activation. However, the inflammatory response declined during the time course. In the SN group, there was, apart from strong microglia activation, a significant dopaminergic cell loss after 1 week of survival time. Our findings clearly indicate that extracellular NM could be one of the key molecules leading to microglial activation and neuronal cell death in the substantia nigra. This may be highly relevant to the elucidation of therapeutic strategies in PD.     

Parallel relationship between microglial activation and substantia nigra damage in a rotenone-induced Parkinson's disease rat model

BACKGROUND:Inflammatory injury induced by microglial activation plays an important role in the occurrence and development of Parkinson’s disease (PD). However, few studies have examined the relationship between microglia and substantia nigra damage or dopaminergic neuron loss in animals with rotenone-induced PD. OBJECTIVE: To explore the relationship between activated microglia and loss of the substantia nigra, and the changes in concentration and dose of rotenone in the brain of rats with rotenone-induced ...     

In vivo detection of iron and neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage.

Early diagnosis of Parkinson's disease (PD) in nonsymptomatic patients is a key issue. An increased echogenicity of the substantia nigra (SN) was found previously in Parkinsonian patients and in a low percentage of healthy adults. These nonsymptomatic subjects also showed a reduced 18F-dopa uptake in striatum, suggesting a preclinical injury of the nigrostriatal system that could later proceed into PD. To investigate the ability of ultrasonography to detect markers of SN degeneration, such as iron deposition and neuromelanin depletion, we scanned postmortem brains from normal subjects at different ages by ultrasound and measured the echogenic area of the SN. The SN was then dissected and used for histological examinations and determination of iron, ferritin, and neuromelanin content. A significant positive correlation was found between the echogenic area of the SN and the concentration of iron, H- and L-ferritins. Multivariate analysis carried out considering the iron content showed a significant negative correlation between echogenicity and neuromelanin content of the SN. In PD, a typical loss of neuromelanin and increase of iron is observed in this brain area. The finding of a positive correlation between iron and ferritin levels and a negative correlation of neuromelanin content with the area of echogenicity at the SN could therefore provide an interesting basis for diagnosis and therapeutic follow-up studies in PD.