Iron deposits in the central nervous system of SJL mice with experimental allergic encephalomyelitis

doi:10.1016/S0024-3205(98)00512-8

Life Sciences

Volume 63, Issue 25, 13 November 1998, Pages 2271-2284

https://doi.org/10.1016/S0024-3205(98)00512-8 Get rights and content

Abstract

Iron has been proposed to promote oxidative tissue damage in multiple sclerosis (MS). In order to gain insights about how iron gets processed during MS, the deposition of iron was investigated in the CNS of mice with experimental allergic encephalomyelitis (EAE), which is a commonly used animal model of MS. Control mice (adjuvant only) and EAE mice (myelin basic protein plus adjuvant), were sacrificed at 4–8 days (preclinical phase), 10–13 days (clinical phase), or 18 days (recovery phase) post injection. Sections from the cerebrum, hindbrain, and cervical, thoracic and lumbar spinal cord were stained as previously described (J. Neurosci. Res. 29:413, 1991), and scored blindly for histopathological staining. There was minimal histopathological staining at any age in control animals or during the preclinical stage in EAE animals. At the clinical stage of EAE, stained pathological features (macrophages, extravasated RBC and granular staining) were significantly increased compared to the preclinical stage. In the recovery phase, macrophage and granular staining persisted but there was loss of extravasated RBC. Dual labeling studies revealed that granular deposits were present in astrocytes and in locations that appeared to be extracellular. In order to gain insights about the origin of iron deposits in EAE mice, additional studies were performed on brains of mice with extravasated blood lesions. These brains had granular, macrophage and RBC staining. Thus, each of the stained features in EAE animals could be due to the extravasation of blood which occurs in the SJL model of EAE, although some of the iron could have originated from myelin and oligodendrocytes damaged during EAE.

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Dietary influence on central nervous system myelin production, injury, and regeneration
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Citation Excerpt :
Derangements in iron metabolism are also evident in animal models of MS. Cuprizone feeding results in altered iron metabolism in the brain and liver, acute reduction of expression of lipid and cholesterol biosynthesis enzymes, and deposition of iron in the extracellular space in cerebral white matter with subsequent uptake by local microglia [236,237]. Alterations in iron metabolism and redistribution of iron from oligodendrocytes are also seen in EAE in both rodents and marmosets, and these changes are associated with markers of oxidative stress [238,239]. Nonetheless there is ongoing debate as to the extent to which aberrant iron accumulation in MS plaque directly contributes to pathology.
Oligodendrocytes not only produce myelin to facilitate nerve impulse conduction, but are also essential metabolic partners of the axon. Oligodendrocyte loss and myelin destruction, as occurs in multiple sclerosis (MS), leaves axons vulnerable to degeneration and permanent neurological deficits ensue. Many studies now propose that lifestyle factors such as diet may impact demyelinating conditions, including MS. Most prior reviews have focused on the regulatory role of diet in the inflammatory events that drive MS pathogenesis, however the potential for dietary factors to modulate oligodendrocyte biology, myelin injury and myelin regeneration remain poorly understood. Here we review the current evidence from clinical and animal model studies regarding the impact of diet or dietary factors on myelin integrity and other pathogenic features of MS. Some limited evidence exists that certain foods may decrease risk or influence the progression of MS, such as increased intake of fish or polyunsaturated fatty acids, caloric restriction and fasting-mimicking diets. In addition, evidence suggests adolescent obesity or insufficient vitamin D levels increase the risk for developing MS. However, no clear or consistent evidence exists that dietary components exacerbate disease progression. Cumulatively, current evidence highlights the need for more extensive clinical trials to validate dietary effects on MS and to identify diets or supplements that may be beneficial as food-based strategies in the management of MS alone or in combination with conventional disease modifying therapies.
Expression of iron homeostasis proteins in the spinal cord in experimental autoimmune encephalomyelitis and their implications for iron accumulation
2015, Neurobiology of Disease
Citation Excerpt :
These results indicate increased oxidative stress at the peak stage of both forms of EAE, and continued high levels at the later progressive stage in CH-EAE. In this study we confirm and extend earlier reports of iron accumulation in the spinal cord in EAE (Forge et al., 1998; Schuh et al., 2014). We provide strong evidence based on ICP-MS analysis and iron histochemistry of iron accumulation in the spinal cord in the progressive and late stages of CH-EAE, and the late stage of RR-EAE, indicating that iron levels increase with disease progression and severity.
Iron accumulation occurs in the CNS in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying such iron accumulation are not fully understood. We studied the expression and cellular localization of molecules involved in cellular iron influx, storage, and efflux. This was assessed in two mouse models of EAE: relapsing–remitting (RR-EAE) and chronic (CH-EAE). The expression of molecules involved in iron homeostasis was assessed at the onset, peak, remission/progressive and late stages of the disease. We provide several lines of evidence for iron accumulation in the EAE spinal cord which increases with disease progression and duration, is worse in CH-EAE, and is localized in macrophages and microglia. We also provide evidence that there is a disruption of the iron efflux mechanism in macrophages/microglia that underlie the iron accumulation seen in these cells. Macrophages/microglia also lack expression of the ferroxidases (ceruloplasmin and hephaestin) which have antioxidant effects. In contrast, astrocytes which do not accumulate iron, show robust expression of several iron influx and efflux proteins and the ferroxidase ceruloplasmin which detoxifies ferrous iron. Astrocytes therefore are capable of efficiently recycling iron from sites of EAE lesions likely into the circulation. We also provide evidence of marked dysregulation of mitochondrial function and energy metabolism genes, as well as of NADPH oxidase genes in the EAE spinal cord. This data provides the basis for the selective iron accumulation in macrophage/microglia and further evidence of severe mitochondrial dysfunction in EAE. It may provide insights into processes underling iron accumulation in MS and other neurodegenerative diseases in which iron accumulation occurs.
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Nitration of proteins, which is thought to be mediated by peroxynitrite, is a mechanism of tissue damage in multiple sclerosis (MS). However, protein nitration can also be catalyzed by iron, heme or heme-associated molecules independent of peroxynitrite. Since microhemorrhages and perivascular iron deposits are present in the CNS of MS patients, we sought to determine if iron is associated with protein nitration. A cerebral model of experimental autoimmune encephalomyelitis (cEAE) was utilized since this model has been shown to have perivascular iron deposits similar to those present in MS. Histochemical staining for iron was used together with immunohistochemistry for nitrotyrosine, eNOS, or iNOS on cerebral sections. Leakage of the blood–brain barrier (BBB) was studied by albumin immunohistochemistry. Iron deposits were colocalized with nitrotyrosine staining around vessels in cEAE mice while control animals revealed minimal staining. This finding supports the likelihood that nitrotyrosine formation was catalyzed by iron or iron containing molecules. Examples of iron deposits were also observed in association with eNOS and iNOS, which could be one source of substrates for this reaction. Extravasation of albumin was present in cEAE mice, but not in control animals. Extravasated albumin may act to limit tissue injury by binding iron and/or heme as well as being a target of nitration, but the protection is incomplete. In summary, iron-catalyzed nitration of proteins is a likely mechanism of tissue damage in MS.
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The treatment was well tolerated except for muscle cramps and one popliteal vein thrombosis in a patient confined to chair. ID was obtained within 28 weeks and was associated with endogenous production of EPO. No bloodletting was further required during a six-month period after introduction of rhEPO. At the end of the follow-up (up to one year), fatigue and walking capacities tended to improve in two patients. Neurophysiological changes were characterized by an increased cortical excitability, including a decrease of motor thresholds and an enhancement of intracortical facilitation and cerebellothalamocortical inhibition.
The combined ID-rhEPO therapy could authorize a prolonged administration of rhEPO in PMS patients, able to modify cortical excitability of the glutamatergic and gabaergic circuits. These preliminary data are encouraging to design a larger, controlled therapeutical trial to assess the value of such a strategy to improve functional symptoms in PMS patients, and maybe to prevent axonal degeneration. Neurophysiological measurements based on cortical excitability studies could provide sensitive parameters to evaluate treatment-induced changes in this context.
Évaluer le concept que la déplétion en fer (DF) induite par des saignées répétées et suivie par l’administration d’érythropoïétine recombinante humaine (EPO-rh) pourrait être une stratégie thérapeutique dans la sclérose en plaques progressive (SEP-P) et que ceci peut être évalué par des mesures neurophysiologiques.
Chez quatre patients atteints de SEP-P, des saignées ont été effectuées jusqu’à ce qu’une DF soit induite, puis l’EPO-rh a été administrée (300 UI/kg par semaine). Les changements induits par le traitement ont été évalués par des scores cliniques, des tests biologiques et l’étude neurophysiologique de l’excitabilité corticale à l’aide des techniques de stimulation magnétique transcrânienne.
Le traitement fut bien toléré en dehors de crampes et de la thrombose d’une veine poplitée chez un patient confiné au fauteuil. La DF a été obtenue dans un délai de 28 semaines maximum et fut associée à la production endogène d’EPO. Aucune saignée ne fut nécessaire dans les six mois suivant l’introduction de l’EPO-rh. A la fin du suivi (jusqu’à un an), la fatigue et les capacités de marche tendaient à être améliorées chez deux patients. Les changements neurophysiologiques étaient caractérisés par une augmentation de l’excitabilité corticale, incluant une diminution des seuils moteurs et une amélioration de la facilitation intracorticale et de l’inhibition cérebello-thalamocorticale.
L’association thérapeutique DF-EPO-rh pourrait permettre une administration prolongée d’EPO-rh chez les patients SEP-P, capables de modifier l’excitabilité corticale des circuits glutamatergiques et gabaergiques. Ces données préliminaires sont encourageantes pour concevoir un essai thérapeutique contrôlé de plus grande ampleur, afin d’évaluer la valeur d’une telle stratégie pour améliorer les symptômes fonctionnels de patients atteints de SEP-P et peut-être de prévenir la dégénérescence axonale. Les mesures neurophysiologiques basées sur l’étude de l’excitabilité corticale pourraient fournir des paramètres sensibles pour évaluer les changements induits par le traitement dans ce contexte.
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2010, Journal of the Neurological Sciences
Citation Excerpt :
Histopathological analysis suggests that deep GM T2 hypointensity is associated with pathological iron deposition [14]. While the mechanisms are still unclear abnormal iron metabolism is implicated in MS and its animal models, and in other neurological diseases [3,25–29]. Iron overload or clearance failure may cause excessive production of hemosiderin and free iron with upregulation of heme oxygenase-1 [30].
Abnormally decreased deep gray matter (GM) signal intensity on T2-weighted MRI (T2 hypointensity) is associated with brain atrophy and disability progression in patients with multiple sclerosis (MS) and is believed to represent excessive iron deposition. We investigated the time course of deep GM T2 hypointensity and its relationship with disability at 3 T in 8 stable relapsing–remitting (RR) MS patients treated with minocycline over 3 years. MRI and disability measurements were compared at baseline, 6, 12, 24, and 36 months. Grand mean deep GM T2 hypointensity was negatively correlated with EDSS over time (r = − 0.94, P = 0.02). This correlation was strongest in the head of caudate (r = − 0.95, P = 0.01) and putamen (r = − 0.89, P = 0.04). Additionally, baseline grand mean deep GM T2 hypointensity appears to predict third year EDSS (r = − 0.72, P = 0.04). These results suggest that iron associated deep GM injury correlates with patient disability in stable RRMS. Measurements of deep GM T2 hypointensity at high field MRI may prove to be useful in monitoring individuals with MS. Further studies are required to confirm these results in a large sample and to determine if T2 hypointensity changes in clinically active MS patients.

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Iron deposits in the central nervous system of SJL mice with experimental allergic encephalomyelitis

Abstract

J. Neuroimmunol.

J. Neuroimmunol.

J. Neuroimmunol.

J. Neuroimmunol.

Neurochem. Int.

J. Neuroimmunol.

J. Neuroimmunol.

J. Neuroimmunol.

Free Rad. Biol. Med.

J. Biol. Chem.

Neurosci.

Neurosci.

Brain Res.

Free Rad. Biol. Med.

Arch. Biochem. Biophy.

Brain Res.

J. Neurol. Sci.

Dev. Brain Res.

Neurobiol Aging

Brain Res.

Arch. Ophthalmol.

J. Exp. Med.