Yes, yes, and yes! Personally, there is not a doggoned thing either of you have just posted that I haven't also found!
Gee....where to start today!
I have spent more time trying to disprove what I believe than I have trying to prove it. So far I have been unable to do so. I personally would welcome any input that would cast doubt on these findings.
Same here! So far, not a soul has been able to cast ONE doubt. From a couple of the top neuros, to a geneticist (PCP), to the NMSS. So.........If you trust what I'm saying here, don't worry, we've at least put a lot of the pieces together allright. I've tried for months for somebody.......anybody........to poke holes. As I said.......so far.......nada.
Wesley: I'll be darned again! Last night I found what you just wrote. Desferal, it was called (i.e. deferoxamine). The thing is, they DID attempt this on MSers back in 1989, with little success. And my thought on why that was, I swear, was exactly what you pointed out. How to get it out of the cells, not just the blood.
In 1989, a trial with an iron chelating agent (Desferal) in 12 SP MS patients with a severe disability was well tolerated, but no long-term clinical benefit was mentioned.34
So, believe it or not, I concluded the same as Robin. Another "piece" but unfortunately, not the WHOLE story. And the more I looked into iron and gray matter, it turned into Parkinson's disease and Alzheimers. All neurological, of course, but........you see the slightly different slant it took. Right away from MS. So....ok....I circled back.
BUT...I was left with some interesting, but TOTALLY unanswerable questions about it. This you both might find interesting....hence, I think the iron "element" of this is worth a second look and should probably be kept in mind as perhaps one of the "triggers" (?), and here's why I was left with that thought (I'll highlight - the highlights are what you may find interesting, as I did). Now the OTHER interesting thing about this hypothesis is how it fits into that previous article I posted that I had no immediate thoughts about (and it was regarding the timing of children being provided iron at specific times in their lives.) Again, no conclusions, but it's sort of left hanging in the back of my mind. All I can say is "hmmmmmmmm", right now:
Ann. N.Y. Acad. Sci. 1012: 224–236 (2004). doi: 10.1196/annals.1306.019
Copyright © 2004 by the New York Academy of Sciences
Brain Ferritin Iron as a Risk Factor for Age at Onset in Neurodegenerative Diseases
GEORGE BARTZOKISa,b,c,d, TODD A. TISHLERc,e, IL-SEON SHINa,f, PO H. LUa,g and JEFFREY L. CUMMINGSa,g
aDepartment of Neurology, UCLA, Los Angeles, California, USA
bLaboratory of Neuroimaging, Department of Neurology, Division of Brain Mapping, UCLA, Los Angeles, California, USA
cGreater Los Angeles VA Healthcare System, Department of Psychiatry, West Los Angeles, California, USA
dDepartment of Psychiatry, Charles R. Drew University of Medicine and Science, Los Angeles, California, USA
eNeuroscience Interdepartmental Graduate Program, UCLA, Los Angeles, California, USA
fDepartment of Psychiatry, Chonnam National University Medical School, Kwangju, Korea
gDepartment of Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, California, USA
Address for correspondence: George Bartzokis, M.D., UCLA Alzheimer's Disease Center, 710 Westwood Plaza, Room 2-238, Los Angeles, CA 90095-1769. Fax: 310-268-3266. firstname.lastname@example.org
Ann N.Y. Acad. Sci. 1012: 224-236 (2004).
Tissue iron can promote oxidative damage. Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Higher iron levels in males may contribute to higher risk for younger-onset PD and recent studies have linked the presence of the hemochromatosis gene with a younger age at onset of AD. We examined whether age at onset of PD and AD was associated with increased brain ferritin iron. Ferritin iron can be measured with specificity in vivo with MRI utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in three basal ganglia regions (caudate, putamen, and globus pallidus) and frontal lobe white matter for younger- and older-onset male PD and AD patients and healthy controls. Significant increases in basal ganglia FDRI levels were observed in the younger-onset groups of both diseases compared to their respective control groups, but were absent in the older-onset patients. The results support the suggestion that elevated ferritin iron and its associated toxicity is a risk factor for age at onset of neurodegenerative diseases such as AD and PD. Clinical phenomena such as gender-associated risk of developing neurodegenerative diseases and the age at onset of such diseases may be associated with brain iron levels.
In vivo MRI can measure and track brain ferritin iron levels and provides an opportunity to design therapeutic interventions that target high-risk populations early in the course of illness, possibly even before symptoms appear.
Now, I did find some information that showed how the oligodendrocytes are involved in iron regulation. Except that where that left me was again, where you two appear to be.
Perhaps the iron deposition
in the brain cells is the result of the O's dying off and therefore unable to assist with iron metabolism? And that just brings us back to what, then, is causing the O's apoptosis? So......all in all, the iron deposition MOST LIKELY is an effect from a different cause and is probably happening later on in the cascade of events, not earlier. Which MIGHT, though, also perhaps HELP explain why it takes some time for MS to appear until later years. Again, notice the "age" factor in this. So, at the very least, PERHAPS this iron factor may be a part of what goes into determination of someone's "predisposition" to MS? Interesting..........
J Anat. 1995 Feb;186 ( Pt 1):165-73.
Transient expression of transferrin receptors and localisation of iron in amoeboid microglia in postnatal rats.
Kaur C, Ling EA.
Department of Anatomy, Faculty of Medicine, National University of Singapore.
The expression of transferrin receptors marked by the monoclonal antibody OX-26 and the localisation of iron were studied in amoeboid microglial cells in postnatal rats. Transferrin receptors were vigorously expressed in amoeboid microglia in rats ranging from 1 to 10 d of age but were undetectable in older rats. Thin serial sections showed that the OX-26 positive amoeboid microglial cells were also immunoreactive for OX-42 and ED1. Using Perls' medium, this study showed the presence of a considerable amount of iron in amoeboid microglial cells in 1-10 d rats. Most iron-containing cells were round but their number had diminished by 2 and 3 wk of age, when the iron was localised instead in some branched cells which were identified as either oligodendrocytes or ramified microglia cells. There has been much speculation on the functional significance of transferrin receptors on amoeboid microglia in postnatal rats. It is suggested that the receptors facilitate the acquisition of iron necessitated for various functions of amoeboid microglia in the developing brain. The presence of iron in some oligodendrocytes suggests their involvement in mediating iron mobilisation and storage. Its localisation in some ramified microglia in older rats indicates the possible role of these cells in sequestration and detoxification of iron in the central nervous system.
PMID: 7649811 [PubMed - indexed for MEDLINE]
I'm sure you guys ran across this same type of the next two abstracts that I'm going to post here, but I thought I'd just post them anyway.......strictly FYI. Not really to make any one "specific" point or anything. I personally have arrived at Robin's point. Interesting, iron MIGHT play a role (probably does), but just doesn't appear to be a HUGE "causal factor"....or at least not that I personally can see at this point. You can see, also, how I kept getting farther away from MS, and into Parkinson's and Alzheimers, which of course, are not to be made light of, but it just got too far away from MS and what we currently DO know is going on. Besides, (and Robin, I think you'll notice this........"), look where it starts to lead us back to again. The adrenals, huh? (Except, I will say again, though, that the focus that I have found in my earlier research on what may be exacerbating the problems in MS is norepinephrine, not dopamine. I'll post an abstract again that has been posted here previously, but perhaps it'll be easier to work it into this current scenario.) At that point, I said ok........enough of the iron research!
At least for now. I've circled back around again. MY suggestion from all this? Everybody load up on antioxidants!
Exp Neurol. 1998 Aug;152(2):188-96.
Astrocyte mitochondria: a substrate for iron deposition in the aging rat substantia nigra.
Schipper HM, Vininsky R, Brull R, Small L, Brawer JR.
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
Little is currently known concerning the cellular substrates for, and the mechanisms mediating the pathological deposition of, redox-active brain iron in Parkinson's disease. In various subcortical brain regions, populations of astroglia progressively accumulate peroxidase-positive cytoplasmic inclusions derived from effete, iron-laden mitochondria. In the present study, histochemical, ultrastructural, and elemental microanalytical techniques were used to demonstrate the existence of peroxidase-positive astroglia in the substantia nigra of adult rats. At 4 months of age and earlier, few GFAP-positive nigral astroglia contained small, electron-dense cytoplasmic inclusions which exhibited faint endogenous peroxidase activity (diaminobenzidine reaction product) and no detectable iron by microprobe analysis. In contrast, by 14-18 months of age, there was a significant, fourfold increase in numbers of peroxidase-positive astrocyte inclusions in the substantia nigra. The nigral gliosomes in the older animals were heterogeneously electron dense, immunoreactive for ubiquitin and a mitochondrial epitope, and often exhibited X-ray emission peaks for iron. Copper peaks were also detected in a minority of nigral gliosomes. Previous in vitro work indicated that the iron-mediated peroxidase activity in these cells promotes the bioactivation of dopamine and other catechols to neurotoxic free radical intermediates. Thus, mitochondrial sequestration of redox-active iron in aging nigral astroglia may be one factor predisposing the senescent nervous system to parkinsonism and other neurodegenerative disorders.
Copyright 1998 Academic Press.
PMID: 9710517 [PubMed - indexed for MEDLINE]
Cysteamine pretreatment of the astroglial substratum (mitochondrial iron sequestration) enhances PC12 cell vulnerability to oxidative injury.-
Frankel D, Schipper HM
Exp Neurol 1999 Dec;160(2):376-85.
Much of the excess iron reported in the substantia nigra of subjects with Parkinson's disease (PD) implicates nonneuronal (glial) cellular compartments. Yet, the significance of these glial iron deposits vis-a-vis toxicity to indigent nigrostriatal dopaminergic neurons remains unclear. Cysteamine (CSH) induces the appearance of iron-rich (peroxidase-positive) cytoplasmic inclusions in cultured rat astroglia, which are identical to glial inclusions that progressively accumulate in substantia nigra and other subcortical brain regions with advancing age. We previously demonstrated that the iron-mediated peroxidase activity in these cells oxidizes dopamine and other catechols to potentially neurotoxic semiquinone radicals. In the present study, we cocultured catecholamine-secreting PC12 cells (as low-density dispersed cells or high-density colonies) atop monolayers of either CSH-pretreated (iron-enriched) or control rat astroglial substrata. In some experiments, the PC12 cells were differentiated with nerve growth factor (NGF). The nature of the glial substratum did not appreciably affect the growth characteristics of the PC12 cells. However, undifferentiated PC12 cells grown atop CSH-pretreated astrocytes (a senescent glial phenotype) were far more susceptible to dopamine(1 microM)-H2O2(1 microM)-related killing than PC12 cells cultured on control astroglia. Differentiated PC12 cells behaved similarly although the fraction killed was about half that seen with the undifferentiated PC12 cells. In the latter experiments, PC12 cell death was abrogated by coadministration of the antioxidants, ascorbate (200 microM), melatonin (100 microM), or resveratrol (50 microM) or the iron chelator, deferoxamine (400 microM), attesting to the role of oxidative stress and catalytic iron in the mechanism of PC12 cell death in this system. The aging-associated accumulation of redox-active iron in subcortical astrocytes may facilitate the bioactivation of dopamine to neuronotoxic free radical intermediates and thereby predispose the senescent nervous system to PD and other neurodegenerative disorders.
Neurobiol Dis. 2004 Mar;15(2):331-9. Astrocytic beta2-adrenergic receptors and multiple sclerosis.
De Keyser J, Zeinstra E, Wilczak N.
Department of Neurology, University Hospital Groningen, Groningen, The Netherlands. email@example.com
Despite intensive research, the cause and a cure of multiple sclerosis (MS) have remained elusive and many aspects of the pathogenesis are not understood. Immunohistochemical experiments have shown that astrocytic beta(2)-adrenergic receptors are lost in MS. Because norepinephrine mediates important supportive and protective actions of astrocytes
via activation of these beta(2)-adrenergic receptors, we postulate that this abnormality may play a prominent role in the pathogenesis of MS. First, it may allow astrocytes to act as facultative antigen-presenting cells, thereby initiating T-cell mediated inflammatory responses that lead to the characteristic demyelinated lesions. Second, it may contribute to inflammatory injury by stimulating the production of nitric oxide and proinflammatory cytokines, and reducing glutamate uptake. Third, it may lead to apoptosis of oligodendrocytes by reducing the astrocytic production of trophic factors, including neuregulin, nerve growth factor and brain-derived neurotrophic factor. Fourth, it may impair astrocytic glycogenolysis, which supplies energy to axons, and this may represent a mechanism underlying axonal degeneration that is hold responsible for the progressive chronic disability.
PMID: 15006703 [PubMed - indexed for MEDLINE]
Robin, note the word "astrocytes"..........there are your microglial connections.
And for those who aren't certain about astrocytes in layman's terms, here's a quick definition:
The largest and most numerous neuroglial cells in the brain and spinal cord. Astrocytes (from "star" cells) are irregularly shaped with many long processes, including those with "end feet" which form the glial (limiting) membrane and directly and indirectly contribute to the blood-brain barrier. They regulate the extracellular ionic and chemical environment, and "reactive astrocytes" (along with microglia) respond to injury. Astrocytes have high- affinity transmitter uptake systems, voltage-dependent and transmitter-gated ion channels, and can release transmitter, but their role in signaling (as in many other functions) is not well understood.
Although, I MIGHT beg to differ about how well "understood" they are these days. hehehe.........I think we're well on our way, don't you?