The connection- Iron, hypoxia, and oligidendrocytes

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

The connection- Iron, hypoxia, and oligidendrocytes

Postby cheerleader » Mon Sep 28, 2009 5:39 pm

When I first came on TIMS in 2007, there was a regular poster, twisted helix, whose posts always gave me plenty to chew on and lots of words to look up. He's not around as much anymore, and we miss him. MS keeps him down physically, but as you can tell from his "voice"...his brain and humor remain vibrant and engaged. He posted this in the general, because we all miss him and were trying to get him back online with us.

Dom posted the first Zamboni study back in 2007
http://www.thisisms.com/ftopict-4794-zamboni.html

Here's his most recent post...with some thoughts about CCSVI. VERY interesting research on how hypoxia affects iron deposition and how chelators are neuroprotective. It appears the iron levels and hypoxia in the MS brain are linked.

Thanks, Dom! Don't be a stranger,
cheer


FROM Dom/Twisted Helix:
Ooh, it's so good to hear your voices again! Just to give you some insight: it took me about 5 hours to write that previous post, so " lurking" isn't a good idea because I'd be so tempted to join in, there wouldn't be time to do the things which normally take up my day, such as yawning, blinking, and the occasional scratch.

To my mind everyone here deserves a medal, but Cheer, your work on CCSVI has been inspirational. I know it has its own thread, but if I can just make a couple of points before I sink back into hibernation:

Many moons ago, I'm sure I posted something about metals and MS. It was about extremely high levels in the urine of patients – I think it was iron in people with PPMS and aluminium in RRMS, but it could be the other way round – I know hypoxia causes a marked increase in the uptake of iron but it's a very complicated process, made more difficult by the fact that not only do different species react very differently, but different cell lines within the same species respond in totally unique ways. This abstract intrigued me because it mentions amantadine as a way to block this, a drug long used as a therapy but I've never heard this method of action before:

Quote:
Titre du document / Document title
Hypoxia alters iron homeostasis and induces ferritin synthesis in oligodendrocytes
Auteur(s) / Author(s)
YAN QI (1) ; JAMINDAR T. M. ; DAWSON G. (1) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Univ. Chicago, dep. pediatrics, Chicago IL 60637, ETATS-UNIS
Résumé / Abstract
Both iron and the major iron-binding protein ferritin are enriched in oligodendrocytes compared with astrocytes and neurons, but functional role remains to be determined. Progressive hypoxia dramatically induces the synthesis of ferritin in both neonatal rat oligodendrocytes and a human oligodendroglioma cell line. We now report that the release of iron from either transferrin or ferritin-bound iron, after a decrease in intracellular pH, also leads to the induction of ferritin synthesis. The hypoxic induction of ferritin synthesis can be blocked either with iron chelators (deferoxamine or phenanthroline) or by preventing intracellular acidification (which is required for the release of transferrin-bound iron) with weak base treatment (ammonium chloride and amantadine). Two sources of exogenous iron (hemin and ferric ammonium citrate) were able to stimulate ferritin synthesis in both oligodendrocytes and HOG in the absence of hypoxia. This was not additive to the hypoxic stimulation, suggesting a common mechanism. We also show that ferritin induction may require intracellular free radical formation because hypoxia-mediated ferritin synthesis can be further enhanced by cotreatment with hydrogen peroxide. This in turn was blocked by the addition of exogenous catalase to the culture medium. Our data suggest that disruption of intracellular free iron homeostasis is an early event in hypoxic oligodendrocytes and that ferritin may sene as an iron sequestrator and antioxidant to protect cells from subsequent iron-catalyzed lipid peroxidation injury
Revue / Journal Title
Journal of neurochemistry ISSN 0022-3042 CODEN JONRA9
Source / Source
1995, vol. 64, no6, pp. 2458-2464 (1 p.)
Langue / Language
Anglais
Editeur / Publisher
Blackwell, Oxford, ROYAUME-UNI (1956) (Revue)


Iron chelators exert a neuroprotective effect and the method of action is interesting, because they do so by triggering a protective response which is normally a reaction to hypoxia. Doubly strange, then, that releasing ferretin-bound iron increases ferretin synthesis… Everything seems to contradict…

Quote:

Iron chelators are pluripotent neuronal antiapoptotic agents that have been shown to enhance metabolic recovery in cerebral ischemia models. The precise mechanism(s) by which these agents exert their effects remains unclear. Recent studies have demonstrated that iron chelators activate a hypoxia signal transduction pathway in non-neuronal cells that culminates in the stabilization of the transcriptional activator hypoxia-inducible factor-1 (HIF-1) and increased expression of gene products that mediate hypoxic adaptation. We examined the hypothesis that iron chelators prevent oxidative stress-induced death in cortical neuronal cultures by inducing expression of HIF-1 and its target genes. We report that the structurally distinct iron chelators deferoxamine mesylate and mimosine prevent apoptosis induced by glutathione depletion and oxidative stress in embryonic cortical neuronal cultures. The protective effects of iron chelators are correlated with their ability to enhance DNA binding of HIF-1 and activating transcription factor 1(ATF-1)/cAMP response element-binding protein (CREB) to the hypoxia response element in cortical cultures and the H19-7 hippocampal neuronal cell line. We show that mRNA, protein, and/or activity levels for genes whose expression is known to be regulated by HIF-1, including glycolytic enzymes, p21(waf1/cip1), and erythropoietin, are increased in cortical neuronal cultures in response to iron chelator treatment. Finally, we demonstrate that cobalt chloride, which also activates HIF-1 and ATF-1/CREB in cortical cultures, also prevents oxidative stress-induced death in these cells. Altogether, these results suggest that iron chelators exert their neuroprotective effects, in part, by activating a signal transduction pathway leading to increased expression of genes known to compensate for hypoxic or oxidative stress


Okay, I've REALLY got to go back to sleep now. Take good care,
Dom.
_________________
Dom
Last edited by cheerleader on Mon Jan 18, 2010 9:54 am, edited 2 times in total.
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby jay123 » Mon Sep 28, 2009 6:40 pm

Cheer,
Sorry I'm real confused on this lone, Is this saying iron is good is some way?
Also, is this saying the 'chelation people' might have something?




BTW, all my info was sent to Dr. D today!
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Postby CureOrBust » Sun Jan 17, 2010 2:57 am

I could not really see where else to post this (if it hasn't already been posted).
Relationship of iron to oligondendrocytes and myelination
Oligodendrocytes are the predominant iron-containing cells in the brain. Iron-containing oligodendrocytes are found near neuronal cell bodies, along blood vessels, and are particularly abundant within white matter tracts. Iron-positive cells in white matter are present from birth and eventually reside in defined patches of cells in the adult. These patches of iron-containing cells typically have a blood vessel in their center. Ferritin, the iron storage protein, is also expressed early in development in oligodendrocytes in a regional and cellular pattern similar to that seen for iron. Recently, the functionally distinct subunits of ferritin have been analyzed; only heavy (H)-chain ferritin is found in oligodendrocytes early in development. H-ferritin is associated with high iron utilization and low iron storage. Consistent with the expression of H-ferritin is the expression of transferrin receptors (for iron acquisition) on immature oligodendrocytes. Transferrin protein accumulation and mRNA expression in the brain are both dependent on a viable population of oligodendrocytes and may have an autocrine function to assist oligodendrocytes in iron acquisition. Although apparently the majority of oligodendrocytes in white matter tracts contain ferritin, transferrin, and iron, not all of them do, indicating that there is a subset of oligodendrocytes in white matter tracts. The only known function of oligodendrocytes is myelin production, and both a direct and indirect relationship exists between iron acquisition and myelin production. Iron is directly involved in myelin production as a required co-factor for cholesterol and lipid biosynthesis and indirectly because of its requirement for oxidative metabolism (which occurs in oligodendrocytes at a higher rate than other brain cells). Factors (such as cytokines) and conditions such as iron deficiency may reduce iron acquisition by oligodendrocytes and the susceptibility of oligodendrocytes to oxidative injury may be a result of their iron-rich cytoplasm. Thus, the many known phenomena that decrease oligodendrocyte survival and/or myelin production may mediate their effect through a final common pathway that involves disruptions in iron availability or intracellular management of iron. © 1996 Wiley-Liss, Inc.

http://www3.interscience.wiley.com/journal/70800/abstract?CRETRY=1&SRETRY=0
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Postby avantitech » Sun Jan 17, 2010 9:18 pm

Cure, this article is spot on linking oxidative stress to the death of the high iron containing (majority) oligodendrocyte subpopulation which resides in highest concentration around cerebral venules in the white matter of the brain.

It highlights the susceptibility of the Iron biochemistry of Glial cell populations to oxidative stress. New research needs to be conducted to clarify the mechanism relating to hypoxia and increased iron loss/deposition as it relates to CCSVI.

The Journal is: Glia - Volume 17 Issue 2 Pages 83 - 93 James R. Connor, Sharon L. Menzies submitted 1996 and published online 6 Dec 1998
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Postby cheerleader » Sun Jan 17, 2010 10:38 pm

Thanks for digging up this thread, Cure. Dr. Haacke and I have been corresponding on this very topic, as he's testing oxygenation levels in MS brains with his BOLD technology and writing about it on his "history" page... I posted this under "hypercoagulation" in the general thread- but it really is about hypoxia and iron deposition, as well. So I'll repost here:

Dr. Mark Haacke and I have been communicating about this theory of an hypoxic event created by CCSVI and endothelial disruption initiating an MS flare. (see Lassmann studies on early MS lesions and hypoxia) He is following up on this theory in his new CCSVI testing protocol, and is already finding some interesting results, as MS patients show "stroke-like" cerebral damage, created by slowed perfusion. From his site:

http://www.ms-mri.com/history.php

Three interesting papers (13-15) point toward other features associated with venous congestion, small thrombi and iron deposition. In the first two, children with early cerebral infarction (13) and children following severe ischemic-anoxic events (14) showed increases in iron content in the basal ganglia, thalami and white matter. Iron deposition was also associated with periventricular gliosis (14). In fact, desferrioximine, an iron chelator, has been used to minimize the damage for patients undergoing cardiac resuscitation (16). These findings also may be consistent with the fact that some MS lesions show iron build up. It has not been shown yet but one might conjecture if the MS lesions with the highest iron content may represent ischemic tissue of lesions and may correspond with the lowest blood volume. Finally, an interesting case of venous congestion shown with SWI that was similar in appearance to a developmental venous anomaly, also in a child, shows that SWI may be able to detect small thrombosed veins. In this particular case, the child was treated and recovered and evidence of the problem on imaging disappeared at two months (15). So iron regulation appears to be disrupted in ischemic-anoxic insult. Could this be what is happening in MS as well?
(13) Cross et al (1990). MR evaluation of brain iron in children with cerebral infarction. AJNR 11; 341-348.
(14) Dietrich et al (1988). Iron accumulation in the basal ganglia following severe ischemic-anoxic insults in children. Radiology 168; 203-206.
(15) Amemiya et al (2008). Venous congestion associated with developmental venous anomaly: Findings on susceptibility weighted imaging. JMRI 28: 1506-1509.
(16) Gutteridge et al (1979). Inhibition of the iron-catalysed formation of hydroxyl radicals from superoxide and of lipid peroxidation by desferrioxamine. Biochem J 184; 469-472.



CCSVI + endothelial disruption= an hypoxic event initiating coagulation cascade and cerebral infarction, leading to iron deposition in brain tissue, activating immune system response. MS in theory. Time and research will tell the rest.

cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby Rokkit » Mon Jan 18, 2010 8:30 am

cheerleader wrote:CCSVI + endothelial disruption= an hypoxic event initiating coagulation cascade and cerebral infarction, leading to iron deposition in brain tissue, activating immune system response.


If this is the formula, then maybe there will be a few controls show up in the Buffalo study (since the numbers are larger) who have their CCSVI but have not yet had their endothelial disruption. I hope there aren't a lot of controls who show up with CCSVI but if there are just a few it could support this.
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Postby cheerleader » Mon Jan 18, 2010 9:43 am

rokkit...search beechwood on this forum. He would be an example of your theory. He is missing one jugular and his other is pinched by the atlas, BUT he does not have demyelination or lesions. He is young, and he has terrible fatigue and depression- I believe due to diffuse cerebral hypoxia- but no immune activation. Doctors have their eyes on him now, and it will be interesting to see if he develops MS before he has vascular surgery to correct his malformations.

I've also mentioned Zivadinov's story in Bologna regarding the young women at Jacobs who was a control, came in with CCSVI, and developed CDMS and later MS within months of her initial testing. So yes, some of the "controls" at Jacobs may show CCSVI initially...then MS later. Maybe this is part of the reasoning behind delaying the publicizing of their results? Time may make a difference? I'm just hypothesizing. It took 20 years for the young Sardianians Dr. Zamboni first studied with jugular malformations to develop MS-so I'm sure we'll see younger controls with CCSVI, but not demyelination.
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http://ccsviinms.blogspot.com
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