relieving hypoxia in EAE rats leads to fast improvement

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relieving hypoxia in EAE rats leads to fast improvement

Postby Cece » Thu Sep 19, 2013 11:20 am

http://www.ncbi.nlm.nih.gov/pubmed/24038279
Ann Neurol. 2013 Aug 16. doi: 10.1002/ana.24006. [Epub ahead of print]
Neurological deficits caused by tissue hypoxia in neuroinflammatory disease.
Davies AL, Desai RA, Bloomfield PS, McIntosh PR, Chapple KJ, Linington C, Fairless R, Diem R, Kasti M, Murphy MP, Smith KJ.
Source
Department of Neuroinflammation, UCL Institute of Neurology, Queen Square, London, WC1N 3BG.
Abstract
OBJECTIVE:
To explore the presence and consequences of tissue hypoxia in experimental autoimmune encephalomyelitis ((EAE), an animal model of multiple sclerosis (MS)).
METHODS:
EAE was induced in Dark Agouti (DA) rats by immunization with recombinant myelin oligodendrocyte glycoprotein (rMOG) and adjuvant. Tissue hypoxia was assessed in vivo using two independent methods: an immunohistochemical probe administered intravenously, and insertion of a physical, oxygen-sensitive probe into the spinal cord. Indirect markers of tissue hypoxia (e.g. expression of hypoxia-inducible factor-1α (HIF-1α), vessel diameter and number) were also assessed. The effects of brief (one hour) and continued (7 days) normobaric oxygen treatment on function were evaluated in conjunction with other treatments, namely administration of a mitochondrially-targeted antioxidant (MitoQ) and inhibition of inducible nitric oxide synthase (1400W).
RESULTS:
Observed neurological deficits were quantitatively, temporally and spatially correlated with spinal white and grey matter hypoxia. The tissue expression of HIF-1α also correlated with loss of function. Spinal microvessels became enlarged during the hypoxic period, and their number increased at relapse. Notably, oxygen administration significantly restored function within one hour, with improvement persisting at least one week with continuous oxygen treatment. MitoQ and 1400W also caused a small but significant improvement.
INTERPRETATION:
We present chemical, physical, immunohistochemical and therapeutic evidence that functional deficits caused by neuroinflammation can arise from tissue hypoxia, consistent with an energy crisis in inflamed CNS tissue. The neurological deficit was closely correlated with spinal white and grey matter hypoxia. This realization may indicate new avenues for therapy of neuroinflammatory diseases such as MS. ANN NEUROL 2013. ©

Ok, it appears that neuroinflammation causes hypoxia, and that this hypoxia is correlated with observable neurological deficits, and that by restoring oxygen to normal, the neurological deficits get restored function.

So even if you had absolutely no venous obstructions, the inflammation present in MS would lead to hypoxia in the brain tissue during the time when the inflammation occurs. If you have venous obstructions and there was already underlying hypoxia, then that's a double whammy.

This provides a possible explanation for the immediate improvements sometimes seen after CCSVI angioplasty: when hypoxia is suddenly relieved, neurological deficits get restored function, sometimes within the hour as seen in the rats. This also provides evidence for the neurologists and/or Big Pharma to pursue treatment of hypoxia in MS. It's a long way from rats to humans but this is a start.
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby 1eye » Thu Sep 19, 2013 1:00 pm

Ok, it appears that inflammation causes hypoxia, and that this hypoxia is correlated with observable neurological deficits
This is not apparent to me; in fact I would have said the opposite is true and that this study indicates the hypoxia is causing the inflammation. That would be indicated also by the symptoms for example of stroke or heart attack, which can even be diagnosed with reference to neurological deficits. Noteworthy might be that stroke doesn't as usually cause foot drop in humans first, but hand problems are common. That would correspond to paws and front legs being the first affected, but maybe we see that less easily in animals that do not have opposing thumbs and can't draw a straight line or sign their names. :-)
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby cheerleader » Thu Sep 19, 2013 1:22 pm

Thanks for the new paper, Cece--good one! Nice to know returning O2 levels to normal helped those rats. It sure helped Jeff, too :)
Here's some info on a paper in the NEJM, written by specialists at the Un. of Colorado in Denver.
It's very relevent--notice that this inflammatory reaction happens in healthy humans at high altitude. All it takes is low O2. I wrote about this on FB a couple years ago.

Found a great paper in the New England Journal of Medicine that discusses how hypoxic environments, like high altitudes, can create inflammation and signal the immune system in the brain. It was written by some specialists in high altitude and hypoxia, researchers at the University of Colorado in Denver.

In persons with mountain sickness, for example, levels of circulating proinflammatory cytokines increase, and leakage of fluid ("vascular leakage") causes pulmonary or cerebral edema. Increased serum levels of interleukin-6, the interleukin-6 receptor, and c-reactive protein--all markers of inflammation--were increased in healthy volunteers who spent 3 nights at an elevation higher than 3400 m.
The development of inflammation in response to hypoxia is clinically relevant
....



Here's the full paper--a must read,
http://www.ucdenver.edu/academics/colle ... ia2011.pdf

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dx dual jugular vein stenosis (CCSVI) 4/09
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby Cece » Thu Sep 19, 2013 5:31 pm

In the EAE rats, though, the inflammation would have come first as a result of the induced myelin autoimmunity, and then hypoxia as a result of that. It's pretty good evidence of that direction of causality (inflammation causes hypoxia) unless I am missing something?

That's in EAE, where the initial cause of disease is obvious (researcher injects rat to induce EAE). In MS, the initial cause is not so clear; that's where the hypoxia resulting from CCSVI might initiate chronic brain inflammation, to which the immune system responds, and a vicious cycle gets going.
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby 1eye » Fri Sep 20, 2013 11:37 am

Cece wrote:In the EAE rats, though, the inflammation would have come first as a result of the induced myelin autoimmunity, and then hypoxia as a result of that.


Maybe you can see that better than I, because again you have the whole paper in front of you?

It's a chain of causality issue for sure. I was thinking the injections would gum up the circulation with lipids and cause both the inflammation and the hypoxia. That would make it hard to know what (if not both effects) was causing the paralysis. I'm thinking it doesn't matter, at least to the rats, if the oxygen relieves one or both. I know my chest pain was relieved when the ambulance people turned on the oxygen. I guess I have more in common with those rats than I thought... :-)

They're probably working on scale-models of syringes and they do have (probably expensive) micro-needles that can extract DNA from a reproductive cell, but I bet they don't swab the little buggers with alcohol and inject their arm veins. I bet the injections' effects are quite wide-ranging.
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby Cece » Fri Sep 20, 2013 11:58 am

I never have the full paper. :(
I don't know much about how EAE is induced but that would be worth investigating if it's possible that the hypoxia occurred prior to the neuroinflammation. But I liked this line
The neurological deficit was closely correlated with spinal white and grey matter hypoxia. This realization may indicate new avenues for therapy of neuroinflammatory diseases such as MS.

because I think hypoxia is playing a contributory role in MS, and this research was in Ann of Neurology so it's respected by neurologists who might follow up.
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby frodo » Mon Oct 07, 2013 7:40 am

I remember that somebody once complained about the lack of animal models. He was insisting so much that Zamboni had to reply "I am not a mouse doctor".

Well, now there is an animal model support. I hope at least this person will be satisfied.
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby 1eye » Mon Oct 07, 2013 8:23 am

INTERPRETATION:
We present chemical, physical, immunohistochemical and therapeutic evidence that functional deficits caused by neuroinflammation can arise from tissue hypoxia, consistent with an energy crisis in inflamed CNS tissue.


I think they are saying the functional deficits caused by neuroinflammation arise from tissue hypoxia. The order sounds to me like hypoxia -> neuroinflammation -> functional deficits. If there is an energy crisis it will cause neuroinflammation, which causes the deficits. That's what it sounds like to me, but what do I know?

Maybe the hypoxia causes both the inflammation and the deficits at the same time. I dunno.
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby Cece » Mon Oct 07, 2013 9:23 am

1eye wrote:
INTERPRETATION:
We present chemical, physical, immunohistochemical and therapeutic evidence that functional deficits caused by neuroinflammation can arise from tissue hypoxia, consistent with an energy crisis in inflamed CNS tissue.


I think they are saying the functional deficits caused by neuroinflammation arise from tissue hypoxia. The order sounds to me like hypoxia -> neuroinflammation -> functional deficits. If there is an energy crisis it will cause neuroinflammation, which causes the deficits. That's what it sounds like to me, but what do I know?

Maybe the hypoxia causes both the inflammation and the deficits at the same time. I dunno.

But the last part of the sentence is "consistent with an energy crisis in inflamed CNS tissue."
Does that mean inflamed CNS tissue (neuroinflammation) -> energy crisis -> hypoxia because the neurons used up all the oxygen/nutrients during the energy crisis?
It has a completely different meaning depending on which way is meant! I think my brain is currently suffering an energy crisis thinking about this.
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby Bethr » Mon Oct 07, 2013 1:06 pm

Maybe there is just an existing susceptibility/inflammation in the brain already. I think I'm similar to Cheer's, Jeff. Because my lack of oxygen was physical, a throat cyst growing over an 18 year period from pea size in 1994 to golf ball size in 2012. My sister has been diagnosed with MS, so a family link and maybe I'm just genetically more prone to inflammation causing damage in the brain if I lack oxygen. But it took the chronic lack of oxygen to really start giving me problems.
Fatigue came first, and a rise in iron levels (I have the hemochromatosis influence too as heterozygous for C282Y, I can see now this was just another symptom and my body switch turned to "make more blood to get more oxygen mode"), a lack of healing when I pulled muscles, overworked myself, even scratches didn't heal and they would scar, a brain lesion caused loss of use of right hand, another lack of healing. My teeth are good and always have been, but I was suddenly taken over with gum disease about the same time as the brain lesion. and my bone holding my teeth was receding dramatically. I see a dentist on a regular basis, always have looked after my teeth, never a problem. Since my operation my gums have stopped receding thank goodness!

The whole time I had no idea that my airway was compromised, it was just so subtle, and I was a heavy smoker.

RESULTS:
Observed neurological deficits were quantitatively, temporally and spatially correlated with spinal white and grey matter hypoxia. The tissue expression of HIF-1α also correlated with loss of function. Spinal microvessels became enlarged during the hypoxic period, and their number increased at relapse. Notably, oxygen administration significantly restored function within one hour, with improvement persisting at least one week with continuous oxygen treatment.


HIF-1a also messes with your gums, the research is there, especially concerning sleep apnea. It's a lack of oxygen setting it off - HIF-1a Expressing itself.
Interestingly I got little dark patches of what I assume is hemosiderin deposits on my gums too, and my gums were inflamed and red and bleeding when I was ill. The patches are there still but slowly fading.
Exploding microvessels? Sounds feasible, and probably happening also in my brain when I lack oxygen.

My sister said yesterday that her fatigue has lessened lately and she is not day time sleeping anymore. This is quite amazing to me as two months ago she had a nose operation to unblock her airway. Correlation? Could sleep apnea, smoking or air pollution set off same?

I've done heaps of research lately on oxygen and hypoxia and it's effects of the body, and I learn't the most amazing thing last week.
In the luteal phase a women's oxygen goes down 25%! for someone already slightly hypoxic, that is huge, and could explain why so many women feel worse in the pre-menstrual phase, and also maybe why women are more susceptable to MS. Mind blowing to me!!
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby zjac020 » Thu Dec 26, 2013 5:23 pm

I may be slightly off topic here, but I have had trouble breathing through my right nostril. As a result I usually breathe through my mouth, although I don't have issues slewing. It has been like this probably since my teens and due to blows on the nose/face when I was about 13 and again at 17. I am now 33 and in CIS since May this year.

The large majority of brain lesions are also on my right side and have always wondered about the connection and whether i should get my nasal bridge fixed/straightened? Of course the op in itself is quite uncomfortable and I'm worried the "trauma" from the intervention could bring on a relapse.

Also just to add that I've just seen new research on MitoQ and mice EAE/MS. I wonder if its time to ditch coenzyme Q10 for MitoQ?
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby Rosegirl » Sat Dec 28, 2013 6:26 am

zjac020,

Before you consider drugs or CCSVI, please get yourself checked by a neuro-dentist (not just a general dentist) or someone who does cranial sacral therapy or neural cranial integration. If you have received blows to the head, you might just need something readjusted!

Of course, there are no guarantees, but both of these options are much cheaper and less invasive than the traditional "MS" remedies.
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby zjac020 » Sat Dec 28, 2013 9:21 am

Rosegirl wrote:zjac020,

Before you consider drugs or CCSVI, please get yourself checked by a neuro-dentist (not just a general dentist) or someone who does cranial sacral therapy or neural cranial integration. If you have received blows to the head, you might just need something readjusted!

Of course, there are no guarantees, but both of these options are much cheaper and less invasive than the traditional "MS" remedies.


Thanks for the suggestion rose girl. I really wish I could find such a specialist here in Madrid. I have found holistic dentists and they agree with removing the Root canals and crowns I have in my mouth, especially the upper right incisor (again..notice it's on the right hands side) and replace we with zirconium implant, but that is costly. All dentists have noticed a sinus issue on the right side, what looks in the x ray like a pocket of mucus.again I think it's all related to the difficulty I have breathing through the right nostril, but without access tot he right professionals it's very hard to do anything about it.
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby Cece » Sat Dec 28, 2013 10:47 am

zjac020 wrote:I may be slightly off topic here, but I have had trouble breathing through my right nostril. As a result I usually breathe through my mouth, although I don't have issues slewing. It has been like this probably since my teens and due to blows on the nose/face when I was about 13 and again at 17. I am now 33 and in CIS since May this year.

The large majority of brain lesions are also on my right side and have always wondered about the connection and whether i should get my nasal bridge fixed/straightened? Of course the op in itself is quite uncomfortable and I'm worried the "trauma" from the intervention could bring on a relapse.

Also just to add that I've just seen new research on MitoQ and mice EAE/MS. I wonder if its time to ditch coenzyme Q10 for MitoQ?

Do you have any chronic inflammation in the nostril or sinus area? I think it's good to get any areas of inflammation under control especially if they're in proximity to veins or brains.

There is research to support being on DMDs if you have CIS, because DMDs have in some percentage of people with CIS delayed the onset of MS.

Blows to the face could potentially cause trauma to the veins, setting in motion "acquired CCSVI" as compared to congenital CCSVI.

Good luck, and in addition to what Rosegirl recommended, there are people who swear by Upper Cervical Care which might also be an avenue to investigate if you have a history of trauma. I myself am a CCSVI advocate as I've had a very good experience with it.
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Re: relieving hypoxia in EAE rats leads to fast improvement

Postby zjac020 » Sat Dec 28, 2013 11:58 am

The problem I see is getting all this looked at when there are no real specialists abound. I'm contacting one clinic which offers CCSVI treatment to see what they can offer.

The sinus area that alway shows up on dental X-rays I believe would qualify as chronic inflammation and doctors have commended I see an ENT specialist. But as you all know if I explain that it's not a comfort issue but something I'd like to resolve to aid with my MS, we'll you know the look they put on.

I have looked for research on dmds and CIS -> MS onset but haven't really found anything. I assume that as usual the research is sponsored by drug companies? We'll if anyone has any links or material they can send id be extremely grateful.

Oh, and I forgot to mention that just to add complication I have a rectified cervical lordosis...
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