gray matter affected in earliest stages of MS

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Postby OddDuck » Wed Nov 17, 2004 9:18 am

Robin,

I expected a volley of rotten fruit to come my way after posting my theory What I may well do is write the whole thing up properly, I have much more to add and many more references but didn't want to clog the thread up with an epic post.


:D Teach me how to do that, will ya? (i.e. not clog up the thread..... :wink:) You won't get rotten fruit from me, that's for sure. I really respect and enjoy your input!

and

Why do I feel that he won't be interested?


Yea, I know what you mean, but give it a shot!!! That's what I did! They smirked at me a lot, but I held my ground. Even INSISTED that they read it! (Wait, I do have to add that it was originally given to me as a research assignment by a neurologist, along with something else to research for him. So I need to give credit where credit is due there.) But the rest of them that I gave it to, I respectfully "encouraged" them to read it.

And then when they finished reading it, they weren't smirking anymore. hehehe....... And I got "interest" all right! (Problem is, so far, that's all I've gotten. Interest and confirmation that my research does not look flawed, but even that's pretty darn good coming from the experts, I suppose, huh?) (And the NMSS still encourages me to send them the "correlations" and such, as I call them, that I find when I'm researching. The very same ones that I post here, as a matter of fact.)

So..........hey, who knows WHAT influence we might really be having, but just don't know it!

I mean, this last batch of grants from the NMSS appears to me to have taken some of my suggestions or ponderings into consideration (at least I can "think" so.) Who knows who else may have written to them with their suggestions and hypotheses, also.

I know what you mean about rewriting our stuff into something professional. I'm still working on mine, also. (Adding footnotes, etc. etc. - geez, I hate that stuff. :wink: A legal person who hates to write "papers"? You gotta find that one hilarious, huh?)

Anyway...........I'm behind you all the way! For what it's worth.

Deb
Last edited by OddDuck on Wed Nov 17, 2004 9:20 am, edited 1 time in total.
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby raven » Wed Nov 17, 2004 9:19 am

While I'm on the subject....

BioDocFL brought up the subject of glutamate. There's a pretty good explanation of how glutamate can cause neuron death here:

http://www.grandrounds.com/pcc/brainstorm/br5806.htm

The key players in inflammation are glial cells, both astrocytes and microglia, which are activated in these brain diseases and in response to glutamate excitotoxicity (13, 14, 15). Activated microglia release a large variety of neurotoxins, including the free radicals hydrogen peroxide, superoxide, and NO, that also is able to nitrate proteins; glutamate and quinolinic acid; extracellular proteases; eicosanoids; and cytokines, such as TNF-a and IL-1b, which further increase microglial proliferation and activation, thereby increasing the release of microglial toxins


So it may be that the microglial activation I mentioned earlier is in response to glutamate excitotoxicity. The above quote also decribes the 'cascade' of microglial proliferation.

Deb's calcium toxicity is also encompassed:

Activation of the N-methyl-D-aspartate (NMDA)3 receptors to a large extent mediates the glutamate excitotoxicity and neuronal death in several neurodegenerative diseases and ischemic stroke (1, 2, 3). Subsequent to activation of NMDA receptors occurs toxic calcium influx, which activates numerous enzymes, including neuronal NO synthase (NOS). NO is able to further increase the excitotoxicity by enhancing glutamate release from presynaptic neurons (4, 5) and inhibiting glial glutamate transporters (6, 7).



Interesting...

Robin

edit: Deb, I'm another one who loathes writing papers.....

edit 2: It may be that the glutamate expression is as a result of microglial activation rather than preceeding it.....

These data suggest that free radicals released from activated microglia may initiate MN injury by increasing the susceptibility of the MN AMPA/kainate receptor to the toxic effects of glutamate
User avatar
raven
Family Elder
 
Posts: 240
Joined: Sat Sep 25, 2004 3:00 pm
Location: Bristol, England

Postby OddDuck » Wed Nov 17, 2004 10:27 am

Yep!

Also, Robin, at least from my angle here, what you might be seeing is a much earlier problematic process going on before the immune system gets triggered completely. And/or maybe sometimes the immune system isn't involved at all!

We've speculated on that before, i.e. the likelihood of something going on BEFORE the traditional immune system kicks in to the mix.

I'm telling ya..........(seriously, too)........you get all of us (and not just us here on this thread right now, but "us" as in the majority of us here who post on thisisms) in one room together, and I'll bet you anything we'd come up with some great stuff! Seriously!

We've got Wesley with his innovative ideas and approaches at the very beginning, you in the middle there, Robin; me at the very end (for the most part, ya know?), and then throw in the mix really great innovative ideas such as Sarah's, Sharon's, Harry's (and many others here), and you tell me we can't at least come up with some good stuff here!

We're ALL on basically the same page here, too, with what we are finding, ya know? That CAN'T be just coincidence. :wink: I keep seeing where it all sort of gels together. But something is just SLIGHTLY out of reach. (Mainly, I think, because we need a LAB! :wink: ) But I bet if we keep going here, at some point, we might find the total connection!

You know what the difference is, though, with us and the way research has been performed up until just recently? We all SHARE information. We aren't money motivated, either, are we? (Sorry.......I had to mention that.)

BUT.............there is always "power in numbers" (of people, that is).

I got off track again.........anyway, the NO, free radicals, glutamate, etc. ........ I found those same types of theories, also. Hence why I tried to cover it all when creating my specific mix of treatment regimen. LOL With drugs, supplements, etc. (which is what we all do, of course.)

Most of my previous research regarding those things is at home (and I'm not right now), so unfortunately, I can't speak all that intelligently until I refresh myself, but what you are posting is what I found, also.

You mentioned LPS earlier, also, Robin. Yes, I did some initial research on LPS. That is one of the major reasons why in my original narrative I make a quick statement (without elaborating) why I thought a person should use extreme caution if/when prescribing desipramine to someone with Lyme disease AND it was one of the many reasons why I didn't believe it was necessarily wise to prescribe desipramine in combination with the interferons. The point here focusing on the LPS part and its actions in MS.

Man, I wish I had my reference material with me here!

Deb

EDIT: Oh yea............glutamate and the motor neurons is a BIG focus right now. I found that when I started researching ALS, when the doctor goofballs (and I say that lovingly) started throwing THAT acronym at me. LOL
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby OddDuck » Wed Nov 17, 2004 11:11 am

Ok, folks, billf has got us on another roll here. Let's see what WE can find that may explain or help treat what they are referring to in the news articles below. It appears like NOW we need to factor in iron deposits. hmmmmmmmmm......new direction altogether!

Any ideas, thoughts?

Deb

****************************

New High-Tech MRI Shows Earlier Signs of MS

Researchers Hope Finding May Help Identify Those With More Aggressive Disease

By Peggy Peck
WebMD Medical News Reviewed By Charlotte Grayson, MD
on Tuesday, October 05, 2004

Oct. 5, 2004 (Toronto) -- A novel imaging technique shows that subtle, but ominous changes occur in unexpected parts of the brains of people with multiple sclerosis (MS) long before they develop symptoms.

Researchers are excited because the new high-tech MRI may help doctors identify "[those] patients whose MS is likely to progress to [cause] disability much earlier in the disease process than previously believed possible," Gerard Davies, MD, a researcher at the Institute of Neurology in London, tells WebMD.

Multiple sclerosis is a disease where the covering of nerves in the brain and spinal cord is gradually destroyed. This covering, called myelin, insulates the nerves and helps them transmit nerve impulses or messages between the brain and other parts of the body. These messages control movement and other functions. As the disease progresses patients typically experience problems ranging from weakness and balance problems to numbness, visual problems, and even impaired thinking.

Currently, MRI testing allows doctors to identify MS-related brain abnormalities in the so-called white matter of the brain where the myelin-sheathed nerves communicate with each other. The new technology images a different type of brain tissue called gray matter. Gray matter consists of the brain cells themselves; gray matter cells rely on the nerves in the white matter to communicate with each other.

gray Matter Examined

In his study, Davies studied 23 patients with relapsing/remitting MS, a form of the disease in which the disease manifests itself as a cycle of attacks separated by periods of relatively good health. The patients had all been diagnosed within the previous three years. "Each had at least two MS attacks," says Davies. He conducted brain imaging studies once a year for three years and compared those scans with yearly brain scans of 19 healthy volunteers.

Using the new imaging technology, the researchers found that "changes in both gray and white matter were evident on even the first scan," says Davies.

Other, sophisticated calculations show that the gray matter changes began nearly three years before the onset of symptoms whereas the white matter changes occurred shortly before the participant's first attack.

Robert Lisak, MD, professor and chair of the department of neurology at Wayne State University in Detroit, tells WebMD that the findings are very encouraging because "this is demonstrating for the first time that gray matter is involved very early in the disease." He says this shows that the purely white matter changes in a person with MS may actually be secondary to changes in the brain cells themselves.

But he cautions that while this finding is important, it will not translate into any immediate treatment strategy for MS patients. "It is good to understand how the disease starts and this may eventually lead to a treatment, but that is unlikely to happen in the short run."

Next, Davies says that these patients will be followed for at least 10 years, so that they "can determine if these subtle changes do predict disease progression."
--------------------------------------------------------------------------------
SOURCES: American Neurological Association 129th annual meeting, Toronto, Oct. 3-6, 2004. Gerard Davies, MD, Institute of Neurology, London. Robert Lisak, MD, professor of neurology, Wayne State University, Detroit.

*********************************

Here's an article from 2003:

Gray Matter Damage Linked to MS
Previous research had focused on the brain's white matter

By Kathleen Doheny
HealthDay Reporter

TUESDAY, Oct. 21 (HealthDayNews) -- The cognitive problems and walking difficulties experienced by multiple sclerosis patients is caused by damage in the brain's gray matter.

And that damage may be due to toxic deposits of iron.

That's the conclusion of a study by Dr. Rohit Bakshi, an associate professor of neurology, and his fellow researchers at the University of Buffalo. They presented their findings Oct. 21 at the annual meeting of the American Neurological Association in San Francisco.

"Conventional thinking has it that multiple sclerosis is a disease of white matter lesions or plaque detected by MRI [magnetic resonance imaging]," says Bakshi. "In the last five years, growing evidence suggests that MS is not just a white matter disease, but that gray is also involved. We now know it's a global disease of the brain and spinal cord. And it targets not only white matter but gray."

"Gray matter is the command-and-control center of the brain, where all the nerve centers are housed," Bakshi adds. "White matter simply connects the gray matter together."

Multiple sclerosis is believed to be an autoimmune disease of the central nervous system, including the brain, spinal cord and optic nerves. Surrounding the nerve fibers is protective fatty tissue called myelin, which helps nerve fibers conduct electrical impulses. Myelin is lost in numerous areas in MS patients, leaving behind scar tissue called sclerosis.

The damage to the myelin is the result, most experts believe, of an abnormal response by the immune system. Several factors are thought to be involved in the onset of MS, including genetics and environmental triggers such as viruses or trauma.

In one of two studies presented at the meeting, Bakshi and his team evaluated 47 people with multiple sclerosis who completed a timed 25-foot walk, commonly used to assess physical functioning in patients with the disease. The times were compared with the amount of unnatural darkness of each patient's gray matter, a condition called T2 hypointensity, which was detected on MRIs. The times were also compared with brain shrinking or atrophy and other brain changes known to occur with MS.

The amount of T2 hypointensity was the only brain change directly associated with impaired walking, Bakshi and his team found. The strongest association was with hypointensity in the dentate nucleus, a structure deep within the brain's cerebellum responsible for coordination and smooth limb movement, Bakshi says.

"That's a major finding and a completely new finding," he says.

In a second study, Bakshi evaluated 34 MS patients, some of them the same ones in the walking study, and 16 healthy controls, testing them for working memory and attention, and performing MRIs to evaluate hypointensity.

He found the hypointensity was independently related to problems with attention and memory and predicted the problems in the MS patients.

"The more hypointensity, the more impairment," he says.

Excess iron entering the brain may be what is damaging the gray matter, Bakshi says. Or, the high levels of iron -- which can increase as people age -- might be the result of the degenerative process that occurs in MS. For instance, high iron levels are seen in Alzheimer's disease, Bakshi says, and experts still debate the cause-and-effect of iron in that disorder.

Stephen Reingold, vice president of research programs for the National Multiple Sclerosis Society, says, "Gray matter damage in MS has been a topic of concern for some time, and it is important that this research group is pursing this systematically. The relative contributions of white matter and gray matter damage to the disease is an important issue that has yet to be determined," he says.

The potential role of iron, whether cause or effect, also remains unclear, Reingold adds.

In another study presented at the meeting, researchers from the University of California, San Francisco reported they have produced an MS-like condition in laboratory animals by exposing them to a virus called herpes hominis virus 6. It is one of several viruses believed by some to play a role in triggering MS.

More information

For more information on multiple sclerosis, check with the National Institute of Neurological Disorders and Stroke and the National Multiple Sclerosis Society .

SOURCES: Stephen Reingold, Ph.D., vice president, research programs, National Multiple Sclerosis Society, New York City; Rohit Bakshi, M.D., associate professor, neurology, University of Buffalo, N.Y.; Oct. 21, 2003, presentation, American Neurological Association annual meeting, San Francisco
Copyright © 2003 ScoutNews, LLC. All rights reserved.

*************************

Shoot, this theory goes back to 2002, even:

http://unisci.com/stories/20022/0520025.htm
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby raven » Wed Nov 17, 2004 11:45 am

I've just this minute found an extremely interesting article (full text rather than abstract) that covers an awful lot of what we've been discussing including glutamate.

http://jon.sagepub.com/cgi/reprint/14/3_suppl/5S

I'm still digesting it but suggest that it's very well worth reading.

Robin
User avatar
raven
Family Elder
 
Posts: 240
Joined: Sat Sep 25, 2004 3:00 pm
Location: Bristol, England

Postby OddDuck » Wed Nov 17, 2004 11:52 am

Great! I'll have to check it out later, so I can give it my undivided attention and thought. Thanks, Robin!!!

Deb

EDIT: Oh, wow, Robin! I did just go take a peak at it real quick, and that IS a good one! Wesley!! Robin found a great article! You might find this one really interesting, also!

Can't wait to get back to it later when I can digest more. I'm just skimming it at the moment.

SECOND EDIT: Yep.......that's a pretty good overview and example of the myriad processes going on in MS (all in one publication).
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby raven » Wed Nov 17, 2004 12:04 pm

BTW... Thanks Wesley, I intend to write everything up purely for my own sake, to try to understand what is happening to me. It will need a lot more work before it's ready to be put forward as a rational theory.

It does however occupy the grey cells (those that are left anyway :lol: )

Robin
User avatar
raven
Family Elder
 
Posts: 240
Joined: Sat Sep 25, 2004 3:00 pm
Location: Bristol, England

Postby OddDuck » Wed Nov 17, 2004 12:13 pm

Thinking from another angle here for a second, also: The reference to this new higher powered or more exacting MRI technique.

Now that's interesting! And it might be helpful in determining prognosis?

Oh....gee....how wonderful would that be?! Anything more exacting, etc. in diagnosing MS in the first place and what type of MS it is, would/should help tremendously with determining correct therapy and treatments.

Even finding types of "markers" for the disease is greatly needed!

Maybe, folks, we might be in a transition phase? You know how things wax and wane. Maybe MS research is back on the uptake? :D

Deb
Last edited by OddDuck on Wed Nov 17, 2004 12:14 pm, edited 1 time in total.
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby BioDocFL » Wed Nov 17, 2004 12:14 pm

I'll try to read it later tonight. I have work to do now and then a Japanese class tonight. Busy, busy.

This is getting interesting: heavy metals generate free radicals, which then damage chromatin and perhaps mitochondrial membranes. The mitochondrial damage could lead to apoptosis. The chromatin damage could lead to chromosome fragmentation, loss of epigenetic control, and possible apoptosis. This loss of epigenetic control could lead to overexpression of some previoulsy sequestered genes and pseudogenes. (Of course my favorites are the X-linked polyamine genes.)
There is then interference in uptake of glutamate by abnormal cells, and an overabundance of glutamate for uptake by or damage of normal cells.

The heavy metals aspect fits with the incidences of MS 'outbreaks' when new water systems are developed (Florida Keys, Faeore Islands). Like the theory that lead in the clay of Roman pottery lead to the madness and decline of Rome. The free radical damage fits as a possible cause of the chromosome fragmentation seen in MS.
User avatar
BioDocFL
Family Elder
 
Posts: 251
Joined: Wed Aug 11, 2004 3:00 pm
Location: Florida

Postby OddDuck » Wed Nov 17, 2004 12:27 pm

Yep, Wesley, and everything you just mentioned goes along with what I found recently regarding the hexavalent chromium toxins (that we touched on previously). Remember the military, and water pollution, and the prevelance of MS in more industrialized parts of the U.S.

See how it all keeps going and coming around?

:D

(And I'm like you.......posting, but unable to really get my thoughts together like I'd prefer because I have so many other things going on right now! :wink: )

Deb

EDIT: Oh, and when we all get more time, (and I pose this question to you specifically, also, Wesley).......what do you think of the iron deposit theory and where that fits in? That one has me puzzled for the moment.
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby billf » Wed Nov 17, 2004 12:56 pm

It is exhilarating to see an age-old MS paradigm gradually being brought down, like the statue of a fallen dictator. Let me be a constant pest reminding all that we should not only share these ideas and energy with each other in this forum, but also push on the beurocracies that are still blindly following the old paradigm without question.
User avatar
billf
Family Member
 
Posts: 40
Joined: Tue Jun 15, 2004 3:00 pm

Postby OddDuck » Wed Nov 17, 2004 2:02 pm

I totally agree, bill!

Hey, guys........I was just hopping around a little bit, and here's an article (it's from 2000), but after I read it myself, I thought I'd post it. It's at http://www.rps.psu.edu/0005/iron.html It talks about a theory regarding the iron/MS connection.

Frankly, after reading it, I'm not sure WHAT I think! That's why I thought I'd post it here. hmmmmmmm......... (once you read it, I think you'll see why I'm sort of stuck "in thought". :? )

Deb
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

Postby bromley » Wed Nov 17, 2004 2:12 pm

Dear all,

Apologies, but I need to say something about the discussion that has taken place.

- The general sense is that the auto-immune theory has had its day.

- Members are getting very 'excited' about new findings i.e damage is occuring in the grey matter, axonal loss, brain cell loss etc etc at a much earlier stage than was thought.

While I can see that there's an intellectual challenge in all this - we also need to remember that this is a devastating disease (physically / mentally etc etc) which affect human beings. The article posted by Raven might be of interest to academics, but those with this disease will realise that there is now less hope than when we thought it was an auto-immune disease. What we seem to have is something much more sinister and something where treatment is even further away / if at all.


These new findings / theories suggest that none of the current treatments are of any use. Even worse, much of the damage has taken place before we realise we have this disease. Hope is what ms sufferers are after - but the above discussion has made me realise that the situation is even worse than I could ever have imagined. In the UK we had a TV programme called 'Dad's Army' and one character had a catchphrase 'We're doomed'. I know how he felt!

Bromley
User avatar
bromley
Family Elder
 
Posts: 1887
Joined: Fri Sep 10, 2004 3:00 pm

Postby billf » Wed Nov 17, 2004 2:31 pm

Bromley,
I understand you concern, but disagree with your conclusion that we have even less to be hopeful for now than we did before. Yes, it is frustrating that some of the new discoveries might lead us to realize that the current therapies are useless. But the extremely exciting thing is that we are finally beggining to break out of a rut that has stifled progress in MS treatment for 50 years! Yes, during this time of transition, it will seem like the mystery is greater than ever before. However, in getting out of this rut, you will see that the progress of understanding the disease will now start to make faster gains than we have ever seen. We are shaking things up, and that seems upsetting in the short run. But that shake up is forcing new approaches down new roads that don't necessarily have the dead-end we've been encountering for so long. Stay positive! You will see.
User avatar
billf
Family Member
 
Posts: 40
Joined: Tue Jun 15, 2004 3:00 pm

Postby OddDuck » Wed Nov 17, 2004 2:46 pm

Oh, my heavens, guys! Check this out! Robin...get a load of this. I think you'll see what I see, huh? How bizarre is this?

Deb

**************************

ProInflammatory Cytokines Promote Glial Heme Oxygenase-1 Expression And Mitochondrial Iron Deposition: Implications For Multiple Sclerosis

Mehindate K, Sahlas DJ, Frankel D, Mawal Y, Liberman A, Corcos J, Dion S, Schipper
J Neurochem 2001 Jun 1;77(5):1386-1395
Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir, Mortimer B. Davis-Jewish General Hospital, Montreal, Canada Depts of Neurology and NeuroSurgery, Medicine (Geriatrics) and Surgery (Urology), McGill University, Montreal, Canada
--------------------------------------------------------------------------------
PMID# 11389189
Abstract
ProInflammatory Cytokines, pathological Iron deposition, and Oxidative Stress have been implicated in the PathoGenesis of Multiple Sclerosis (MS) and Experimental AutoImmune EncephaloMyelitis (EAE).

HO-1 mRNA levels and Mitochondrial uptake of [(55)Fe]Cl(3)-derived Iron were measured in rat Astroglial cultures exposed to InterLeukin-1beta (IL-1ß) or Tumor Necrosis Factor-alpha (TNF-).

Alone or in combination with the Heme Oxygenase-1 (HO-1) Inhibitors, Tin Mesoporphyrin (SnMP) or Dexamthasone (DEX), or Interferon-beta-1b (INF-ß).

HO-1 expression in Astrocytes was evaluated by ImmunoHistoChemical staining of Spinal Cord tissue derived from MS and control subjects.

IL-1ß or TNF- promoted sequestration of Non-Transferrin-derived (55)Fe by Astroglial Mitochondria.

HO-1 inhibitors, Mitochondrial permeability Transition Pore (MTP) Blockers and AntiOxidants significantly attenuated Cytokine-related Mitochondrial Iron sequestration in these cells.

IFN-ß decreased HO-1 expression and Mitochondrial Iron sequestration in IL-1ß- and TNF--challenged Astroglia.

The percentage of Astrocytes coexpressing HO-1 in affected Spinal Cord from MS patients (57.3% +/- 12.8%) was significantly greater (p < 0.05) than in normal Spinal Cord derived from controls subjects (15.4% +/- 8.4%).

HO-1 is over-expressed in MS Spinal Cord Astroglia and may promote Mitochondrial Iron deposition in MS Plaques.

In MS, IFN-ß may attenuate Glial HO-1 Gene induction and aberrant Mitochondrial Iron deposition accruing from exposure to ProInflammatory Cytokines.

*******************

Ok....I think this "iron" connection appears to be something of maintaining a delicate balance. Too much HO-1 and you get iron deposition (which as we read earlier, it appears that iron deposition causes damage in gray matter; but you don't want to inhibit HO-1 too much or you lose neuroprotection from apoptosis by proinflammatory cytokines.) Oh..........boy! I gotta think about this more. :?

************************************
Diabetes. 2001 Sep;50(9):1983-91. Related Articles, Links

Heme oxygenase-1 induction in islet cells results in protection from apoptosis and improved in vivo function after transplantation.

Pileggi A, Molano RD, Berney T, Cattan P, Vizzardelli C, Oliver R, Fraker C, Ricordi C, Pastori RL, Bach FH, Inverardi L.

Diabetes Research Institute, University of Miami School of Medicine, Miami, Florida 33136, USA.

Transplantation of islets of Langerhans represents a viable therapeutic approach for the treatment of type 1 diabetes. Unfortunately, transplanted islets are susceptible to allogeneic recognition and rejection, recurrence of autoimmunity, and destruction by local inflammation at the site of implantation. The last of these phenomena might not only result in functional impairment and death of islet cells but could also contribute to amplifying the subsequent specific immune response. Induction of islet cell protection against inflammation could therefore be postulated to be a powerful means to improve overall graft fate. Heme oxygenase-1 (HO-1) has been described as an inducible protein capable of cytoprotection via radical scavenging and apoptosis prevention. The purpose of the present study was to analyze whether HO-1 upregulation in a beta-cell line and in freshly isolated murine islets could result in protection from apoptosis and improve in vivo functional performance. HO-1 upregulation was induced reproducibly with protoporphyrins and was correlated with protection from apoptosis induced in vitro with proinflammatory cytokines or Fas engagement. Furthermore, in vivo HO-1 upregulation resulted in improved islet function in a model of marginal mass islet transplantation in rodents. Strategies aimed at inducing HO-1 upregulation might result in improved success in islet transplantation.

PMID: 11522663 [PubMed - indexed for MEDLINE]

************************

All I can say, is this is really interesting....... Next stop.......how do you test for levels of HO-1?

Induction of heme oxygenase-1 inhibits IL-1b nitrite oxide production in articular chondrocytes

F Rannou
Division of Biomedical Sciences, University of California, Riverside, California, USA and Division of Rehabilitation, Cochin Hospital, University of Paris V, France

from 3rd World Congress of the Global Arthritis Research Network (GARN): International Arthritis Summit
Summit Hall at Sheraton Resorts in Miyazaki, Japan, 14–17 September 2003

Arthritis Res Ther 2003, 5(Suppl 3):52 doi:10.1186/ar853

Published 12 September 2003

--------------------------------------------------------------------------------

Outline

Top

IL-1b is one of the main cytokines leading to the degradation of articular cartilage. One mechanism through which this cytokine exerts its effects is by articular chondrocytes being induced to produce nitrite oxide (NO). These findings are supported by clinical studies revealing a significant increase of NO production in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis. Modulating IL-1b-induced NO in articular chondrocytes appears to be an interesting challenge for reducing or inhibiting the cartilage destruction.

Heme oxygenase-1 (HO-1) is an inducible enzyme catalyzing the degradation of heme. The beneficial effects of HO-1 have been described for several diseases. This enzyme confers protection mainly through its antioxidant and anti-inflammatory functions.

The objectives of this work were to investigate the expression and activity of HO-1 in IL-1b-treated articular chondrocytes, and the corresponding molecular mechanism.

We used high-density primary cultures of rabbit articular chondrocytes. HO-1 expression was evaluated by Western blotting. HO-1 activity on IL-1b-induced NO was evaluated with use of the Griess reaction. Transient transfection of and Western blotting for IkBa, NF-κB, inducible nitrite oxide synthase and HO-1 elucidated the molecular mechanism of the HO-1 activity on IL-1b-induced NO.

We found evidence, for the first time, of the inducible expression of HO-1 in articular chondrocytes. Overproduction or overexpression of HO-1 is able to decrease dramatically in a dose-dependent manner the IL-1b-induced NO release in the culture medium from articular chondrocyte culture. The inhibition of NO production occurs at the transcriptional level through an NF-κB-dependent pathway.

These results demonstrate the critical role of HO-1 in inhibiting the IL-1b-induced NO. In vivo experiments are under investigation.
User avatar
OddDuck
Contributing Author
 
Posts: 1040
Joined: Sat Jun 19, 2004 3:00 pm
Location: Tennessee

PreviousNext

Return to General Discussion

 


  • Related topics
    Replies
    Views
    Last post

Who is online

Users browsing this forum: No registered users


Contact us | Terms of Service