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Damn those lucky mice------

Alleviating the burden of Multiple Sclerosis
Researchers discover a cellular signal that aggravates the symptoms of MS and might be targeted in new therapeutic approaches
Depression, coordination and speech problems, muscle weakness and disability are just a few of the symptoms of Multiple Sclerosis (MS). Researchers from the Mouse Biology Unit of the European Molecular Biology Laboratory (EMBL) in Italy and the Department of Neuropathology at the Faculty of Medicine, University of Göttingen, Germany, have now discovered that these symptoms are aggravated by a specific signal in cells in the nervous system. The study, which will appear in this week's online issue of Nature Immunology, suggests that blocking the proteins that regulate the signal might be an efficient strategy for new therapies against MS.

Nerve cells in our brain and spinal cord communicate with each other using electrical signals. This communication is fast and efficient because - just like wires in an electrical circuit - the axons of our nerves are surrounded by an insulating layer. In MS this protective sheath, made up of a mixture of lipids and proteins called myelin, gets destroyed by cells of our own immune system, and the communication between nerve cells gets disrupted. A central player in the molecular mechanisms behind MS is a signaling molecule called NF-kB.

"We have known for a long time that NF-kB is crucially involved in MS," says Manolis Pasparakis, a former Group Leader at EMBL's Mouse Biology Unit who now works as a Professor at the Institute for Genetics at the University of Cologne, "but until now it was not clear if it was friend or foe. We were not sure whether it protects the brain cells against the consequences of the disease or actually aggravates the damage."

To get a clear picture of NF-kB's role in MS, Pasparakis and his scientific collaborators at the University of Göttingen investigated what happens to mice with an MS-like condition if the action of NF-kB is blocked. To shut down the signal they inactivated IKK2 and NEMO, two proteins that activate NF-kB.

"This was quite a challenge because NF-kB is involved in many crucial processes throughout the entire body, and shutting down its activation in all cells kills the mouse before it is born," says Pasparakis, "To observe the effect of NF-kB in MS, we used sophisticated genetic techniques to generate mice that do not express IKK2 and NEMO in brain cells only."

The results were mice that showed much milder MS symptoms than normal, an effect that is very likely to be linked to the lower amount of inflammatory messengers produced by their brain cells.

"NF-kB regulates the production of messengers that are released during inflammation to recruit and activate immune cells," says Marco Prinz, whose group at the University of Göttingen collaborated in the research. "Generally this is a good strategy to protect the body from infections. But in MS it is exactly these immune cells that cause the problem and their hyperactivation through NF-kB only makes the situation worse."

Blocking IKK2 and NEMO interfered with this pathological action of NF-kB and alleviated the symptoms of MS. This makes the proteins promising as potential drug targets for new therapies against the disease. The human NF-kB signaling network is very similar to that of mice, so that compounds that inhibit IKK2 and NEMO are likely to lead to the same alleviation of symptoms in humans.

another article on NF-kB

Target for new MS drugs revealed

MS affects the brain and spinal cord
Scientists say they have found a drug target for new therapies to aid people with multiple sclerosis.
Blocking a cell signal in the nervous system alleviated MS symptoms in mice, the German team told Nature Immunology.

Experts say more work is now needed to check that blocking this signalling molecule, called NF-kB, will achieve the same desired effect in humans.

Every week in the UK about 50 people, typically aged between 20 and 40, are diagnosed with MS.

Immune system malfunction

The exact causes of MS are not known, but it is believed that MS is caused by something foreign to the body, like a virus or a pollutant.

This causes the body's immune system to malfunction and start attacking and destroying the protective myelin sheath that coats the nerves in the brain and spinal cord.

The disease affects people differently and symptoms can last for several weeks to several months at a time.

Initially MS causes loss of balance, reduced vision and bouts of localised paralysis. Eventually, patients may become totally paralysed and wheelchair-bound.

This looks exciting. More and more is being discovered about MS at the cell level

Chris Jones, chief executive of the MS Trust

Scientists have known for some time that NF-kB is involved in MS. But it was not clear whether NF-kB protected the brain cells against the consequences of the disease or aggravated the damage.

To investigate this, Dr Marco Prinz and colleagues studied genetically altered mice with an MS-like condition.

In these mice it was possible to turn NF-kB on and off by manipulating two proteins, called IKK2 and NEMO, which activate the molecule.

Blocking IKK2 and NEMO, thereby switching off NF-kB, alleviated MS symptoms in the mice.

Given that the human NF-kB signalling network is very similar to that of mice, the researchers believe compounds that inhibit IKK2 and NEMO should be investigated further as potential MS treatments.

Dr Prinz said: "NF-kB regulates the production of messengers that are released during inflammation to recruit and activate immune cells.

"Generally this is a good strategy to protect the body from infections. But in MS it is exactly these immune cells that cause the problem and their hyperactivation through NF-kB only makes the situation worse."

Chris Jones, chief executive of the MS Trust, said: "This looks exciting. More and more is being discovered about MS at the cell level."

However, he stressed that much more work was needed to determine whether the same effects would be seen in humans.

Dr Lee Dunster, head of research and information at the Multiple Sclerosis Society, agreed, saying: "We have to remember that what works in mice does not unfortunately always work in men."

Scooby

Thanks for the info. The "hormone" perspective is that DHEA may play a role in this.

DHEA Inhibits NF-kB

Altogether, these results suggest that DHEA/DHEAS have an antiinflammatory effect in such a way that they inhibit proinflammatory cytokine-stimulated, NF-kappaB-mediated transcription, at least partly through their antioxidant properties.

DHEA Suppresses EAE

In vivo administration of DHEA significantly reduced the severity and incidence of acute EAE, along with a decrease in demyelination/inflammation and expressions of (pro)inflammatory cytokines in the CNS. These studies suggest that DHEA has potent anti-inflammatory properties, which at least are in part mediated by its inhibition of NF-kappaB activation.

If you have your DHEA levels measured and they're low, it's another thing for you and your physician to think about. They do tend to be low in people with MS.

A little OT but I noticed the NMSS Aug-Sept. Inside MS magazine had a small paragraph mentioning estriol, testosterone and DHEA.

Sharon

There is stuff out there on this. I've posted about this in relation to acorbic acid. It also seems to be the case that not all ascorbic acid is the same. I'm still looking into this, but the one we're taking is oxidized from potassium and other minerals.

you need to dig a bit through this post to get to the NF-KB part, but IMHO it's worth the effort napay

NF k-B is also inhibited by aspirin. IT also inhibits Chlamydia pneumoniae, so we have a citation in our CPn archives on this. Here is a link to that research
CPn Help/pdfs/Aspirin:Cpn.pdf
read this paper and you will see that ASA inhibits NF-kB through a mechanism unrelated to CPn (I had a hard time with the link as it keeps putting a space in it after cpn but all the words are there for the interested person)

Aspirin works fairly well in people with RA to reduce inflammation but once again we have old bugaboo issue of people's disease progressing in spite of this reduced inflammatory activity.

Aspirin has also been tested in MS and found to be useless. Here is a blerb on a NMSS site that mentions this:

Quote: Aspirin and sodium salicylate are two moderately anti-inflammatory agents that affect the prostaglandin pathways. Peptic ulceration and gastrointestinal bleeding are two side effects common to these agents which appear to have no effect on MS. Aspirin may be beneficial for pain relief, but acetaminophen has fewer side effects and certain advantages over aspirin. Neither are used to treat MS".end quote

Since ASA inhibits NF-kB and it has also been tested in MS and found to be ineffective, I submit that this is another blind ally for research.

I am in the "MS is not autoimmune " camp and therefore the constant focus on the proinflammatory cytokines and the vast amounts of research dollars spent looking for ways to inhibit inflammation are to me very off topic. NF-kB is just another of these approaches. ( For those in the CPn camp of course the issue that CPn causes upregulation of NF-kB is yet another smoking gun for CPn being potentially related to MS.)

In the first post a hint of the size of the problem is there when the authors state the difficulty they had in creating a mouse that did not express NF-kB....they DIED in the womb. This suggests how many problems will ben encountered should they find a way to ihnibit our NF-kB. I would not invest in a company making this product ! I'll be much happier to see more in the neuroprotective and regeneration research arenas.

Marie

Sharon, I saw those articles too, particularly on the success with the testosterone gel trials. I was kind of surprised because I thought that previous small trials found little benefit. Of course as always they have to perform bigger trials before they know anything for sure. Hard to get excited about anything in early trials but hormones seem to be a hot topic. Marie, I totally agree about being more excited to see progress in the neuroprotective and regenerative fields but maybe they will be able to find something effective at relieving symptoms that will lead to research breakthroughs in other fields. That's my hope anyway.

First I want to thank Lyon for finding me the archive site, I've not really used it yet, but I'm expecting the loss of this find again, so I'm putting the links up.

It's hard to find papers on NF-KB and I found 3 in one place. So you might want to print them up while you can.

http://minf.vub.ac.be/~chrisvs/PapersMCD9.pdf
http://www.archive.org/http://minf.vub. ... rsMCD9.pdf

Ken

Resveratrol (Red Wine) and Tumeric (Curcumin) are also two known NF-Kb inhibitors.

--Frank

Another bit of recent research on NF-kappa B:


Researchers discover a new pathway that regulates inflammation

March 11, 2009 - Inflammation, the body's earliest response to damage or infection, can aid the healing process and trigger an immune response against invading pathogens. But inflammation gone awry can also undermine health, as in diseases such as rheumatoid arthritis or asthma.

Researchers at the University of Illinois have identified a novel pathway that controls the activity of a key protein involved in inflammation. Their findings could have important implications for the treatment of diseases or conditions linked to chronic inflammation.

At the heart of the cell's inflammatory response is a protein complex called NF-kappa B. In the new study, biochemistry professor Lin-Feng Chen and his colleagues deciphered a molecular code that controls its function. Their results appear in the European Molecular Biology Organization (EMBO) Journal.

for the rest of the story:
http://www.physorg.com/news155993656.html