Nogo-A, stroke and MS?

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Nogo-A, stroke and MS?

Postby dignan » Wed Jan 25, 2006 9:11 am

This is about stroke, but could this experimental treatment help in MS?



Stroke Brain Fix

During a stroke, like the one that felled Israeli Prime Minister Ariel Sharon, brain cells die from a lack of oxygen. But brain researchers may have found a way to make stroke-damaged nerve cells re-grow. This ScienCentral News video has more.

Stroke Hope

If Ariel Sharon wakes up from his coma, he could still face a long and hard recovery from his stroke. With the help of extensive therapy, stroke sufferers can sometimes regain lost speech and movement.

But research led by neurologist Wendy Kartje could spur stroke recovery by blocking a natural inhibitor of nerve cell re-growth.

When a stroke occurs, blood flow to part of the brain is interrupted when a blood vessel becomes damaged or blocked. The blood normally brings oxygen and nutrients that the brain cells in the immediate area need to survive. Without the blood the brain cells begin to die and stroke victims lose the functions that were controlled by those brain cells.

About 80 percent of all strokes are ischemic, caused by a blood clot that blocks a blood vessel or artery in the brain. The other 20 percent are caused by a weakened blood vessel that breaks and bleeds into the brain. This is known as hemorrhagic stroke, and is often fatal. Around 600,000 new strokes, or "brain attacks" are reported each year.

In the developing systems of young people and other animals, the central nervous system (CNS), which consists of around ten billion nerve cells, have the ability to spontaneously grow new nerve cell connections. "So there's really no blockade to new growth in the young developing system," says Kartje, from the Hines Veterans Administration Hospital in Illinois. But, when these young animals grow up and their nervous systems mature, this spontaneous re-growth no longer occurs — something is blocking it. "We know that adults have the same capacity to re-grow, it's just that they're being stopped from re-growing," she says.

In recent years, an international team of brain researchers, led by Swiss neurologist Martin Schwab, discovered that a protein called "Nogo-A" inhibits the re-growth and repair of injured nerve cells of the brain and spinal cord in adults. Nogo-A appears to be one of the stabilizers that come into play after development of the central nervous system has finished — when all the nerve fibers have grown to their places, made their appropriate connections, and the whole network is in a functionally mature state. "Nogo-A is one of the major inhibitors to new growth, there are others but, Nogo appears to be one of the major ones," Kartje explains.

Ladder walk
Ladder-rung walking test for leg movement.
image: Martin Schwab
In tests on stroke-damaged rats Kartje and her research team used a very specific antibody, an immune-system protein, to stop Nogo-A from binding to receptors on nerve cells. Without the inhibitory affect of Nogo-A, the injured nerve cells were able to re-grow, restoring lost movement to the front paws of the rats. "For the first time really we know that there is hope for people who have been disabled from stroke," says Kartje.

As she reported in the Journal of Cerebral Blood Flow & Metabolism, they initially trained aging rats — the equivalent of 70 or 80 years old in human terms — to perform highly skilled tasks, such as reaching through a small hole for food and walking along the rungs of a ladder, which required precise forelimb movement and coordination. A stroke was surgically induced in either the left or the right side of the sensory-motor cortex — the area at the top of the brain that controls conscious body movement — left the rats with paralysis of the paws on one side, and unable to do the tasks.

A week after the stroke, the rats began the two-week antibody treatment to block Nogo-A. "We're giving it one week after the stroke, which gives us a lot of time in the clinical world to get things organized and set up and to actually get therapy to the patient," Kartje explains. Just nine weeks after the treatment the aged rats recovered the use of their paralyzed paws. "Basically they begin to dramatically improve," she says. "And we've looked at the connections in the brain, and it's because of reorganization. So, new brain connections are actually formed."

This means in people the treatment would not have to be given immediately, "In humans it could be effective for quite a while after stroke," she explains, maybe even many months after a stroke hits, "and therefore there is a lot of hope to use this patients that have been disabled for quite a while."

So, the big question really is how long after a stroke would this kind of therapy work? Something Kartje and her colleagues are continuing to look into.

Kartje's team was only testing the therapy in the part of the brain that controls sensory movement – an area commonly affected by stroke – "More than likely, this kind of therapy could even be useful for other types of stroke in other parts of the brain," says Kartje, helping to restore lost speech and vision.

Kartje's research was published in Journal of Cerebral Blood Flow & Metabolism, October 2005, and was funded by The Veterans Administration, the National Institutes of Health, the American Heart Association and Loyola University Chicago.

http://www.sciencentral.com/articles/vi ... =218392726
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Postby viper498 » Wed Jan 25, 2006 9:29 am

I can't see why this wouldn't be applicable in patients with MS, AD, Parkinsons, Lou Gehrigs or even traumatic brain damage, and even spinal cord injuries. MS and the other actual diseases will of course be more challenging due to the fact that no one knows what is really causing the damage to begin with.

I wonder... If NOGO-A is inhibited MS patients, even when the underlying cause of the degeneration is active, would/could it repair the damage done, and/or could it outpace the degeneration? Hmmmmm.. Sounds like a promising lead.

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Postby OddDuck » Wed Jan 25, 2006 11:46 am

We had a discussion with regard to Nogo and MS back in 2004. For anyone interested, it is at: <shortened url>

(Disregard the first few lengthy posts between me and Willy. Anyone remember Willy? HAH! Anyway, Willy was just critiquing my writing style of my very first narrative for those first few posts - which is quite hilarious now, though........so whatever, Willy. :lol: )

Anyway, if you're interested, the best stuff starts about half-way down the page on page 1 when I start posting abstracts, then the probable more interesting stuff continues all through page 2 of that thread.

(Once again, please forgive me for the reference therein to desipramine, but........well need I say more?)

:wink:

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Postby Berserker » Wed Jan 25, 2006 12:01 pm

In regards to the previous thread about the myelin in MS patients being developmentally immature, perhaps the defect is this Nogo-A somehow prematurely becomes active during a critical stage in neural development. Thus makes the myelin more susceptible to attack or damage from an otherwise common virus or infection.

Interesting information, thanks for the post dignan....
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Postby OddDuck » Wed Jan 25, 2006 12:08 pm

Bottom line on the above?

I'd say "yes" to viper's question above, PROVIDED that Ca2+ influx and sodium density (for just a couple) are also regulated. They DO know a lot of what is degenerating the axons, etc., just not WHY it is doing it. Two different things.

We had a good discussion (here I go again, I know) back in January, 2005 about regeneration: <shortened url>

There are some really interesting research findings posted in that thread that also goes along with this discussion with regard to Nogo and regeneration.

At one point in that thread, I see I proposed the following (the whole post and references to other items of interest you can read can be found in the thread):

Wesley, and all:

Ok.......regarding axon "regeneration" in the ADULT CNS. I found a terrific LENGTHY article.

I'll post some of it here, but what it basically is saying is what Wesley alluded to earlier here, and what the original discussion I posted first in this thread is talking about. Axon regeneration in the adult CNS is somehow inhibited. This is what researchers are now working on. How to "trigger" or activate the regeneration process in the adult (i.e. postnatal) CNS.

These excerpts below are talking about how to activate "in vivo" (key words there) axonal regeneration in the CNS. The thought is it takes not only growth factors and neurotrophins, but ALSO an elevation in cAMP at the same time in order for CNS regeneration to result.

I propose to go one step farther (based on prior research of mine). If you can also block PKC activity, inhibit Nogo-A/NgR (which is a protein that has been found to impair regeneration in the CNS after injury), and also enhance GAP-43 at the same time as increasing neurotrophins and elevating cAMP, what have you got then? The possibility or even probability of activating axonal regeneration in the adult CNS in vivo?? I'd say YES!

Here are some interesting findings. I'll warn you, they are lengthy. The whole article can be found at http://www.genesdev.org/cgi/content/full/17/8/941 ...."
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