BBB leaks in lesions

[TwistedHelix]

If you can get through all the numbers and jargon in this abstract, I think it says that there is a small amount of BBB leakage in non-active lesions, and that natalizumab does nothing to stop this.

LeakyBBB
Dom.

PS Special clue for you, Bob: try clicking on the words 'leakyBBB'

[TonyJegs]

-finn
from the abstract:
There is evidence of a subtle BBB leakage within visibly non-enhancing lesions in RRMS that was not modified by alpha4 integrin blockade in this substudy cohort. -end

Of course there will be leakage, this drug couldn't prevent it by mechanism of its action.
The difference between visibly enhancing and non-enhancing lesions: first ones you can compare with flash flooding area, second ones - wet spot/pool under leaking drainage pipe.
BBB always break down as a response of brain tissue damage, this is a fundamental rule, we're build this way.
What this drug do is removing/blocking a part of highly specialized immune response developed by Nature in mammals, that's all.

Kind regards,
Tony

[daisy]

Tony,

Please clarify your above post. You wrote "BBB always break down as a response of brain tissue damage, this is a fundamental rule, we're build this way. "

Setting aside trauma, CVA's, etc... as brain tissue damage...

Is your opinion, that the BBB breaks down as the result of something that happens in the way of brain tissue damage in Multiple Sclerosis or is it that something breaks down the BBB that leads to MS?

Thanks!

Daisy

[TwistedHelix]

Tony,

This drug was never intended to block leaks in the BBB. It works, as I'm sure you know, by blocking the adhesion molecules on the surface of CD4+ T helper cells to stop them sticking to endothelial cells and beginning the process of crossing the BBB. Since it appears to be successful in reducing the relapse rate, there is at least some merit to this approach. In my opinion this piece of research merely serves to confirm these facts, and I think it's always worthwhile investigating what a drug does inside a real living body because there have often been surprises in the transition from the lab.

I know that the BBB opens up in response to injury to allow more blood products through, but is that the same thing as breaking down and leaking? In BBB leakage the tight junctions between the endothelial cells are compromised because of failure in proteins like ZO-1, which allows damaging substances such as Fibrinogen through. Is this exactly what happens in the injury response, or is it something more selective? Natalizumab at least seems to have a role to play in closing down one illegal point of entry into the CNS.

Dom. (definitely not Finn).

[TonyJegs]

- Dom

The specific mechanism(s) by which TYSABRI exerts its effects in multiple sclerosis have not been fully defined. In multiple sclerosis, lesions are believed to occur when activated inflammatory cells, including T -lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and their counter-receptors present on endothelial cells of the vessel wall.
The clinical effect of natalizumab in multiple sclerosis may be secondary to blockade of the molecular interaction ofa4ßl-integrin expressed by inflammatory cells with VCAM-l on vascular endothelial cells, and with CS-L and/or osteopontin expressed by parenchymal cells in the brain.
Data from an experimental autoimmune encephalitis animal model of multiple sclerosis
demonstrate reduction of leukocyte migration into brain parenchyma and reduction of plaque formation detected by magnetic resonance imaging (MRI) following repeated administration of natalizumab. The clinical significance of these animal data is unknown.
-from FDA protocol-

MS is an auto-immune disease that damages and prevents the creation of the tissues that protect nerves, called myelin. This creates lesions, or scar tissue known as sclerosis. Lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier. Leukocyte migration involves interaction between adhesion molecules on inflammatory cells, and their counter-receptors present on endothelial cells of the vessel wall. The drug works by blocking the integrin molecule and preventing immune cells from migrating through blood vessels in the brain to areas of inflammation; however the specific mechanism by which TYSABRI exerts its effects in multiple sclerosis have not been fully defined.
-from centerwatch.com (drug info site) –

http://www.medscape.com/viewarticle/543478_9 - for additional information

http://www.natalizumab-moa-cme.com/content/Main.swf
Good presentation, someone could get seduced. Everything looks fine, except the main idea – organized attack on the myelin from the bloodstream. Round we go, old “autoimmunity” deployed.

Do you know that there are preferred sites of MS plaque distribution? That rises a question - how they know where to attack.? Why they do not attack at random and do not launch massive/total attacks? There are millions of leukocytes in the blood, why we do not see these attacks everywhere in the body where myelin is present (myelin is present virtually in every organ of the body via innervation)?

About MS plaques:
-
The four patterns that were identified are:
Pattern I
The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation.
Pattern II
The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, as before, but also signs of complement system activation can be found.
Pattern III
The scars are diffuse with inflammation, distal oligodendrogliopathy and microglial activation. There is also loss of myelin associated glycoprotein (MAG). The scars do not surround the blood vessels, and in fact, a rim of preserved myelin appears around the vessels. There is evidence of partial remyelinization and oligodendrocyte apoptosis.
Pattern IV
The scar presents sharp borders and oligodendrocyte degeneration, with a rim of normal appearing white matter. There is a lack of oligodendrocytes in the center of the scar. There is no complement activation or MAG loss.
- from Wikipedia, Mayo clinic research –

Dunno why there are only 4 now left, there were 5 types before (I. MacDonald times)
There is more, one patient could have different types of plaques in combination. How that fits in “autoimmunity”?
EAE model was good for last century 50ties, but how long it will be explored?

More powerful drug, more toxicity we would expect. Potentially it will open the gate to brain for all kind of neuro-“attractive” viruses, remember the passage of increased Herpes cases in treated patients? Remember the findings that there is a correlation with elevated Herpes antibodies and MS?

This is going to be very huge post. I would like to cover more, but there are technical limits.
With all my respect to this forum I would like to keep my post shorter, simply I have not so much spare time for that.
Let’s be patient and walk trough all this stuff step by step.

-daisy
BBB breaks down as a result of brain tissue damage.
Usually we deal with BBB breaks during neuro-infections, but it must be a massive attack. Say, it's kinda hard to break it.
In case of erupted aneurysm BBB breaks first also, but this is ‘mechanical’ breakdown.
In EAE model BBB breakdown induced artificially by injecting special toxic substance.

Kind regards,
Tony