The blood brain barrier and neurons

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The blood brain barrier and neurons

Postby TwistedHelix » Tue Apr 08, 2008 5:58 am

Although this article focuses on ALS, it's a good summary of the effect of a leaky BBB on the central nervous system. The gene for SOD 1 has also been implicated in MS. The review mentioned at the end of the article sounds interesting: has anyone had a chance to read it?
Contact: Tom Rickey
tom_rickey@urmc.rochester.edu
585-275-7954
University of Rochester Medical Center
Leaky blood vessels open up nerve cells to toxic assault in Lou Gehrig's disease

Leaky blood vessels that lose their ability to protect the spinal cord from toxins may play a role in the development of amyotrophic lateral sclerosis, better known as ALS or Lou Gehrig’s disease, according to research published in the April issue of Nature Neuroscience.

The results mark the first time that scientists have witnessed molecular changes occurring long before key nerve cells start dying. The unexpected finding opens up a new front in studies of ALS, a disease in which motor neurons in the spinal cord die off for unknown reasons, resulting in dramatically weakened muscles. Patients lose their strength, their ability to move or swallow, and eventually lose their ability even to breathe. Most patients live only a few years after diagnosis.

“We believe these changes contribute to or possibly initiate the onset of ALS,” said lead author Berislav Zlokovic, M.D., Ph.D., of the University of Rochester Medical Center. “It’s clear that these changes occur before the loss of neurons, and it’s well known that the types of changes we are seeing certainly injure or kill these types of cells, which are extremely sensitive to their biochemical environment.”

The results, discovered by studying mutant mice that have an inherited form of the disease, were made by a collaboration of neuroscientists from the University of Rochester Medical Center working together with a team of ALS experts from the University of California at San Diego. Zlokovic, a pioneer in learning how the body’s vascular system plays a role in neurodegenerative diseases like Alzheimer’s disease and ALS, led the team, and the first author is post-doctoral researcher Zhihui Zhong, Ph.D.

While it’s unlikely the new findings will help ALS patients immediately, the results open up a new and unexpected way to think about the disease. Zlokovic’s team is currently testing in the laboratory a compound that may help seal up leaky vessels and protect the neurons targeted by ALS.

The team studied mice with a mutation in a gene for superoxide dismutase 1 (SOD-1), which in healthy people and mice plays an important role keeping cells safe from damaging molecules known as free radicals. Scientists estimate that SOD-1 mutations play a role in a small number of cases of ALS overall in people, about one-quarter of the 10 percent or so of cases that are inherited. But those cases provide a unique window to study the disease’s initial steps.

In the Nature Neuroscience paper, the group from Rochester’s Center for Neurodegenerative and Vascular Brain Disorders and UCSD showed that a breakdown in the natural barrier between the blood and the spinal cord breaks down early on in mice destined to get ALS, long before nerve cells appear sick or die.

In this work, the team showed that the barrier between the blood and the spinal cord weakens in all three types of genetically based ALS cases that involve SOD-1 mutations, allowing toxic substances to flood into the spinal cord and directly affect neurons.

That barrier is crucial for the health of our central nervous system, which is treated like the inner sanctum of the body. Like a high-performance race car that demands a choice fuel, our neurons work well only if the chemical environment in the brain and spinal cord is precisely maintained within a strict, narrow set of conditions.

To maintain that select environment, the body has strict barriers or gateways for substances entering or exiting the central nervous system. Blood vessels run through our brain and spinal cord and supply oxygen and other nutrients, and the lining of those blood vessels constitutes a biochemical barrier to protect the central nervous system from toxins, inflammatory cells, red blood cells, blood products, and a variety of other potential toxic insults.

The barrier between the blood and the spinal cord isn’t some stand-alone structure that keeps all substances away from the spinal cord. Rather, the word “barrier” describes an elaborate molecular lattice that lines the insides of the blood vessels that weave throughout the spinal cord. The lattice controls which molecules can cross from the blood to the neurons in the spinal cord, and which cannot. It’s a bit like netting with very small openings that line the inside of blood vessels.

Oxygen and many nutrients get the OK to pass through the barrier in measured amounts. And the barrier readily accepts waste products from the spinal cord, transporting them away from the central nervous system and eventually out of the body. But the “netting” should be taut and should bar substances in the blood that have no business being near neurons.

The team found that a SOD-1 mutation disrupted key building blocks in the barrier. Essentially, the mutations loosened the lattice, creating bigger holes in the barrier that allowed molecular interlopers to pass from the blood to the spinal cord.

Mice with the mutation had lower levels of three types of “tight junction proteins” that are key components of the barrier: ZO-1, occludin and claudin-5. In mice just two months old, the numbers of those important tight junction proteins in the linings of blood vessels were reduced by about half, by 40 to 60 percent, allowing the lattice to loosen abnormally.

The weakened barrier brought about several problems. Neurons were exposed directly to biochemical byproducts of hemoglobin, which forms reactive oxygen molecules that injure neurons. Where the barrier had weakened, tiny hemorrhages dotted the spinal column. The smallest blood vessels crucial to nerve health shrunk: Mice with the mutation had total capillary length in the spinal cord 10 to 15 percent less than healthy mice, and their blood flow in the spinal cord was reduced by 30 to 45 percent.

Scientists must investigate whether the same processes happen in forms of ALS that are not inherited. Zlokovic notes that from what is known so far, the disease progresses exactly in inherited forms and forms that are not inherited.

“The vascular system is crucial to health – it’s how oxygen and other nutrients are delivered to cells, and how toxins are removed,” said Zlokovic, who is professor of Neurosurgery and Neurology and director of the Center for Neurodegenerative and Vascular Brain Disorders. “Any damage to the vascular system is a serious threat to the organism. It’s clear now that the vascular system is certainly involved in the development of ALS.”

Zlokovic first began doing research on the disease in 2004, when a former classmate from medical school who had been diagnosed with ALS and was looking for new treatments contacted him. By the time his friend died two years later, Zlokovic was well underway in studies investigating the possible role of the vascular system.

During the last 15 years, Zlokovic has pioneered the view that the vascular system plays a central role in many neurodegenerative diseases. He has found that a breakdown in the barriers between the blood and the central nervous system may be at the root of diseases like Alzheimer’s. In January, Zlokovic reviewed the evidence for involvement of the barrier in diseases like Alzheimer’s, ALS, and multiple sclerosis in a 24-page review in Neuron.
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Postby Lyon » Tue Apr 08, 2008 7:27 am

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SOD's law

Postby gibbledygook » Tue Apr 08, 2008 8:12 am

SOD in MS is discussed in a paper by
K. Lund-Olesen
I have abbreviated the paper as follows:
He has demonstrated extremely low levels of superoxide
dismutase (SOD) in the cerebrospinal fluid (CSF) of
patients suffering from multiple sclerosis (MS) (and low
levels have also been shown in other neurological diseases)
(2). It is hypothesized that MS is caused by a deficiency
of SOD; this deficiency can result from either far
too little being produced or the production of inactive
SOD.
EVIDENCE
While working as the Senior Physician at Ringe Hospital,
he was engaged in research, the object of which was to
study the effects of the injection of a bovine SOD given to
patients suffering from various conditions. The compound
proved to be an effective anti-inflammatory agent
(3); its effects were also studied in patients suffering from
MS. The CSF was analyzed
using electrophoresis and NBT staining for its content of
SOD, and it was found that the content of this compound
in patients suffering from MS was so low that in some
cases it was impossible to determine the level.
DISCUSSION
The above observations appear to indicate that MS, as
well as other neurological diseases, are either caused by a
lack of active SOD or a non-active type of SOD, as suggested
in recent reports describing the part played by
SOD in the blood of patients with amyotrophic lateral
sclerosis (1).
The question then arises as to just how a lack of active
SOD leads to a number of neurological diseases. It is
known that an excess of free electrons occurs in all living
multicellular organisms having an oxidative metabolism.
These electrons are immediately bound to O2 forming
O2–. The absence of oxygen in such cells would immediately
lead to cell death. However, O2– is also a dangerous
oxidant, which must be removed if the cell is to survive.
When sufficient quantities of SOD are available there is
little danger of cell death because lactalase and peroxidase
remove the H2O2 formed. However, if sufficient
quantities of SOD are not present, then reactive oxidant
species are formed, which oxygenate the double bindings
in the cell wall, including those of the fatty acids. Should
this take place the cell wall will become permeable to Caions inter alia; this will result in an increase in the rate of
function of the cell. When this occurs in motoric neurones,
it will lead to muscle contractions and possibly
spasticity. This increased activity of the cell requires
increased metabolism and thus if the need for SOD cannot
be met in the normal way by increased formation of
the compound, or by supplementation from the intercellular
space, then a vicious circle occurs and results in the
death of the cell, with subsequent paralysis. As motor
neurones are some of the most active brain cells, they are
those most likely to suffer injury by the reactive radicals.

I took substantial amounts of glisodin, a form of sod which can be readily absorbed by the gut for about a month recently. This seemed to induce a relapse, so maybe people with MS are low in SOD for a reason.

Perhaps epstein barr contributes to our lack of sod.
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3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Postby cheerleader » Mon Oct 27, 2008 1:50 pm

Wanted to bump this paper Dom posted last spring, in case folks missed it- in light of all of our vascular musings and my (and lots'o others) continued hunch that MS is a neurodegenerative, rather than autoimmune, disease. Jeff's done well on glisodin and antioxidants.
AC
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dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby rainer » Mon Oct 27, 2008 9:16 pm

The barrier between the blood and the spinal cord isn’t some stand-alone structure that keeps all substances away from the spinal cord. Rather, the word “barrier” describes an elaborate molecular lattice that lines the insides of the blood vessels that weave throughout the spinal cord. The lattice controls which molecules can cross from the blood to the neurons in the spinal cord, and which cannot. It’s a bit like netting with very small openings that line the inside of blood vessels.


I didn't realize this until about a month ago and was really struck by how entwined the BBB is with the nervous system. It becomes much easier to see how vascular abnormalities could cause damage to nerves when they're like vines wrapping around a tree.
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Postby gibbledygook » Tue Oct 28, 2008 4:18 am

To my mind, this is exactly the problem and that MS isn't even neurodegenerative. It is merely a problem of the vasculature. My improvements with salvia and ginkgo which dilate the endothelium (amongst other things) leads me to this conclusion. If blood gets into places it shouldn't be, a whole cascade of activated microglia and assorted inflammatory cytokines will hit the various affected areas but this is only a result of the initial insult of blood getting where it didn't oughta! 8)
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Postby Loobie » Tue Oct 28, 2008 6:23 am

OK, this discussion is way over my head. But after reading I have, hopefully, a simple question for those that understand this. Could this be why the MAB drugs like Tysabri and others are working a bit better than the CRAB's? Because they block things that do damage whey they cross over? I hope I'm not completely missing the point. Let me know if this question even makes sense on this thread.
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Postby cheerleader » Tue Oct 28, 2008 7:41 am

Loobie wrote:OK, this discussion is way over my head. But after reading I have, hopefully, a simple question for those that understand this. Could this be why the MAB drugs like Tysabri and others are working a bit better than the CRAB's? Because they block things that do damage whey they cross over? I hope I'm not completely missing the point. Let me know if this question even makes sense on this thread.


You got it, Lew. Your question makes absolute sense. It's really not that complicated. Just "medicalese". There's two different ways to tackle this problem:
1. Kill the invaders
2. Heal the defensive "netting" or barrier
The endothelium is the blood vessel lining, or the barrier they refer to. It's only one cell thick and is responsible for keeping vessels intact, coagulation, immune function and vascular dilation. It runs throughout the body, into the spine and brain. It also secretes nitric oxide, which makes this whole system balanced. If there is damage to the endothelium from toxins, free radicals, bacteria, the netting frays and lets the bad guys in.
I'm looking at ways to heal the breech (posted my paper on regimens thread) These researchers at U of R have found a genetic mutation for SOD-1, which protects the endothelium and which they believe predisposes some people to this breakdown. Perhaps stem cell therapy may someday address this.
Until that time, CRABS, antibiotics and chemo are killing the invaders, with a variety of success. Copaxone tries to retrain the rogue killer t-cells, antibiotics go after the bacteria, and chemo knocks the crap out of everything. BUT (and this is a big BUT) if the endothelium is still not healthy, the leakage will continue.
This is all just my 2 cents, but it makes more "sense" and includes more of the MS theories than anything else I've read in the last couple of years.
AC
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby Loobie » Tue Oct 28, 2008 7:56 am

Thanks Joan,

I get my first Ty. infusion this Thursday and am a little apprehensive about it and trying to learn all I can.
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Postby cheerleader » Tue Oct 28, 2008 8:16 am

Be thinking of you, Lew. I pray that tysabri puts the brakes on for you, and gives you a chance to heal.
Joan
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Postby Lyon » Tue Oct 28, 2008 2:00 pm

.
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Postby Terry » Tue Oct 28, 2008 2:35 pm

Me too, Loobie.
I have what I think are called Beau's lines on my fingernails. Had them for many years. I've been looking, and there is a vascular issue with these. (never saw that before now) I have Alopecia Areata. Also a vascular link. (never saw that, either) Also checked pregnancy and vascular and find that there are endothelial (precursor?) cells that come out of the bone during pregnancy. The reason some get better during?
I am behind you, Cheer. It is looking good!
Link this to sinus or why folks get optic neuritis usually first, and I think you deserve a party! Ha!
That said, I still haven't been out to restock on supps, but I will soon. Been feeling bad. Probably a reason to hurry, but there seems to be no hurry in me right now.
Really, Cheer, I think you deserve a party anyway. And Gibbledygook, too. All the studying you all do would wear me out!
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Postby CureOrBust » Tue Oct 28, 2008 6:06 pm

Good luck and all the best with your infusion.
Loobie wrote:I get my first Ty. infusion this Thursday ... and trying to learn all I can.
The one thing I have been trying to "learn" about Tysabri, is the "rebound" effect that was talked about, when patients stopped treatment. Please let me know if you find the answer / explanation to this.
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Postby Loobie » Wed Oct 29, 2008 12:15 pm

Thanks for all the well wishes guys! Well I just got off the phone from my infusion site. They have to reschedule me (take deeeeep breaths, you all remember me from last X-mas, no?) since the infusion nurse is sick. Well we've become friends through the Tovaxin debacle and I have his cell phone so I called him and told him he is a wuss. Now I feel much better and will get dosed Friday or Monday. That's a lot better than the four month delay I had on my blood draw!

I love this thread though. It's almost as if a bunch of laypeople (sorry to all you out there who really are researchers!) have stumbled into putting some pretty concrete concusions together. You guys with all the gray matter just keep it up. I'm loving reading it. gives me hope since I almost think maybe we've been running down many blind alleys. IF MS turns out to be vascular, there will be much egg on many faces......
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Postby dignan » Sun Nov 09, 2008 1:05 pm

Cure,

Regarding that rebound effect, this new abstract suggests that maybe there isn't one...


Immunologic and clinical status 14 months after cessation of natalizumab therapy.

Neurology. 2008 Nov 5.

Stüve O, Cravens PD, Frohman EM, Phillips JT, Remington GM, von Geldern G, Cepok S, Singh MP, Cohen Tervaert JW, De Baets M, Macmanus D, Miller DH, Radü EW, Cameron EM, Monson NL, Zhang S, Kim R, Hemmer B, Racke MK.

From the Neurology Section (O.S.), VA North Texas Health Care System, Medical Service, Dallas; Departments of Neurology (O.S., P.D.C., E.M.F., G.M.R., M.P.S., E.M.C., N.L.M.), Immunology (O.S., E.M.C., N.L.M.), Ophthalmology (E.M.F.), and Clinical Sciences (S.Z.), University of Texas Southwestern Medical Center at Dallas; Department of Neurology (O.S., G.v.G., S.C.), Heinrich Heine University Düsseldorf, Germany; Multiple Sclerosis Center at Texas Neurology (J.T.P.), Dallas; Departments of Clinical and Experimental Immunology (J.W.C.T.) and Neurology (M.D.B.), University Hospital Maastricht, The Netherlands; Department of Neuroinflammation (D.M., D.H.M.), Institute of Neurology, Queen Square, London, UK; Institute of Neuroradiology (E.W.R.), Department of Medical Radiology, University Hospital Basel, Switzerland; Biogen-Idec (R.K.), Cambridge, MA; Department of Neurology (B.H.), Klinikum Rechts der Isar, Technische Universität München, Germany; and Department of Neurology (M.K.R.), The Ohio State University Medical Center, Columbus.

OBJECTIVE: Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis (MS). A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy. The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunologic parameters in peripheral blood and CSF, as well as safety in patients with MS after discontinuation of natalizumab therapy.

METHODS: This study is a longitudinal and serial cross-sectional assessment, in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled. A subgroup of patients was followed over 14 months. The annual relapse rate, neurologic disease progression assessed by the Expanded Disability Status Scale, disease surrogate markers on MRI, cellular and humoral immune markers in peripheral blood and CSF, and adverse events of the drug were monitored.

RESULTS: With regard to clinical disease activity, neuroimaging, and immune responses, the majority of patients in our cohort were stable. Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab. No infectious complications were observed.

CONCLUSION: This is the first long-term follow-up of patients who discontinued natalizumab. We did not observe a clinical, radiographic, or immunologic rebound phenomenon after discontinuation of natalizumab therapy.

Pubmed link
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