I have Parkinson's disease (PD), and have had it now for 16 years. Below is a review I have done on the dysfunction of the blood brain barrier as a cause of PD, (and of MS and possibly ALS?).
Ron

Total BBB Review

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

I have finally got all my information together in one place!!!
There is a lot of evidence that the Blood Brain Barrier (BBB) permeability plays a very significant part in PD. It also seems significant in ALS, (and they have less time than we have, fatal in 2 to 5 years), and in MS. It seems to be only part of the story in AD, (Alzheimers), but may improve matters somewhat.
Either we were born with defective BBB's, or we damaged it by some mechanism or other, during life. We did polls and surveys to try and find out what it is we all have in common, sweet tooth consuming too much sugar, stress while in the womb, anxiety complex, and the rest. However Prof Leenders in Holland has shown one thing we do all have, a defective BBB.
Below, there are statements quoted from the literature, such as
" BBB disruption is one of the hallmarks of Multiple Sclerosis", and
""Increased permeability of the BBB is a feature of many diseases of the CNS (Central Nervous System)" There is much more work we could do to make a more watertight case. Add to the list of substances that close the pores of the BBB, GDNF, alpha lipoic acid, curcumin, citicoline, bilberry extract, doesn't the list look familiar? What about Q10, ginko biloba or any others?
Have a look at the following and add to it, constructive negative facts welcomed too, which may help to crystallise our thoughts.

Ron
The role of the Blood- Brain Barrier in Neurological diseases
The BBB is a membrane which protects the delicate brain from toxic substances, which come from a number of sources, but in a person with a normal efficient BBB, the toxins circulate harmlessly in the blood. However, people can be born with defective organs, such as the heart, lungs,, kidney, liver or BBB, or they could be damaged during life.
Can a defective BBB be the major cause of PD, MS, ALS and AD (Alzheimer’s Disease).

In
http://lpi.oregonstate.edu/ss03/zinc.html
It states,
", Alterations or dysfunction of the BBB have been observed in many brain disorders. Free radicals may play an important role in damaging the BBB because it is especially sensitive to oxidative damage. This vulnerability may be due to the high polyunsaturated fatty acid content of the BBB membrane—fatty acids that are very susceptible to free radical attack—as well as the relatively low antioxidant capacity of the BBB. Oxidation of the membrane drastically compromises its barrier properties and may lead to subsequent brain tissue damage, resulting in a host of pathologies.”


The data below shows a strong connection between a defective or porous BBB on neurological diseases.

l. Parkinson’s Disease.

This article states that the BBB Blood Brain Barrier is defective in PD patients, and that it might in the course of years allow toxic compounds … to enter the brain.
http://www.imakenews.com/wemove/e_ar...m0s,b1QrWd7M,w
E-MOVE reports from the 9th International Congress of Parkinson’s Disease and Movement Disorders, New Orleans 5-8 March, 2005. Pages and abstract numbers are from Movement Disorders 2005;20(suppl 10).
Blood-brain barrier dysfunction in Parkinson’s disease
KL Leenders, R Kortekaas, AL Bartels, J Oostrom, A Willemsen, J Bart
S77, P257
The blood-brain barrier is defective in PD patients, according to this study. PET imaging of verapamil was used to measure activity of the P-glycoprotein system, which transports unwanted substances out of the endothelium back into the blood. Comparing five PD patients to five controls, the authors found significant differences in the brain penetration of verapamil (18% higher for PD patients, p=0.02) only in the midbrain region. All patient values were higher than all controls. The authors suggest, “A faulty BBB function on the basis of genetic predisposition might in the course of years allow toxic compounds—or compounds normally circulating in the blood but not passing the BBB—to enter the brain in certain regions and damage vulnerable cells.”
It could therefore be expected that treatments which open the BBB, would intensify symptoms, whilst treatments which close or tighten the BBB would improve the Parkinson’s sufferer.

Treatments which open the BBB, (and cause a worsening of symptoms)

1. Stress.

http://www.sciencenews.org/pages/pdf...4/15024-10.pdf

The effect of stress causing a worsening of symptoms in PD sufferers is well known and documented.
http://www.sciencenews.org/pages/pdf...4/15024-10.pdf
"After receiving a drug to protect them against chemical weapons,
many Israeli soldiers serving
in the Persian Gulf War suffered adverse side effects from the
inoculation. These reactions
puzzled physicians, who had expected the blood-brain barrier to keep
this drug—like many
other chemicals circulating in the blood—out of the brain.
Now, an Israeli study suggests that stress may have temporarily
opened the blood-brain barrier.
"It was surprising—we saw quite large amounts of brain penetration,"
says Hermona Soreq of
the Hebrew University in Jerusalem, a coauthor of the report in the
December NATURE MEDICINE."


http://www.blackwell-synergy.com/doi...8.2006.05223.x
European Journal of Neuroscience
Volume 24 Issue 12 Page 3393 - December 2006
“functional studies demonstrate that noradrenaline controls the permeability of the blood–brain barrier,”

2. Nitric oxide

http://64.233.161.104/search?q=cache...k&ct=clnk&cd=1

“Nitric oxide is a compound associated with causing a worsening of
the symptoms, and is a well known compound causing neurological damage. It is
reported that nitric oxide "promotes BBB dysfunction"

3. Carbon monoxide

Another known toxin to cause PD, carbon monoxide also opens up the
BBB.
http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract
“Conclusion: Carbon monoxide, involving in the occurrence of hypo tension and the increase of blood-brain barrier permeability,”

4. Organic Phosphates(OP’s)

Organic in this context does not mean produced as in organic food. Organic here means a phosphate group in a molecule containing other groups consisting of carbon and hydrogen, and or a carbohydrate group. There chemicals are used in agriculture, which already has a reputation for an increased incidence of PD. I made and handled many organo phosphates when I worked as a research chemist.
http://www.foresight-preconception.o...oklet_agro.htm

“Chronic exposure to OPs has been found to result in a gradual loss
of brain stem cholinergic muscarinic and nicotinic (97-101) and
serotonergic (102,103) receptors, as well as to an increased
permeability of blood-brain barrier (104).”

5. Old Age

Although younger people can be afflicted, PD is predominantly an older person’s disease.
The reason for this could well be the fact that as the body ages, the BBB loses its ability to keep the brain free of toxins, and becomes more porous.
http://www.molmed.org/content/2001/810.pdf
“old age significantly increases BBB permeability”

6. Sarin
http://cat.inist.fr/?aModele=afficheN&cpsidt=13856336
“Acute exposure to sarin increases blood brain barrier permeability and induces neuropathological changes in the rat brain: Dose-response relationships.”



Treatments which close the BBB permeability (and improve symptoms?)
A, Citicoline (CPD Choline),
http://www.naturalproductsinsider.co...ngredient.html
“citicoline was found to reduce brain edema and decrease breakdown of the blood-brain barrier in rats at a dose of 400 mg/kg. (31)”


B. Alpha Lipoic Acid (LA)
A popular supplement amongst \PD sufferers, being a thio antioxidant, which recycles glutathione. It is made in the body, but decreases with age.

The Journal of Immunology, 2006, 177: 2630-2637.
Copyright © 2006 by The American Association of Immunologists
Lipoic Acid Affects Cellular Migration into the Central Nervous System and Stabilizes Blood-Brain Barrier Integrity1
Gerty Schreibelt*, René J. P. Musters , Arie Reijerkerk*, Lody R. de Groot*, Susanne M. A. van der Pol*, Esther M. L. Hendrikx*, Ed D. Döpp*, Christine D. Dijkstra*, Benjamin Drukarch and Helga E. de Vries2,*
“LA has a protective effect….by stabilization of the BBB”

C. Curcumin (Tumeric)
Another popular non prescription supplement, being a powerful antioxidant, anti inflammatory, and a chelator of heavy metals.
http://en.wikipedia.org/wiki/Turmeric
It is also said that turmeric can strengthen the blood-brain barrier against attacks that result from auto-immune diseases (such as Multiple sclerosis)[verification needed].
D. Bilberry extract
http://www.lef.org/magazine/mag2000/mar00-cover1a.html
“In addition, bilberry extract has been shown to enhance the blood-
brain barrier, which tends to become impaired with aging, showing a
decrease in vascular density, increased permeability and other
abnormalities. The normal functioning of blood-brain barrier is
important not only for keeping out toxins and undesirable compounds,
but also for glucose transport to the brain. Anthocyanins and
related compounds seem able to decrease capillary permeability
(possibly by stabilizing membrane phospholipids). Animal studies
have also shown that if the blood-brain barrier becomes damaged and
too permeable, anthocyanins help restore normal permeability”

E. GNDF
http://www.pdf.org/News/news.cfm?sel...005%26type%3D1

“Glial cell line-derived neurotrophic factor, or GDNF, was first identified in 1993. It is one of the most powerful naturally-occurring human factors known to nourish and foster the growth of dopamine-generating neurons.”
For their own reasons, Amgen halted their clinical trials with this material, but it does also reduce the porosity of the BBB.

http://www.ihop-net.org/UniPub/iHOP/gs/88604.html

“We previously reported that GDNF reduced the endothelial
permeability of the blood-brain barrier (BBB).”

================================================== =========================
ll. Multiple Sclerosis (MS

http://www.ncbi.nlm.nih.gov/entrez/q..._uids=17124345
“Blood-brain barrier (BBB) disruption is one of the hallmarks of multiple sclerosis (MS).”

In
http://www.mult-sclerosis.org/news/D...rrierinMS.html
it states,

"Increased permeability of the BBB is a feature of many diseases of the central nervous system (CNS), among them MS.3 BBB increased permeability is an early and critical event, often preceding symptoms, and, in most cases, being present in chronic lesions"

"MRI is used frequently by clinicians as a major criterion to define lesion activity, and is thought to reflect BBB damage. Although this is considered to be one of the earliest changes in observed MS lesions, neuropathological and immunocytochemical studies reveal that BBB leakage can be found to variable degrees in every MS lesion,"


lll. Amyotrophic Lateral Sclerosis (ALS) or Lou Gerhrigs Disease

ALS is a progressive neuromuscular disease that causes degeneration of some of the largest of all nerve cells, called motor neurons. Motor neurons control the movement of voluntary muscles. ALS results in fatality within two to five years from the first appearance of the symptoms.
In
http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract
it states
“These findings support the hypothesis that blood-brain barrier damage occurs in ALS.”
================================================== =====================================

lV Alzheimers Disease, (AD)

In both the reports below, a significant but low number of AD patients had defective BBB’s.

http://www.springerlink.com/content/061856503303q982/
“18% of patients with probable Alzheimer's disease showed BBB dysfunctions”

http://www.medicalnewstoday.com/medi...p?newsid=49999

“The study found BBB impairment in a significant minority of subjects with AD. Furthermore, BBB disruption may be clinically significant by allowing antioxidants to "diffuse down" their respective concentration gradient facilitating unabated oxidative processes in the brain that underlie AD pathology. The relationship between this phenomenon, BBB impairment and maintenance, and the neurodegenerative process remains to be clarified.”


CONCLUSIONS

In PD, the BBB plays a major and very significant part, and merits much more research into methods of controlling the permeability of the BBB. A process that locks down the BBB to all but the few allowed molecules, must be found. It then must be tried on newly diagnosed patients, to establish whether it stops progression of the disease. Then it needs to be tried with advanced sufferers, to establish whether neurogenesis, or birth of new cells, whilst preventing any influx of toxins causing loss of established cells, means that a gradual recovery takes place.
Similarly, the process to totally tighten the BBB needs to be tried on ALS and MS patients, in a similar manner.
BBB porosity does not seem to be the major cause of AD, but it may make a significant improvement in the quality of life of AD sufferers.

Thanks Ron. The new MS medication Tysabri does just what you suggest, it alters blood-brain barrier permeability by inhibiting adhesion molecules. Unfortunately a seemingly rare side effect seen to date is that if there are latent infections in the CNS already, by shutting the immune system out of the CNS, these latent infections can run amuck and cause great damage. The JC Virus is the one seen and some patients developed PML, a very devastating condition, while on Tysabri. It's still too early to know if there are other infectious concerns with the use of Tysabri, but it has been shown to increase infection rates in those taking it.

Thanks for sharing your work though. It would sure help if there were more paragraph breaks - much easier for us MSer's to read.

Great thread, Ron. Thanks for the research and links.

The question is whether anyone has a "normal" BBB anymore. Air pollution and hydrogenated oils can also increase BBB permeability, as do allergic and other immune-mediated reactions. That is part of the spiral, in which an individual is becoming more and more ill, becoming more allergic to the things to which they are allergic and developing allergies to more things. Histamine reactions are known to make the BBB more permeable. What about constant, chronic allergies (e.g. food allergies)? What I am studying now is the effect of lectins (http://www.krispin.com/lectin.html ) on the blood brain barrier. I think we will find that those of gluten, dairy, soy, etc can do direct harm as well as indirect harm by inducing chronic inflammatory reactions.

I personally don't think that drugs to "shut" the BBB are the answer, at least not long term, for the reason that Wannabe mentions. I would always start with the known offenders that increase permebility and try to avoid them (e.g. trans fats, allergens/lectins, and environmental pollution). It is well-known that these neurodegenerative diseases are their worse in polluted cities.

(They are also working on drugs that will "open" the BBB to allow them to get more drugs (e.g. chemo) into the brain. That one really scares me. )

Thanks again for the info and links.
John

Ron,

Thanks for the time that you put into this thread. It is very interesting. Do you remember seeing a recommended dosage of ALA?

I recently restarted taking ALA at the dosage of 1200mg daily. It gives me heartburn, but I am plodding along with it this time as well as 1200mg of Acetly-L-Carnitine, which supposedly works in synergy with the ALA.

I also put tumeric in everything reasonable and have been eating it for several years.

gmi

Hi Gonnamakeit,
Thanks for your input. For general antioxidant support, the recommended dose of ALA is 20 mg to 50 mg per day

Doctorj and Wannabe, Thank you both for your replies

Have any of you any objection if I reproduce your replies on the Parkinson's Disease site?
Best wishes
Ron

No problem here. I very am interested in checking out that site. What is the site again?

Are you familiar with the "Sleeping Sickness" virus that occurred between the end of the 1800's the early 1900's that has been tied to Parkinson's? I think there is real clue as to the origin of Parkinson's there. ( http://72.14.209.104/search?q=cache:...lnk&cd=4&gl=us )

John

No objections here.

Interestingly, many MSer's already take ALA and tumeric for their potential to help in MS.

Also, there was a small study in a group of MSer's where it was shown that inosine, which raises uric acid levels, may have some beneficial effect in people with MS. They tried this because they noted that virtually no MSer ever got gout which results from high uric acid levels. Their thinking was that nitric oxide may be involved in the pathophysiology of MS and increasing uric acid levels might be good because uric acid scavenges Peroxynitrite which is a product of nitric oxide.

http://www.ncbi.nlm.nih.gov/entrez/q...942&query_hl=2

Neurochem Res. 2005 Jan;30(1):139-49.


Evidence of nitrosative damage in the brain white matter of patients with multiple sclerosis.

Bizzozero OA, DeJesus G, Bixler HA, Pastuszyn A.

Department of Cell Biology and Physiology, University of New Mexico-Health Sciences Center, Basic Medical Sciences Building, 914 Camino de Salud, Albuquerque, NM 87131-5218, USA. obizzozero@salud.unm.edu

Nitric oxide (NO) has been implicated in the pathophysiology of both experimental autoimmune encephalomyelitis and multiple sclerosis (MS). NO-mediated protein damage in MS appears to be confined to large plaques where 3-nitrotyrosine has been detected.

To determine whether nitrosative damage takes place beyond visible MS plaques, the occurrence of various NO-triggered protein modifications in normal-appearing white matter (NAWM) of eight MS brains was assessed and compared to that in white matter (WM) of four control brains.

As determined by amino acid analysis and western blotting, no evidence of tyrosine nitration was found in the MS samples studied, suggesting that they did not contain appreciable amounts of plaque-derived material. The amino acid composition of total myelin proteins and proteolipid protein (PLP) was also unaltered in the diseased tissue, as was the fatty acid composition of PLP. In addition, we detected no changes in the number of protein free thiols suggesting that oxidation do not occur to any appreciable extent.

However, the levels of nitrite in MS-NAWM were higher than those in control WM, while in the MS-gray matter (GM) the concentration of this ion was unaltered. Furthermore, five of the MS samples analyzed, and the same as those with high levels of glial fibrilary acidic protein, showed increased amounts of protein nitrosothiols as determined by the "biotin switch" method. S-nitrosation of GM proteins was again normal. There was no indication of N-nitrosation of tryptophan and N-terminal amino groups in both control and MS tissue.

Overall, the data suggests that WM, but not GM, from MS brains is subjected to considerable nitrosative stress. This is the first report to present direct evidence of increased protein S-nitrosation and nitrite content in the brain parenchyma of MS patients.


http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

Vojnosanit Pregl.
2006 Oct;63(10):879-82.

Therapeutic value of serum uric acid levels increasing in the treatment of multiple sclerosis.

Toncev G.
Clinical Center Kragujevac, Center of Neurology, Kragujevac, Srbija.

BACKGROUND/AIM: Uric acid was successfully used in both, prevention and treatment of the animal model of multiple sclerosis (MS). Recently it has been shown that inosine, a ribosylated precursor of uric acid, might be used to elevate serum uric acid levels in MS patients. The aim of this study was to evaluate the safety and efficacy of oral inosine as a single drug treatment in patients with MS.

METHOD: We administered inosine orally to 32 MS patients from 2001-2004 year at doses from 1-2 g daily (given twice) depending on the pretreatment serum uric acid levels. The mean follow-up interval was 37.69+/-6.55 months. The other 32 MS patients, without any treatment except for a relapse period (matched by age, sex, duration of disease and functional disability), were used as controls. The follow-up interval of these patients was 36.39 +/- 2.68 months. The neurological disability was evaluated by the Expanded Disability Status Scale score (EDSS).

RESULTS: During the observed period the treated MS patients were found to have the lower relapses rate than the non-treated MS patients (Chi-square test, p = 0.001). None of the patients have showed any adverse effect of inosine treatment. The non-treated MS patients were found to have a higher increasing in the mean EDSS score than the treated ones (two-way ANOVA-repeated measures/factor times, p = 0.025).

CONCLUSION: Our results suggested that the treatment approaches based on the elevation of serum uric acid levels might prove beneficial for some MS patients.

PMID: 17121380 [PubMed - indexed for MEDLINE]

Thanks Wannabe, gonnamakeit and John,
Wannabe, You say Tysabri does exactly what I suggest, it alters blood-brain barrier permeability by inhibiting adhesion molecules. You mean it closes down the pores of the BBB? Do you have a reference to this please?
Very interesting that ALA and Tumeric are also of value in MS.(both close the BBB).
I have not heard of inosine, do you know what its effect is on the permeability of the BBB?

John, The PD site is on
http://neurotalk.psychcentral.com/fo...aysprune=&f=34

Your refs on the virus causing the sleeping sickness are interesting,
It is known that the encephalitis outbtreak in 1915 - 26 caused PD, and the virus does open up the BBB.

Ron

Hi Ron,

Tysabri

Tysabri has some effect on the BBB but it doesn't close it down completely. I think we'd die if it was closed down completely since we still need many components to pass our BBB in order to nourish/protect our brains.

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

Neurology.
2004 Jun 8;62(11):2038-43.
Comment in:
Neurology. 2005 Jan 11;64(1):174-5; author reply 174-5.

Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects.

O'Connor PW, Goodman A, Willmer-Hulme AJ, Libonati MA, Metz L, Murray RS, Sheremata WA, Vollmer TL, Stone LA; Natalizumab Multiple Sclerosis Trial Group.

St. Michael's Hospital, Toronto, Ontario, Canada. oconnorp@smh.toronto.on.ca

BACKGROUND: Relapses in multiple sclerosis (MS) can cause significant neurologic disability. Natalizumab (Antegren) is a humanized anti-alpha4-integrin antibody that inhibits the trafficking of leukocytes across endothelium by blocking binding of alpha4beta1-integrin to vascular cell adhesion molecule-1.

OBJECTIVE: To assess the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses.

METHODS: In this randomized, double-blind, multicenter trial, the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses were assessed. MS patients (n = 180) in acute relapse were randomly assigned to receive a single dose of natalizumab 1 or 3 mg/kg or placebo and were followed for 14 weeks.

RESULTS: There was no difference in Expanded Disability Status Scale (EDSS) score change over time between treatment and placebo groups. In all three groups, approximately half of patients showed EDSS improvement after 2 weeks, rising to 67% by 8 weeks. EDSS improved by a mean value of 0.8 point at week 1, 1.2 points at week 4, and 1.6 points at week 8 in the natalizumab group compared with EDSS improvement of 1.0 point at week 1, 1.6 points at week 4, and 1.6 points at week 8 in the placebo group. A significant decrease in Gd-enhancing lesion volume was seen in both active treatment groups at weeks 1 and 3 compared with placebo.

CONCLUSIONS: A single dose of IV natalizumab did not hasten clinical recovery after relapse, although a significant decrease in Gd-enhancing lesion volume was observed at 1 and 3 weeks after treatment. These MRI findings are consistent with prior studies of natalizumab and support its further investigation as an agent for the treatment of MS.

PMID: 15184611 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

Mult Scler.

2004 Oct;10(5):540-8.

Macrophage brain infiltration in experimental autoimmune encephalomyelitis is not completely compromised by suppressed T-cell invasion: in vivo magnetic resonance imaging illustration in effective anti-VLA-4 antibody treatment.

Deloire MS, Touil T, Brochet B, Dousset V, Caille JM, Petry KG.
EA 2966 Neurobiology of Myelin Diseases Laboratory, University Victor Segalen Bordeaux 2, Bordeaux, France.

Large inflammatory infiltrates of T cells, macrophages and B cells in the central nervous system (CNS) contribute to the pathogenesis of multiple sclerosis (MS). The passage of T cells through the blood-brain barrier can be suppressed with antibodies directed against alpha-4 integrins (VLA-4) that mediate T-cell adherence. This treatment, in phase III of clinical trial evaluation, reduces lesion development in MS patients.

In the ongoing inflammatory disease process the consequences of T-cell inhibitory anti-VLA-4 antibodies on inflammatory compounds are still poorly investigated. We show that anti-VLA-4 antibody treatment during the late preclinical phase of the acute experimental autoimmune encephalomyelitis (EAE) MS rat model interrupts T-cell egress out of the vascular compartment and suppresses clinical disease and histological alterations but macrophage recruitment in the CNS is not fully compromised.

Among the treated EAE animals not developing disease, none presented foci of T-cell infiltration in CNS. However, in 75% of the treated EAE rats monocyte ingress in CNS was observed in vivo by magnetic resonance imaging with the ultrasmall superparamagnetic iron oxide contrast agent. Our data shed new light on the role of remaining macrophage brain infiltration in an induced but interrupted T-cell-mediated EAE disease process.

PMID: 15471371 [PubMed - indexed for MEDLINE]

ALA and Curcumin (turmeric)

Alpha lipoic acid does seem to help maintain BBB integrity. Curcumin (turmeric) has been found to have anti-inflammatory properties that have suppressed the mouse model of MS.

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

J Immunol.

2006 Aug 15;177(4):2630-7.

Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity.

Schreibelt G, Musters RJ, Reijerkerk A, de Groot LR, van der Pol SM, Hendrikx EM, Dopp ED, Dijkstra CD, Drukarch B, de Vries HE.
Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.

Reactive oxygen species (ROS) play an important role in various events underlying multiple sclerosis (MS) pathology. In the initial phase of lesion formation, ROS are known to mediate the transendothelial migration of monocytes and induce a dysfunction of the blood-brain barrier (BBB). In this study, we describe the beneficial effect of the antioxidant alpha-lipoic acid (LA) on these phenomena.

In vivo, LA dose-dependently prevented the development of clinical signs in a rat model for MS, acute experimental allergic encephalomyelitis (EAE). Clinical improvement was coupled to a decrease in leukocyte infiltration into the CNS, in particular monocytes. Monocytes isolated from the circulation of LA-treated rats revealed a reduced migratory capacity to cross a monolayer of rat brain endothelial cells in vitro compared with monocytes isolated from untreated EAE controls.

Using live cell imaging techniques, we visualized and quantitatively assessed that ROS are produced within minutes upon the interaction of monocytes with brain endothelium. Monocyte adhesion to an in vitro model of the BBB subsequently induced enhanced permeability, which could be inhibited by LA. Moreover, administration of exogenous ROS to brain endothelial cells induced cytoskeletal rearrangements, which was inhibited by LA. In conclusion, we show that LA has a protective effect on EAE development not only by affecting the migratory capacity of monocytes, but also by stabilization of the BBB, making LA an attractive therapeutic agent for the treatment of MS.

PMID: 16888025 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

J Immunol.

2002 Jun 15;168(12):6506-13.

Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes.

Natarajan C, Bright JJ.
Division of Neuroimmunology, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.

Experimental allergic encephalomyelitis (EAE) is a CD4(+) Th1 cell-mediated inflammatory demyelinating autoimmune disease of the CNS that serves as an animal model for multiple sclerosis (MS). IL-12 is a proinflammatory cytokine that plays a crucial role in the induction of neural Ag-specific Th1 differentiation and pathogenesis of CNS demyelination in EAE and MS. Curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant Curcuma longa. It has profound anti-inflammatory activity and been traditionally used to treat inflammatory disorders.

In this study we have examined the effect and mechanism of action of curcumin on the pathogenesis of CNS demyelination in EAE. In vivo treatment of SJL/J mice with curcumin significantly reduced the duration and clinical severity of active immunization and adoptive transfer EAE.

Curcumin inhibited EAE in association with a decrease in IL-12 production from macrophage/microglial cells and differentiation of neural Ag-specific Th1 cells. In vitro treatment of activated T cells with curcumin inhibited IL-12-induced tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4 transcription factors. The inhibition of Janus kinase-STAT pathway by curcumin resulted in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that curcumin inhibits EAE by blocking IL-12 signaling in T cells and suggest its use in the treatment of MS and other Th1 cell-mediated inflammatory diseases.

PMID: 12055272 [PubMed - indexed for MEDLINE]

For full article:

http://www.jimmunol.org/cgi/content/full/168/12/6506

Inosine

With respect to inosine, its effects are not direct, but on its impact on uric acid levels. Since uric acid is a Peroxynitrite scavenger (which, like nitric oxide, is a bad actor in the CNS), its ability to increase peroxynitrite scavenging levels is a good thing. Nitric Oxide increases permeability of the BBB, so decreasing NO levels and peroxynitrite levels by increasing UA levels would help reduce disruption of the BBB.

http://www.ncbi.nlm.nih.gov/entrez/q..._uids=16410551

Full article:

http://jcs.biologists.org/cgi/content/full/119/2/339

J Cell Sci. 2006 Jan 15;119(Pt 2):339-49.

Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice.

Parathath SR, Parathath S, Tsirka SE.

Program in Molecular and Cellular Biology, Department of Pharmacological Sciences, University Medical Center at Stony Brook, Stony Brook, NY 11794-8651, USA.

Stroke and many neurodegenerative diseases culminate in neuronal death through a mechanism known as excitotoxicity. Excitotoxicity proceeds through a complex signaling pathway that includes the participation of the serine protease tissue plasminogen activator (tPA). tPA mediates neurotoxic effects on resident central nervous system cells as well alters blood-brain barrier (BBB) permeability, which further promotes neurodegeneration. Another signaling molecule that promotes neurodegeneration and BBB dysfunction is nitric oxide (NO), although its precise role in pathological progression remains unclear. We examine here the potentially interrelated roles of tPA, NO and peroxynitrite (ONOO-), which is the toxic metabolite of NO, in BBB breakdown and neurodegeneration following intrahippocampal injection of the glutamate analog kainite (KA). We find that NO and ONOO- production are linked to tPA-mediated excitotoxic injury, and demonstrate that NO provision suffices to restore the toxic effects of KA in tPA-deficient mice that are normally resistant to excitotoxicity. NO also promotes BBB breakdown and excitotoxicity. Interestingly, BBB breakdown in itself does not suffice to elicit neurodegeneration; a subsequent ONOO(-)-mediated event is required. In conclusion, NO and ONOO- function as downstream effectors of tPA-mediated excitotoxicity.

Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

PMID: 16410551 [PubMed - indexed for MEDLINE]



http://cat.inist.fr/?aModele=afficheN&cpsidt=3622581

Titre du document / Document title

Role of nitric oxide in disruption of the blood-brain barrier during acute hypertension

Auteur(s) / Author(s)
MAYHAN W. G. ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
Univ. Nebraska medical cent., dep. physiology biophysics, Omaha NE 68198-4575, ETATS-UNIS

Résumé / Abstract
The goal of this study was to determine the role of nitric oxide in disruption of the blood-brain barrier during acute hypertension. We examined the microcirculation of the cerebrum in vivo. Permeability of the blood-brain barrier was quantitated by the formation of venular leaky sites and clearance of fluorescent-labeled albumin (FITC-albumin) before and during phenylephrine-induced acute hypertension.

We compared disruption of the blood-brain barrier during acute hypertension in untreated rats and in rats treated for 1 h with topical application of N[G]-monomethyl-L-arginine (L-NMMA ; 100 μM) or N[G]-nitro-L-arginine methyl ester (L-NAME ; 100 μM). Under control conditions, no venular leaky sites were visible and clearance of FITC-albumin was minimal in untreated rats and in rats treated with topical application of nitric oxide synthase inhibitors. Phenylephrine (20 μg/kg/min for 5 min) infusion increased systemic arterial pressure by a similar magnitude in all groups of rats and produced disruption of the blood-brain barrier in venules. However, the magnitude of disruption of the blood-brain barrier during acute hypertension was significantly less in rats treated with L-NMMA (52% reduction in the clearance of FITC-albumin) and L-NAME (47% reduction in clearance of FITC-albumin). The findings of the present study suggest that synthesis/release of nitric oxide contributes to disruption of the blood-brain barrier during acute hypertension.


http://www.fasebj.org/cgi/content/abstract/14/5/691

(The FASEB Journal. 2000;14:691-698.)
© 2000 FASEB

Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood–CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis

D. C. HOOPER1, G. S. SCOTT, A. ZBOREK2, T. MIKHEEVA, R. B. KEAN, H. KOPROWSKI and S. V. SPITSIN
Department of Microbiology and Immunology, Kimmel Cancer Institute, and the Biotechnology Foundation Laboratories, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA

1Correspondence: Department of Microbiology and Immunology, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107-6799, USA. E-mail douglas.c.hooper@mail.tju.edu

Peroxynitrite (ONOO-), a toxic product of the free radicals nitric oxide and superoxide, has been implicated in the pathogenesis of CNS inflammatory diseases, including multiple sclerosis and its animal correlate experimental autoimmune encephalomyelitis (EAE).

In this study we have assessed the mode of action of uric acid (UA), a purine metabolite and ONOO- scavenger, in the treatment of EAE. We show that if administered to mice before the onset of clinical EAE, UA interferes with the invasion of inflammatory cells into the CNS and prevents development of the disease. In mice with active EAE, exogenously administered UA penetrates the already compromised blood–CNS barrier, blocks ONOO--mediated tyrosine nitration and apoptotic cell death in areas of inflammation in spinal cord tissues and promotes recovery of the animals. Moreover, UA treatment suppresses the enhanced blood–CNS barrier permeability characteristic of EAE.

We postulate that UA acts at two levels in EAE: 1) by protecting the integrity of the blood–CNS barrier from ONOO--induced permeability changes such that cell invasion and the resulting pathology is minimized; and 2) through a compromised blood–CNS barrier, by scavenging the ONOO- directly responsible for CNS tissue damage and death.—Hooper, D. C., Scott, G. S., Zborek, A., Mikheeva, T., Kean, R. B., Koprowski, H., Spitsin, S. V. Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood–CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis.

Hi Wannabe,
Thanks for all your literature, sorry I am late in replying. ON Friday this week, I fly to Tahiti for 16 days holiday, so won't be around to post replies.
Ron