[Ronhutton]

There has been several papers in the scientific literature describing the link to PD of pesticide exposure. A typical publication is:

http://www.news-medical.net/?id=25774
Researchers in Britain have discovered that high levels of exposure to some pesticides may be bad for peoples' health.
A team at Aberdeen University say exposure to pesticides could lead to an increased risk of contracting Parkinson's disease by as much as 39% and even low levels of pesticides raised it by 9%.

Every time I see something that may cause PD, or make our symptons worse, I look up its effect on the Blood Brain Barrier, (BBB). This is typical for what I found for pesticides.

http://www.ingentaconnect.com/conten...00003/0900687a
This study showed that developing BBB is highly vulnerable to single or repeated exposure of certain pesticides. The observed persistent effects during brain development even after withdrawal of the treatment may produce some neurological dysfunction at later life as well

Also,
http://www.getipm.com/articles/bbb-lawn.htm
Brain Damage Caused by
Exposure to Lawn Pesticides
The pesticide MCPA, used as an ingredient in some lawn pesticides, has been found to damage a part of the brain known as the blood brain barrier (1). The blood brain barrier (BBB) is the brain's primary defense system which works to keep toxic substances out of the brain cells and is literally protecting all of us from developing immediate neurological illness. The blood brain barrier has been found to be defective more often in patients with Alzheimer's and some psychiatric disorders (2)

We can add pesticides now to the list of other substances that increase the permeability of the BBB AND make our symptons worse.
I recently posted, "Medical opinion moving towards defective BBB"

http://www.nature.com/nrn/journal/v7...m/nrn1824.html
states,
"There is increasing evidence that the function of the BBB is altered in several neuropathologies, including brain oedema, epilepsy, Alzheimer's disease and Parkinson's disease."

I have got much more evidence in a very large file, but it would take me a long time to list it all. The important thing is all the data points in the same direction. I have looked for substances that reduce the permeability of the BBB, and have found that statins and hypertension drugs (high blood pressure) reduce the permeability. Do they also improve PD symptons?? I have some evidence that hypertension drugs do reduce symptons.

When I post on evidence for the BBB idea, there is some enthusiasm, but it soon dies, and we go on to other things. Prof Leenders has shown that PWP do have defective BBB's. How much more evidence do we need. Who can we interest in this, to get some progress?
Below is a summary of previous evidence.
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.

[paula_w]

Thanks Ron,

It's fascinating and so logical. They did ask about the blood brain barrier at the FOX keynote q & a at BIOS. Nothing we already didn't learn here yet. It's mostly discussed in terms of getting around it but Dr. Eugene Johnston, FOX lead scientist, did say -'we have to remember that the blood barrier is our friend too.' I guess I was among people familiar with what that meant; it was rather abstract. More work to be done with the BBB research as you know.

Dr. Johnston as an item of interest is one of the developers of neurturin, the replacement of GDNF in many locations. The Ceregene trial is of great interest to him.

Those questions were sent into the FOX site in advance of the conference - you could submit them up to a certain date before the conference. It had to be chosen from many.

paula

[Daffy Duck]

Much of what is written concerns : other medical disorders rather than Parkinson's Disease (such as ALS, AD, MS), solutions that would only be relevant only if the theory were correct (Curcumin, ALA, CDP choline), or claimed potential causes that either don't cause Parkinson's Disease or that can cause Parkinson's Disease symptoms by other means (Sarin, CO, stress). Some of the studies quoted claim that the BBB is defective but they provide no evidence in support of their claims.

The key staring point on which all else relies is the Leenders study, which claims that the BBB is defective in people with Parkinson's Disease. Have you read the complete study ? Do you have a copy ? Could you make it available here for analysis ? Alternatively can you provide the results for each individual patient. What were the ages of each patient in both groups ?

[reverett123]

...to contrast the "academic" mindset where everything is a matter of scoring points in some macabre debate with status as the prize with that of the "real world" where life is on the line.