Thanks.This is very interesting and makes sense.How does it relate to agonists such as Requip which it has been suggested are neuro protective?

Hi,

I just came across this post while browsing new posts~ and can't pass by something on the BBB without mentioning the relatively new discovery of zonulin, a protein that regulates the intestinal and blood brain barriers.

People with autoimmune diseases like celiac disease, diabetes, and ms... have been found to have increased levels of zonulin (associated with leaky gut and possibly 'leaky brain')... and it may be implicated in some other neurological condtions as well. Too early to know.


A zonulin blocker (ABOVE) is actually in development, now, and showing promise for both celiac disease and diabetes. I've also read they hope this research may lead to the developement of other drugs which may control the BBB...possibly open it for a controlled period to allow other drug treatments to pass the barrier.

Most of the zonulin research seems centered on the intestinal barrier, but here is one about the BBB~
Affinity purification and partial characterization of the zonulin/zonula occludens toxin (Zot) receptor from human brain. PMID: 10617135 Jan 2000

And here is a user friendly explanation:
http://www.autism-pdd.net/bloodbrain.html



And this study seems to say that gliadin (gluten..found in wheat, barley, rye) activiates zonulin signaling in everyone, although moreso in those with celiac disease.

CONCLUSIONS: Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.
Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. PMID: 16635908 April 2006



In any case, I have no idea if this is something of interest..and my understanding of it is quite limited... but you may want to keep your ears open for more research on zonulin and the BBB. I have not seen anything that connects Parkinson's Disease with zonulin research, but zonulin is relative to the BBB. Here is list of the most of the zonulin related studies to date~ Zonulin

Food for thought~

Cara

Hi jccglutenfree,
Thanks so much for taking the trouble to post this.
Zonulin appears to open the BBB pores, not tighten them down as we need. However, anything which increases our knowledge of the BBB is very usefull. One of your references says,
"The discovery and characterization of this receptor from human brain may significantly contribute to our knowledge on the pathophysiological regulation of the BBB."
This is the type of compound that I spoke about in one of my posts above. I warned that the Docs may not have considered that while the BBB is opened temporarily to admit the good drug, a rush of toxins which are in the bloodstream (and circulate harmlessly in the bloodstream when the BBB is closed), may rush in also. This could bring forward the date this person gets PD.
Any new knowlegeabout the BBB is useful, so thanks again.
Ron

Those of you who have never visited the Gluten File really should. It is a fine piece of work with a lot of relevance to PD. Maybe far more then we realize. PD, celiac disease, diabetes, chronic fatigue syndrome - all share a set of similarities that is maddening to study.

One thing that is worth thinking about is just what happened in the 100 years prior to Parkinson's 1817 essay. The Industrial Revolution had brought new toxins of course, but other factors came too. Increased and chronic stress increases inflammation and opens the BBB and its cousin in the gut. Working into the night disrupts circadian rhythms than our systems depend on. Increased dust exposure ups the toxin load - especially in our nose, the short cut to the brain.

And the new machinery quickly increased wheat production.

Hi Ron,

Zonulin does open the pathways... so increased levels of zonulin lead to more open spaces~ leaky gut / leaky brain.

The drug currently in development, AT-1001, is a zonulin blocker. It's function is to block zonulin thereby tightening up the leaky gut. As I said, most of the research moving forward is in regard to the intestinal barrier and autoimmune disease (celiac and diabetes to date, but may be applicable to other autoimmune and other neurologic conditions in the future).

Since zonulin does regulate the BBB as well, a zonulin blocking drug may possibly prove to be useful in other conditions that may be caused by a "leaky brain" (some I've seen mentioned are autism, MS, Alzheimers, gluten ataxia, etc). This research is new, in its infancy, and as I said, at the moment seems to be focused on the gut barrier...not the brain barrier.

In the future, this may lead to development of other drugs that will allow control over the BBB, to open or close it. The current drug being worked on, though.. is working to close the intestinal barrier.


What is interesting about the one study I posted above...
Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. PMID: 16635908 April 2006
is that it appears gluten/gliadin (found in wheat, rye, barley) increases zonulin levels in both celiacs and non-celiac patients. Can you see where I'm going? Could gluten play a role in leaky gut or leaky brain... even in patients without celiac disease? OK..I'm pushing ahead of the research now..but there is so much they don't know yet!

Gluten sensitivity (even without celiac disease) is responsible for wide ranging neurological problems~ gluten ataxia, peripheral neuropathy, myoclonus, and much more... and the research is so early on all of this. There are a few of us on the gluten sensitivity forum, who do not have celiac disease, but would love to have our zonulin levels tested!

But... in any case... This new zonulin blocking drug appears to be working to close the leaky gut. Will it also work to close the leaky brain? I'm not sure the research has focused on that yet.

Cara

P.S. Thanks reverett... I remember we have compared notes in the past. This zonulin discovery, and the development of this zonulin blocking drug, is something to be watched. Can you imagine if it is successful to prevent the developement of diabetes in susceptible patients? It has worked in rats.. now, onto human studies.

And what about the BBB??? Will it also shore that up? I honestly don't think the research has looked at that yet, other than to say that zonulin levels also regulate the BBB.

Talking directly to organizer reverett and suggesting that you assign people who are interested in this to research substances, conditions, or anything that could increase or decrease the porous openings in the brain barrier and report which it does. Make a list of what opens the BBB and closes it from the research currently available. Ron has already started this. Look for ways to rule out this hypothesis...maybe assign a few people to see if it can be disproven based on infor currently available.

On Saturday, the 10th of February, the FOX Foundation is briefing all the PAN Coordinators on current research, before the PAN forum begins the next day. This is a ROUND TABLE and guess what we can discuss?

You have 12 days.

Too cool,
paula

http://www.michaeljfox.org/research/abstract.php?id=188

Ron - ok let's just add to what they already know if there is anything new

Another question all - do you think treatments in development should slow down until we understand the BBB?

Where is your trust on this and all the implications?

Next..what is the meaning of lif....nah....lol.

paula

edited to add: The more we know, the less we know. Can you see several years down the road, the article - " certain brain treatments found to weaken the brain blood barrier, which we now know our brains are depending upon. The ultimate chasing our tails.

It is extremely intriguing - we just don't know where it will take us. It lends itself so well to the fact that so many of us get better and worse at the same time, especially when we add l-dopa to the mix.

<Doing my very best Groucho imitation> ...have I ever told you how lovely you look in this light? That I just love the way that you type your "w's"? That I admire your mind as much as your body?

It sounds like a unique opportunity and I will do some work on it BUT (and please forgive me Ron) I think it is too limited as currently presented. There is a lot at stake here and, if you are going to have the ear of someone who has some weight in Fox;s group, I would be a darned fool and a traitor to Parkiedom if I didn't speak plainly.

I think that the BBB issue is indeed important but that it is just one effect of the bigger problem of inflammation and the resulting activation of the brain's microglial defenders resulting in neuronal loss in the substantia nigra. Inflammation also opens the BBB and toxins do indeed make things worse for some of us (an explanation for differing rates of progression, but the hyperactive response of the microglia is what wipes out your substantia nigra, which coincidentally has one of the highest density microglia populations in the entire brain.

For this reason, inflammation has to be considered one of the two most critical factors in PD. The other is sress induced cortisol elevation, but that is getting into heavier territory and I wouldn't want to dilute the opportunity by taking on too much.

I'm going to tack on a couple of abstracts but I can make a concise case for this with everything footnoted to peer reviewed publications and keep it to a couple of pages. If you are willing to consider it, I will put it up here and defend it for a week before it leaves so that we can polish it as a group. That, in turn, might get us a little attention itself.

Like i said, I would be betraying us all if I didn't pipe up here. The reason is that treatments for this already exist and more targeted ones are easily within reach. Just see the last abstract below. <What is that cologne you are wearing my dear? Could I rub your feet? Could you rub mine then? )



1: Ann N Y Acad Sci. 2003 Jun;991:214-28.

The role of glial reaction and inflammation in Parkinson's disease.

Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP.

INSERM U289, Experimental Neurology and Therapeutics, Hopital de la Salpetriere,
75651 Paris Cedex 13, France. hirsch@ccr.jussieu.fr

The glial reaction is generally considered to be a consequence of neuronal death
in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease,
and Parkinson's disease. In Parkinson's disease, postmortem examination reveals
a loss of dopaminergic neurons in the substantia nigra associated with a massive
astrogliosis and the presence of activated microglial cells. Recent evidence
suggests that the disease may progress even when the initial cause of neuronal
degeneration has disappeared, suggesting that toxic substances released by the
glial cells may be involved in the propagation and perpetuation of neuronal
degeneration. Glial cells can release deleterious compounds such as
proinflammatory cytokines (TNF-alpha, Il-1beta, IFN-gamma), which may act by
stimulating nitric oxide production in glial cells, or which may exert a more
direct deleterious effect on dopaminergic neurons by activating receptors that
contain intracytoplasmic death domains involved in apoptosis. In line with this
possibility, an activation of proteases such as caspase-3 and caspase-8, which
are known effectors of apoptosis, has been reported in Parkinson's disease. Yet,
caspase inhibitors or invalidation of TNF-alpha receptors does not protect
dopaminergic neurons against degeneration in experimental models of the disease,
suggesting that manipulation of a single signaling pathway may not be sufficient
to protect dopaminergic neurons. In contrast, the antiinflammatory drugs
pioglitazone, a PPAR-gamma agonist, and the tetracycline derivative minocycline
have been shown to reduce glial activation and protect the substantia nigra in
an animal model of the disease. Inhibition of the glial reaction and the
inflammatory processes may thus represent a therapeutic target to reduce
neuronal degeneration in Parkinson's disease.

Publication Types:
Review

PMID: 12846989 [PubMed - indexed for MEDLINE]


1: Neurobiol Dis. 2000 Aug;7(4):429-47.

The single intranigral injection of LPS as a new model for studying the
selective effects of inflammatory reactions on dopaminergic system.

Herrera AJ, Castano A, Venero JL, Cano J, Machado A.

Departamento de Bioquimica, Bromatologia, Toxicologia, y Medicina Legal,
Universidad de Sevilla, Calle Prof., Garcia Gonzalez s/n, Sevilla, 41012, Spain.

We have injected lipopolysaccharide (LPS) into the nigrostriatal pathway of rats
in order to address the role of inflammation in Parkinson's disease (PD). LPS
induced a strong macrophage/microglial reaction in Substantia nigra (SN), with a
characteristic clustering of macrophage cells around blood-vessels. The SN was
far more sensitive than the striatum to the inflammatory stimulus. Moreover,
only the dopaminergic neurons of the SN were affected, with no detectable damage
to either the GABAergic or the serotoninergic neurons. The damage to the DA
neurons in the SN was permanent, as observed 1 year postinjection. Unlike the
direct death of dopaminergic neurons caused by agents as MPP(+) or 6-OHDA, LPS
seems to cause indirect death due to inflammatory reaction. Therefore, we
suggest that the injection of a single dose of LPS within the SN is an
interesting model for studying the selective effects of inflammatory reaction on
dopaminergic system and also potentially useful for studying PD. Copyright 2000
Academic Press.

PMID: 10964613 [PubMed - indexed for MEDLINE]

1: J Neurosci Res. 2004 Dec 1;78(5):723-31.

(-)-Epigallocatechin gallate inhibits lipopolysaccharide-induced microglial
activation and protects against inflammation-mediated dopaminergic neuronal
injury.

Li R, Huang YG, Fang D, Le WD.

Health Science Center, Shanghai Institute for Biological Science, Chinese
Academy of Science, Shanghai Second Medical University, Shanghai, Peoples
Republic of China.

Microglial activation is believed to play a pivotal role in the selective
neuronal injury associated with several neurodegenerative disorders, including
Parkinson's disease (PD) and Alzheimer's disease. We provide evidence that
(-)-epigallocatechin gallate (EGCG), a major monomer of green tea polyphenols,
potently inhibits lipopolysaccharide (LPS)-activated microglial secretion of
nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) through the
down-regulation of inducible NO synthase and TNF-alpha expression. In addition,
EGCG exerted significant protection against microglial activation-induced
neuronal injury both in the human dopaminergic cell line SH-SY5Y and in primary
rat mesencephalic cultures. Our study demonstrates that EGCG is a potent
inhibitor of microglial activation and thus is a useful candidate for a
therapeutic approach to alleviating microglia-mediated dopaminergic neuronal
injury in PD.

PMID: 15478178 [PubMed - indexed for MEDLINE]


But as I said I will work on the BBB angle as well regardless of your decision.

Ron can do as much as he wants - I'm the one who got all excited and said -Let's go........it's a habit to do that sorry.....i'll stay out of it. I'm just a connector by nature...technilogically speaking...and this seemed like a great one to seriously look at.

If I hadn't seen this good stuff you guys are coming out with, I would have not specifically taken anything to the table. [still in mourning for GDNF] So do what you are both led to do......and don't be shy about it lol.........

sorry for confusion,
paula

Rick,
We all have our pet theories, and we don't have the medical knowledge we could use. THis thread is clear in it's definition, and Paula came up with a good plan of action. Please put your other ideas in a separate thread, and we will try and contribute to them. It will confuse and kill this thread if you propose ideas on a different tangent here. Having had yourself and Wanda stay with us last year, in Merry England, we know each other very well, and lets keep both ideas alive and persue them. We may both be wrong, but sooner or later, between all of us, as PD sufferers, we have an excellent chance of stumbling on to a cure.
Very best wishes
Ron