[Ronhutton]

How about this for a theory.
We all know dopamine can't pass the BBB, so in our medication, we take levodopa which can penetrate the BBB, and is converted to dopamine in the brain. In the brain, the dopamine can't leak out, since the famous BBB is keeping it in. This is true for a normal person, but not for us. Prof Leederman has proved we have leaky BBB's. See where I am going? If the BBB is leaky, perhaps after all, we can generate dopamine in our brains, but with a body that is much larger than our brain, and many pints of blood circulating in it, our precious dopamine leaks OUT through our defective BBB, into the body.
Dopamine is natural in the body, where it acts as a hormone, and regulates heartbeat. In an operation, where a patient's heart falters, doctors administer dopamine to get a sluggish heart to beat stronger.
We may not have a deficiency of dopamine neurons, they may work perfectly well, but the bulk of the dopamine we make in our brains may leak out. It puzzled me, that things which widen the BBB, like stress, have such a quick effect on PD symptons.. So, the cause of our sudden deterioration in PD symptons could not be that the more leaky BBB lets in toxins from the bloodstream, and then attacks our dopamine neurons. That must take time,the effect would not be instant on PD symptons. Stress must cause the BBB floodgates to open, and allow the remainder of our dopamine to escape to the body. Don't heartbeats also speed up, as well as PD symptoms go worse, when we encounter stress!!! The influx of toxins as the BBB gets more porous, may be a secondary longer term process aggravating our symptons. We can counter that by taking things which slowly lower the BBB permeability, like curcumin, alpha lipoic acid, GDNF, etc
This leakage may be the major route by which we have a deficiency of dopamine, and restricted movement. PD may be a predominently old person's disease, since the BBB, like the rest of our body, deteriorates slowly, and becomes more leaky. The permaeability of the BBB may then reach a threshold value, when it gets to the stage of just starting to leak dopamine. At that point, we are diagnosed as having PD.
We continue to age, and our small leakage gets ever faster, hence our disease is progressive with time, and PD is an old persons disease. Our meds last less time, as we progress, since increasingly, the dopamine we synthesise from the levodopa starts to flood out as soon as we make it.
We could go on answering questions about PD, such as why have hypertension (high blood pressure) drugs just been found to be of value in PD? See the Isradipine thread. From the above now we can answer that question. High blood pressure also damages the BBB.
There are other questions we could ask ourselves, which may add to the above evidence, (Or they may shoot it down!!!)
The following increase the symptons of PD. Do they widen the pores of the BBB?
Paraquat,
Rotenone,
Maneb (fungicide)
Manganese
MTPT
Toluene
N-hexane
Any help in doing the literature searches gratefully received
Also, any contributions, positive or negative so we can get to the bottom of this.
So the question to research may be, how do we control the permeability of the BBB, rather than look at ways to regenerate brain neurons. If they aint broke, don't fix them!!!

[stevem53]

That is interesting Ron..Stress does wreak havoc with my symptoms, and the more peacful my life is, the less pd is an issue..Attitude makes a difference

[Jaye]

Wow. Brilliant, Ron, just brilliant.


Exercise definitely stops the leakage. How?

Isradipine would slow it by reducing fluid pressure.


I will help when my soon-to-arrive guest departs.

Jaye

[reverett123]

While this doesn't address the leakage of the BBB itself, it does point out that there is another route that leads from the brain and into the rest of the system. The nerves themselves can provide routes of transit. Whether a dopamine molecule could follow this path or not I don't know but don't assume it is impossible.

1: Curr. Top. Microbiol. Immunol. 1995;202:63-78.

Penetration of solutes, viruses, and cells across the blood-brain barrier.

Brightman MW, Ishihara S, Chang L.

Laboratory of Neurobiology, National Institutes of Health, Bethesda, MD 20892,
USA.

The aspects presented here of how solutes, viruses and cells are able to cross
the BBB indicate that there must be an active interaction of endothelium with
viruses and immune system cells before they can penetrate the brain and spinal
cord. The axoplasmic pathway taken by lectin-solute conjugates is similar but not
identical to that followed by viral particles during their retrograde or
anterograde transit through the axoplasm. Both the conjugates and virus are
transferred to other neurons transsynaptically but the receptor mediated transfer
utilized by viruses is far more specific. Cranial nerves are involved in both the
entry and egress of antigens into and out of the brain. Antigen, generated within
the CNS, may be able to escape from the brain to lymphoid tissue by passing into
the fluid around a cranial nerve, thence via the lymph into lymph nodes to
initiate an immune response involving the CNS.

Publication Types:
Review

PMID: 7587371 [Pubmed - indexed for MEDLINE]

[paula_w]

I need help putting this together. I recently heard that some research has yielded the possibility that something causes PD, but our immune system perpetuates it. Does that fit with what you are saying?

paula

[reverett123]

1: Nippon Yakurigaku Zasshi. 2003 Jul;122(1):55-64.

[Molecular mechanisms of drug influx and efflux transport at the blood-brain
barrier]

[Article in Japanese]

Ohtsuki S, Hori S, Terasaki T.

Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

The blood-brain barrier (BBB) segregates the circulating blood from interstitial
fluid in the brain and restricts drug permeability into the brain. Recent studies
have revealed that the BBB exhibits not only blood-to-brain influx transport for
the supply of nutrients, but also brain-to-blood efflux transport to excrete
drugs and endogenous compounds. The influx transport system allows drugs to enter
the brain. (L)-DOPA is transported into the brain by the large neutral amino acid
transport system, system L. A cationic mu-opioid peptide analogue enters the
brain by adsorptive-mediated endocytosis. In contrast, efflux transport limits
the distribution of drugs in the brain. The ATP binding cassette transporter B1
(ABCB1) mediates the efflux transport of lipophilic drugs at the BBB by using ATP
energy. Furthermore, organic anion transporter 3 (OAT3) is expressed at the BBB
and mediates the efflux transport of homovanillic acid, a dopamine metabolite.
This efflux transport is also likely to be involved in the transport of anionic
drugs such as 6-mercaptopurine and acyclovir. Clarifying the BBB transport could
give us important information allowing the development of better CNS drugs and
improving our understanding of the relationship between CNS diseases and BBB
functions.

Publication Types:
English Abstract
Review

PMID: 12843573 [Pubmed - indexed for MEDLINE]

[Ronhutton]

Jaye,
Thanks for your enthusiasm, and a very good question. I missed exercise, and have only found references which are confusing as to the effect on BBB permeability.
Rick, Your reference is a bit too medical; to follow exactly, but it does seem to be possibly a trojan horse type of crossing the BBB. I don't think it hasd a direct connection with what I have proposed.
Paula,
I don't think the immune system plays a party. What I am saying is,
Assume the permeability of a perfect BBB is say 100, where lower is less permeable, and higher is leaky or defective.
At 100, it lets levodopa pas through it, but not dopamine. If dopamine is allowed through at a low rate, when the permeability is say, 130, then when this threshold is reached, we start to show PD sym[ptons
I imagine people will be born with permeabilities ranging from say 90 to 110, averaging at a 100. Those people who start at 110, will reach the threshold of 130 sooner than the rest and will be young onset. Those who start at 90, may never reach 130, and won't suffer PD in their lifetime.
Our score will increase with age and environmental insult, like pesticides, and those of us starting with a permeablity of say 110 or over will soon reach 130. The leakage rate will be low at those levels, and our symptoms mild.
Taking things like curcumin will slow the rate of increase from 110 to 130 or over. Acute stress may bump up the porosity to say 150, and would cause dopamine to flood out. It probably goes back to the value just before the stress. The numerical values are of course pure fiction to try to explain what I am proposing. I hope it shows better what I have posted.
Previously, I always thought of leakage of toxins INTO the brain, but I then realised that in a defective BBB, molecules like dopamine, which can't ordinarily enter through the BBB, can also leak OUT.
Thanks for your inputs.

[oyster]

i'm curious about the lymph system, it covers our entire body, ithought so anyway. does it enter the brain? are there lymph vessels aand nodes inside or skulls?
i'm not satisfied that modern allopathic medicine has a complete understanding of the lymph systems function. we know that it ccarries alot of stuff to and from the gi track and that it has some mysterious immune functions. then there is the spleen, a huge organ, that gets glossed over all the time.

i know i'm ignorant about this but i wonder how it relates to pd.

[rosebud]

Isn't it amazing that we understand perfectly that the wind can blow one direction but it never occurs to us until a moment of revelation that it can blow the other direction as well. What you are proposing makes sense and could be very possible. If stress opens the floodgates the comparison could be to what happens when we flush a toilet! oops, there goes my dopamine!

But if that were the case couldn't we get rid of dyskinesia by just exposing ourselves to a small dose of stress?

A good piece of mental chewing gum all the same. I'll be checking in tomorrow to see what the over-nighters have to say.

[Ronhutton]

The severity of multiple Sclerosis is also dependant on the permeabilty of the BBB. See http://www.medicalnewstoday.com/medi...p?newsid=67397
Jefferson Immunology Researchers Show Blood-brain Barrier Damage Could Affect MS Severity
Main Category: Multiple Sclerosis News
Article Date: 11 Apr 2007 - 14:00 PDT
Immunology researchers at the Kimmel Cancer Center at Jefferson studying a multiple sclerosis (MS)-like disease in mice have shown that the amount of "damage" to the central nervous system's protective blood-brain barrier - in essence, opening it - almost always correlates to the severity of the disease. The findings, reported online in the Proceedings of the National Academy of Sciences, can be used for testing potential MS therapies and for better understanding the role of the blood-brain barrier in disease processes

I wonder how this fits in, is there a deficiency of something that causes MS??
Ron