http://sulcus.berkeley.edu/mcb/165_0...ipts/_572.html
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The "Cause" of P.D. Symptoms and its Drug Treatments

The effect of dopamine levels on fluidity of movement can be followed by tracing the pathway "upstairs" from the substantia nigra to the motor cortex. In the normal human brain, the substantia nigra (via dopamine) stimulates the corpus striatum, to which it is attached by many thin fibers. The corpus striatum inhibits the globus pallidus which in turn inhibits the motor thalamus, which finally stimulates the motor cortex (at the top of the brain) to initiate muscle action.

This delicate balance of excitatory and inhibitory pathways is disrupted in the patient with a degenerating substantia nigra. Diminished dopamine levels cause the corpus striatum to be less inhibiting on the globus pallidus, which in turn overinhibits the motor thalamus. This means that the motor cortex is hardly stimulated at all, resulting in the bradykinesia characteristic of Parkinson's Disease.

Clearly, treatment should either restore dopamine levels in the brain, involve drugs that imitate dopamine, or modify the brain in some way to compensate for the deficiency in dopamine. With the aim of restoring brain dopamine levels, the administering of levodopa is the prevalent form of treatment today. Levodopa is converted to dopamine in the body via AADC (aromatic amino acid decarboxylase). Levodopa taken orally is absorbed by the small intestine and enters the circulation to all parts of the body, peaking in blood around 2-3 hours after ingestion, and the effects slowly wear off after 4-6 hours. These peaks and valleys in levodopa effects are referred to as "on/off" periods. Only about 10f the levodopa finally penetrates the brain (dopamine being unable to cross the blood-brain barrier), implying that one must take large as well as continuous doses of the drug for it to be effective. Several months of continuous treatment are necessary to fill up dopamine stores in the brain.

Unfortunately, a common side effect to levodopa treatment is nausea and vomiting. Today, levodopa is administered in conjunction with carbidopa (or another enzyme inhibitor) which prevents levodopa from being converted to dopamine except in the brain. This significantly reduces the side effects as well as allowing levodopa to be administered in much lower doses, eliminating the "dilution effect" caused by AADC's converting L-DOPA to dopamine while it is still floating around in the body.

Another side effect of levodopa treatment is chorea, the neurological term for a series of jerky, involuntary movements. The severity of the chorea increases with levodopa levels, but cutting back on the dosage results in the reappearance of parkinsonian symptoms. A compromise must be made, which is a major drawback of levodopa therapy.

Depression is a commonly reported side effect of Parkinson's Disease itself. Most anti-depressants (and other prescription drugs in general) are safe and will not interact negatively with levodopa. However, a group of antidepressants called "monoamine oxidase inhibitors" (MAO inhibitors) must never be administered with levodopa. Monoamine oxidase keeps dopamine, norepinephrine, and epinephrine levels in the body in check; levodopa will quickly be converted to these substances in the presence of MAO inhibitors, leading to an "overdose" and possibility of a heart attack or a cerebral hemorrhage.

The idea behind the second form of treatment is that administering drugs that mimic dopamine will eliminate the possibility of side effects caused by levodopa. The first dopamine receptor agonist to be tested on P.D. patients was apomorphine, a drug that was already used as an emetic (to induce vomiting). It had been reported in the 1950s that apomorphine alleviated the tremors of P.D. However, not only was it half as effective as levodopa, it was also discovered to have a toxic effect on the kidneys. Other drugs were tested but either did not improve the P.D. or else were also toxic to the kidneys. Finally, bromocriptine (or Pardolel) was found to have about the same potency as apomorphine (half that of levodopa) but the main advantage is that it lasts longer. Bromocriptine acts as a prolactin suppresser and in the future may also be used to treat premenstrual syndrome. It is usually co-administered with levodopa, has the same side effects, and is expensive, being very difficult to synthesize. Consequently, although it can help a select few, it is not the treatment of choice. The search for dopamine receptor agonists is exacerbated by the fact that there are several types of dopamine receptors (D-1 and D-2 included here) and drugs such as bromocriptine are agonists of one but antagonists of the other. Drugs that imitate the natural effects of dopamine through fine-tuned interactions with the receptors remain to be found.

The third method of treatment focuses on compensating for reduced brain dopamine levels. Acetylcholine is present in the brain in much larger amounts than dopamine, and levels are normal even in people with P.D. These two hormones have a reciprocal relationship; dopamine has a restraining effect on acetylcholinergic nerve cells and when it is gone, acetylcholine is no longer regulated, resulting in parkinsonian symptoms. Anticholinergic drugs aim to alleviate this problem.

The first anticholinergics were derived from plants and used to treat P.D. at least as far back as the 19th century when Jean Charcot prescribed hyoscine/ scopolamine to his P.D. patients.

The closely-related atropine (from the belladonna) and hyoscyamine, both from the potato family, have also been used medicinally since ancient times. However, anticholinergics only reduce P.D. symptoms about 25% (compared to levodopa). Interestingly, post-encephalitic P.D. patients respond to anticholinergics much more positively than regular P.D. patients.

The GTS gene isn’t the only gene involved with Tourette syndrome. Tourette’s is actually caused by many genes (no one knows how many yet) that are slightly abnormal. The GTS gene seems to act as a catalyst for all the other genes, and makes their effects more pronounced. Each of these minor genes codes for a trait too, and the abnormalities in the genes cause an abnormality in its product.

Every thought that you have and action that you perform, begins in the brain . Billions of brain cells, called neurons, connect to each other to form pathways. When a thought is had, an electrical pulse starts at one neuron and passes from one to another down a long predetermined pathway. (To be honest, no one has worked out how this actually translates into conscious thought...but we’ll leave that to psychologists and philosophers to fight out.) However, neurons aren’t actually connected directly to each other. Between the end of the dendrites (the little “tentacles” coming out of the cell body) and the body of the next cell there is a gap of about 10-20 nm. (1 nm is one billionth of a metre). This gap is called a synapse. The electrical impulse cannot cross the synapse, so chemical transmitters are used – neurotransmitters. When the electrical impulse arrives at the end of the dendrite, a chemical neurotransmitter is released which crosses the gap and sparks off another electrical impulse on the other side. This is how messages get around the brain.


Dopamine
In Tourette syndrome, however, there appears to be a problem with the receptors of some of these neurotransmitters.
It had been thought for ages that many of the tics in Tourette’s are caused by too much of the neurotransmitter Dopamine.
The theory says:
The brain tends to randomly fire off weak impulses of electricity just to check that everything is connected and healthy. These pulses are so weak that the thought or action they code for does not actually occur. In Tourette’s, however, when some of these random pulses reach the synapses, a larger than normal amount of dopamine is released. And the more dopamine, the stronger the signal released when the chemical reaches the other side. And this stronger pulse would be amplified again at the next synapse, and so on. Very soon, the action would actually be performed.

However, this theory was not quite right. Post-mortem studies of adults who were diagnosed with Tourette syndrome, showed a large increase in dopamine receptor sites. Dr Comings (1991) then discovered that defects in the genes D2A1 and DAT2 increases the number of Dopamine Type Two receptors (D2) while another gene (unidentified) affects the D3 receptors. The increase was about 44% more on average across the whole brain. This would have the same effect as excess dopamine on multiplying the signals passed through the brain, but would do it in a different way.
When the neurotransmitters are released into the synapse, a lot is wasted. At the far end of the synapse there are uptake carrier sites. These sites grab onto the neurotransmitter and, once the chemical is bound to the site, it releases the impulse. But not all of the neurotransmitter reaches the uptake sites. It’s like shooting arrows at a target while blindfolded – only some of them are going to hit it. If you increase the number of targets though, you’re more likely to hit one. It’s the same with dopamine uptake sites, if you have more sites; more dopamine is going to be absorbed. And more dopamine means a stronger impulse at the other end.
Many medications for Tourette’s are dopamine blockers. Once in the body they get into the synapses and bind with the dopamine uptake sites. The dopamine blockers don’t trigger an impulse, they just sit there and stop dopamine from using the uptake sites. This effectively reduces the number of uptake sites in the synapse.
The reason you get sluggish when on dopamine blockers is that ALL movements require the passage of dopamine, not just tics. The blockers do not discriminate between the purpose behind movements .


Norepinephrine
Dopamine is also converted in the body to norepinephrine.
Brain norepinephrine plays a role in general arousal level. Norepinephrine is at lowest levels while asleep, and is released in large quantities to wake you up in the morning. Hormonal norepinephrine is released from the adrenal glands (located just above the kidneys) during stress. It is part of the “fight or flight” response to danger and increases heart rate and blood pressure, relaxes smooth muscle to allow more efficient breathing and increases the conversion of food and sugar into energy. This may cause part of the excess energy Touretters have, as well as things like difficulty sleeping and increased appetite.
Hormonal norepinephrine is also important for learning and the formation of memory.

Because norepinephrine and dopamine are part of the same chemical pathway, the body has to make a choice between which of the two chemicals it needs. The body is very clever and has its own ideas about how much of each chemical it needs, focusing primarily on the balance in the most vital area, the brain. When a Touretter is in an unmedicated state the body detects that it needs to produce a lot less dopamine because the messages are getting through very easily. So the dopamine is converted to norepinephrine in an attempt to lower dopamine levels to the body's idea of normal (actually lower levels than in non-Touretters). So unmedicated Touretters have higher than average norepinephrine levels.
When a Touretter is on a dopamine blocker medication, however, the body feels that messages that should be getting through are not.
This is a weird thought to grasp but for Touretters, tics are the desirable normal state for the body, and it will fight to keep them.
So the body will stop producing as much norepinephrine in order to increase dopamine levels and help the messages get through more easily.
The problem with this is not only are you getting sedation from the lack of dopamine getting through (because producing more dopamine won't get it past the blockers, just like having more people on one side of a wall won't get them through it) you get sedated by the sudden drop in brain norepinephrine.
Some people feel their memory gets weaker if they are on large doses of anti-psychotics and this would be why. Lower norepinephrine levels mean that the body has a bit more trouble forming new memories.



Serotonin (5HT)
Serotonin, often known as 5HT (but actually not), is another type of neurotransmitter. It affects many of our positive and negative experiences of life, so it is often known as the “happy drug”. Very generally, high levels of serotonin bring on good moods - low levels bring on low moods. For this reason antidepressant drugs work to delay the breakdown of serotonin and thus lift our mood.
Serotonin is produced in the body from Tryptophan, a chemical found naturally in high carbohydrate foods. As can be seen in the diagram to the left, about 10% of the body's tryptophan intake is converted to serotonin via the stage of 5HT (5-hydroxytryptophan). The other 90% is converted to kynurenine.

Serotonin acts on three different receptors numbered 5HT1, 5HT2 and 5HT3.

When serotonin acts on a 5HT1 receptor it mainly causes disruption of neurochemicals. This is the receptor pathway that ensures you are not flooded with serotonin, the 5HT1 receptors stop production of any more serotonin, both in the body and in the brain. It also causes the levels of noradrenaline released into the body to drop.

When a 5HT2 receptor comes into contact with serotonin it causes a stress management reaction. The human body can be stressed in many ways; injury, hard work, fear. The reaction of 5HT2 is to cause inflammation of any injured area (e.g. bruising), create faster breathing, send more energy to muscles, contract the smooth muscle in the body (i.e. the stomach to slow down digestion) and basically speed up the metabolism.

5HT3 receptors are the ones that make this the "happy" drug. Serotonin is converted in the brain through a neurochemical pathway into a feeling of well being. (Don't ask me how this works...no-one knows yet.)

What this means in Tourette syndrome is quite convoluted. It has been shown by many researchers that the levels of serotonin in Touretters is quite low. This is immediately made obvious by the fact that anti-depressants can help control tics.
Dr Comings(1990,1991) went further to find that there is a problem in the Tryptophan to 5HT to serotonin pathway in Touretters. Instead of turning 10% of our dietary tryptophan into serotonin we only use 0 - 4%. This means our serotonin production is very low and our kynurenine levels are high.

Oh crud!
"our kynurenine levels are high"
In 2001 I couldn't find out what this implied.
By 2004 I still had no idea.
Now I know.
It's not nice.

I always guessed kynurenine was somewhat toxic...after all, it does have the word "urine" in it and that's one of the body's most toxic wastes. But recent research seems to show that where you find high levels of kynurenine, you find brain damage. Most of the research has been done on HIV patients (HIV causes the higher levels of kynurenine), but there have also been studies that show kynurenine inhibitors (things that stop more of it being made) can reduce the risk of Alzheimer's disease, inflammatory brain conditions, and dementia.
Wow. Aren't you glad I found that out!




So what does this cause physically?
If a low amount of serotonin hits the 5HT1 receptors then norepinephrine is released in larger quantities, making the whole norepinephrine/dopamine problem worse than it already is. This is probably the main reason why SSRI's work on tics, because they would reduce the amount of norepinephrine in the body.

If a low amount of serotonin hits the 5HT2 receptors the body is less able to cope with stress. You are more likely to react badly to temperature changes, low food levels, and injury.

If a low amount of serotonin hits the 5HT3 receptors, you get depressed. This tends to also make you eat more in an attempt to raise serotonin levels.

All this means that it is important to have decent serotonin levels in the body and the brain. This is easy for the body, you can just take a serotonin tablet. But the brain is protected by the BBB (blood brain barrier) which screens out most chemicals from the blood, including serotonin. The way we deal with this is to use SSRI's. Selective Serotonin Re-uptake Inhibitors stop the serotonin in the brain from being broken down, so there ends up being more around.
However, SSRI's won't work forever.
As has been said before, the body has a preset idea of what is a "normal" amount of neurochemical to have. With serotonin in Touretters, that level is quite low. But if you put more serotonin into the system via SSRI's, then the brain will make even less natural serotonin. The artificially higher levels will also begin to "burn out" the serotonin receptors, so more is needed to get the same result. This is the reason why SSRI levels have to be upped occasionally as the drug just stops working. It also explains the huge withdrawal after stopping SSRI's, the body is not producing serotonin, but you need high levels to get any reaction...in Touretters this translates to depression and lots of tics.

To understand a bit how this "burn out" works:
"Imagine a pool. It starts off full of salt water. By the side of the pool sits a life guard, his job is to make sure that (a) the pool is full and (b) that there isn’t too much salt in the pool. However this particular pool has a slow leak from the bottom. To counter this ten men are hired to walk to a nearby sea, fill a bucket with sea water, and walk back to pour the water into the pool.

In a normal pool, the men fill their buckets from the Mediterranean sea, which has exactly the right level of salt for the pool. The pool stays full, and the salt level stays correct.

In a Tourette pool, however, the men fill their buckets from the dead sea. The dead sea has 4 times the salt of the Mediterranean, so as time goes on, the salt levels in the pool rise. The life guard notices that the pool is getting too salty, so as the next man comes to tip in his bucketful, the life guard talks to him, and he puts down his bucket and heads to the bar. When the second guy comes and tips in his bucket, the lifeguard also talks to him, and one by one the men put down their buckets and go to the pool bar.
Because the pool is leaking, the salt levels in it begin to drop, but so does the water level. It actually starts to drop quite suddenly after the last bucket is put in, and soon the water level has gone from full to too shallow to swim. The life guard runs over to the bar, grabs the men and they run back to the pool, pick up their buckets, and begin running to the sea to fill them up. The water level in the pool begins to rise at a moderate speed, but soon the men are drunk from the bar and are tired from all the running. So the life guard hires another 5 men to help bring in the water. So now there are 15 men lugging water from the sea to the pool. The pool level rises a bit, until the lifeguard notices that the pool is getting to salty…"

So although SSRI's are very effective, they should be considered carefully before any are taken.

Dr Comings (1990, 1991) believed that the serotonin gene at 4q31 was the GTS gene, but that has been disproved.

The best way to raise serotonin levels is exercise. Not only are levels raised during the activity, they stay high for a couple of days afterwards.



Androgens
It has long been known that androgens (such as testosterone, the male sex hormone) affect Tourette syndrome. This is why Tourette syndrome affects three times more males than females. Also, Shapiro et al. (1988) and Scahill (1990) reported that anabolic steroids made Tourette syndrome symptoms worse.
The reason these androgens aggravate Tourette syndrome is probably related to serotonin. It is known that steroids lower serotonin levels, and it is probable that high levels of other androgens will as well.




Cortisol and DHEA
Cortisol is known as the “stress hormone”. It maintains blood pressure and cardiovascular function, reduces the immune system’s inflammatory response, balances the effect of insulin in breaking down sugar for energy, and regulates the metabolism of proteins, carbohydrates and fats. When the body is stressed, the level of cortisol in the body increases. (e.g. athletes, pregnant women, depressed people, alcoholics, malnourished people and those with panic disorders have higher than normal levels of cortisol.)

It is believed by many that cortisol has a negative effect on Tourette syndrome; that is, it makes tics worse. So it may be cortisol that makes tics worse under stress.
Discoveries (Biol. Psychiatry 1996 – as cited by J. M. Howard 1997) have shown that Touretters have significantly higher levels of corticotropin-releasing factor, the precursor to cortisol, than normal.

Dehydroepiandrosterone (DHEA) is an “anti-cortisol” hormone according to Howard. DHEA has been known to have calming effects and is packaged by some companies as a “wonder anti-aging drug!” It is believed that low levels of DHEA will add to the negative effect of high cortisol levels.

The strange behaviour of antipsychotics and neuroleptics when used to treat Tourette syndrome can be partially explained by DHEA/cortisol reactions. It is believed that these drugs cause the release of prolactin, the precursor to DHEA. This increased DHEA counters the high cortisol levels. The drugs, unfortunately, overwhelm the natural production of DHEA and “burn out” the adrenal glands. This then means the levels of cortisol rise again, usually to a higher level than where they started.
This means the brain is not getting enough DHEA. Howard suggests that tics are actually small seizures designed to stimulate DHEA production. How this works:
"...the increased melatonin found in untreated epileptics builds up and is released so that nerves are shut down. Individuals susceptible to epilepsy must have entire sections of the brain shut down so much that they "rebound" and call up a large response of DHEA. It is this rebound response that is the large area of stimulated nerves that cause the seizures. Once the brain has stimulated sufficient DHEA, then the seizure stops."
So TSers may find that (directly affected by DHEA levels) this rebound in small sections of the brain (instead of large sections as in epilepsy) causes not an overall muscle contraction seisure; they cause a small nerve impulse to be sent; which gets multiplied by the Dopamine receptor abnormalities described above. So the brain's attempt to create DHEA, in order to relieve stress, may cause tics that way.

This (in my mind) is actually the most plausible explanation for how tics start.

Stress → need for more DHEA → mini seisure → small electrical impulse + excess dopamine receptors
= TICS

DHEA levels are known to start low in childhood and increase during adolescence to peak at about age 25. It is also common knowledge that Tourette syndrome often decreases in severity or disappears following the same pattern. DHEA then may be the reason for this decrease.

Also, in an article on epilepsy, Howard states:
"I suggest migraines result from low MLT and increased DHEA. Women produce more DHEA from birth than men. This extra DHEA should have most effect on migraines prior to the onset of interfering sex hormones, before puberty. It has been found that "when the onset [of migraines] is below the age of puberty there is a striking predominance of women over men in a ratio of 3:1," (Headache 1994; 34: S8). It is part of my theory that the hormone, testosterone, causes DHEA to be used for "testosterone target tissues." This use of DHEA by these tissues should reduce the availability of DHEA, i.e., increased testosterone should decrease migraines. "
This is of interest to us as the ratio of Women over Men in Tourette syndrome is the exact opposite; 1:3. If testosterone does cause DHEA to be used for "testosterone target tissues" (parts of the body that make men men) and reduces overall DHEA then not only will women have 3 times more DHEA to aggravate migraines, they will have 3 times more DHEA to stop tics!

References
David E. Comings (1990) Tourette Syndrome and Human Behaviour
David E. Comings (1991) Search for the Tourette Syndrome and Human Behaviour Genes
buy Dr Comings' books at amazon.com
James Michael Howard (1997) A potential explanation of Tourette's syndrome and DHEA, Migraine and Epilepsy
Norepinephrine info site http://www.csuchio.edu/psy/BioPsych/norepinephrine.html
Getting 'high' on serotonin - Neurotransmitters and Health website


Ron can this be of information on dopamine receptors,
hard to find information that sticks to the subject and doesn't go into the symptoms of parinsons and what it entails. Will keep trying for more up to date info for you. but the information contained here on Migraines and Tostesterone is now accepted as fact so that speaks well for the author

12/6/2004

Protecting microtubule "highways" may lead to novel therapies, study shows". Parkinson's disease may be caused by an environmental-genetic whammy on the neurons that produce dopamine, the neurotransmitter that controls body movement, a new study has shown.

Researchers at the University at Buffalo, using cultures of rat neurons, have shown that the presence of mutated parkin genes, combined with the toxic effects of the chemical rotenone, results in a cascade of highly toxic free radicals, the destruction of microtubules that transport dopamine to the brain's movement center, and eventual death of the dopamine producing neurons.

When microtubules are broken down by rotenone, the disassociated protein building blocks, called tubulin, are left behind. These tubulins are probably misfolded proteins. Left unattended, they could interfere with the normal assembly of microtubules. Based on previous work that parkin marks this "old" tubulin for rapid degradation, we theorize that parkin may thus prevent this interference.

Mutated parkin loses this protective ability, however, allowing rotenone to do its damage unchecked.

Rotenenone damages the microtubules, which prevents dopamine from reaching the brain's movement center, causing a back-up in the dopamine traansport. Meanwhile the backed-up dopamine accummulates in the neuron's cytoplasm and breaks down, allowing the breakdown of toxic free radicals, which destroy the neurons.

Rick, this blows your BBB sky high. If the dopamine cannot get out of the substantia niagra it can't leak out of the brain barrier.

Those of us who have definite mutations, espiecially 2 or more, as I do, are the trunk of the tree. Because our Parkin gene is not acting to protect the microtubiles it was almost certain we would get Parkinson's. Each of the others who have been diagnosed with idiopathic Parkinson's are different limbs or branches who were exposed to a toxin or anoxic brain damage The tree is huge with many different branches joining to limbs then joining with the trunk.

There are many different paths to Parkinson's disease. We can follow each and every branch to the limb to find the source of one shared cause, then follow the limbs to the trunk to find more about the etiology of Parkinson's disease.

Or research could focus on the trunk of the tree and find a way to make the trunk healthy again, hense, the limbs and branches would follow. All of you can make your choice of how to effectively research the etiology and eventual cure for Parkinson's disease. Either focus your funds toward the trunk or do what is being done now. Chase each and every branch throwing money at them, hoping to get lucky and find a cure for a few while never finding the etiology of the making of Parkinson's disease.

GABA deficiency signs/symptoms:


Anxious/nervous/jumpy
Panic attacks
Feel stressed/pressured/overwhelmed
Have trouble relaxing/loosening up
Low stress tolerance
Body tends to be stiff/uptight
Butterflies in stomach
Lump in throat
Trembling/twitching/shaking
Cold or clammy hands
Crave carbohydrates

Valium/xanax/avitan/GABA relax
Alcohol/food/cigarettes relax
Feel terrible if skip meals
Heart palpitations and fast pulse

GABA is our relaxing (anti-anxiety) neurotransmitter which is raised by valium. GABA levels may be low due to a combination of genetic and acquired reasons. GABA can be raised effectively using either nutrient based therapies or medications. GABA is synthesized from the amino acid glutamine.

Factors which reduce GABA levels:
Glutamaine (precursor) deficiency
B1, B6, zinc, manganese & iron deficiency
Chronic stress
Chronic pain
Progesterone deficiency
Mercury and lead exposure
Alcohol withdrawal
Caffeine excess

I am not sure where we are going with this thread. Recent replies are useful information, but have little to do with the mode of operation of the BBB.
Also, to get a solution to PD, we must question "established facts". If billions of $ have been spent, and we still don't know
1. what causes PD.
2. How to permanently cure it.
3. How to avoid side effects as bad as the disease.
then some or all of the "established facts" are wrong!!!
vlhperry says,
" Rick, this blows your BBB sky high. If the dopamine cannot get out of the substantia niagra it can't leak out of the brain barrier."
But can we be sure that it is true that dopamine cannot get out of the substantia nigra (not niagra!). Also, I didn't think that Rick had started this thread! LOL
I like the simplest of explanations, there is less to go wrong.
My concept is the BBB is a membrane, through which, substances can pass both ways. The permeability can be made higher or lower. Osmotic pressure drives substances from one side to the other. If a substance is on one side of the membrane, it will diffuse through the membrane until equilibrium is reached. If stress opens the membrane wide, equilibrium will be established fast. The brain is one side, the body and bloodstream is the other side. The body is a much larger mass and has much more blood and fluids than the brain. The body would therefore have much more dopamine than the brain at equilibrium. But dopamine can't cross the BBB (in a normal person), so the brain dopamine is kept in the brain, and movement is normal.
In our case, if the BBB is leaky, there is a strong osmotic pressure to drain it out into the body and bloodstream.
Can it be a coincidence that all the things which make our symptoms worse, stress, old age, pesticides,... all open the pores of the BBB.
Things which improve, curcumin, alpha lipoic acid, CDP choline, GNDF, all close the pores.
Add to this Prof Leenders has shown PWP have defective BBB's.
A recent report states, Though the BBB has been thought to be intact in neurodegenerative illnesses, PD and AD, recent evidence argues otherwise.
This is my point exactly, challenge the "established facts" until they are irrefutable, or modify them until they are irrefutable.
You can give answers to many questions using this concept.
Why is PD predominently an old person's disease.
A. Because the BBB gets more porous with age.
Why does stress cause an immediate worsening of symptoms
A Because it causes a catastrophic opening of the BBB.
There are still questions that can't be answered,
eg Why does eating start dyskinesia? (See a previous thread)
Does operation of the bulbar muscles, which control chewing close the pores of the BBB suddenly and give a temporary high level of dopamine in the brain? It may be a mechanism to prevent the new substances we are eatiing from passing the BBB into the brain, until they have been checked.
We need to research any unanswered questions until we either kill or confirm the concept.
Ron

My information is supported by research studies. Please contact the researcher I listed in my Title to affirm the study. Genetic research is still in its infancy stages but is evolving fast. I do not doubt the outcome of the research as it is carefully documented and based on science and not on guesswork. We can make any theory look reasonable if we really believe in it. The genetic information does not back up your theory. The more persons who participate in genetic research, the sooner we might solve the puzzle of PD. Proof of rotenene poisoning with mutations of the Parkin2 mutations is one limb on the tree. It could be that it is a matter of degree of exposure to toxins that determines who could be a branch which feeds into a limb.

Understanding how the rotenene and the gene cause the Parkinson's disease is the first step. The second will be to find a way to compensate for the Parkin2 genetic mutation to prevent or substitute a way to prevent the protein mutations normally marked for destruction by normal Parkin2 cells.

Right now the genetic information is being collected and the information derived is sold to pharmaceutical industries who patent different lines. Some create patents before they know what possibilities there are on its use to cure more than one disease. If these patents continue to be allowed, it will hinder research dramatically. We, the patients who participate in this research, are the only ones who can stop this practice by ceasing participation in the studies or contacting our legislators and urging them to pass the bill introduced by a California representative as a bipartisen issue.

The only reason I am sure I have the mutations is because I had the test performed by Allinia Diagnostics, the only commercial company offering the test. If you participate in private research, under the contracts the patients sign, you sign away not only right to your gene information, a very personal piece of information which will help you make treatment decisions, but also your right to know if you have mutations.

Persons who have more than one mutation have different symptoms than those with no mutations. They are more prone to dystonia than tremors, they are extremely sensitive to levodopa/carpadopa therapy (too much causes a rare malignant syndrome which I experienced twice in one summer,) treatment by muscle relaxants are safer, eye problems develop more, and other numerous symptoms. As persons with mutations approach their senior years the symptoms speed up until they are the same as other Parkinson patients. In Europe these patients are classified as having Parkin disease, not idiopathic Parkinson's disease. This classification is important because the treatment is geared toward the different symptoms. In Europe, where patents are almost nonexistant, patients are aware of if they have mutations in their genes and share the information. In America, the pharmaceutical industry patents gene information as soon as a strand of DNA has been completed, and does not share information. They then claim that America has the most advanced medical technology in the world. That is why persons with the money come to the Mayo clinics for treatment. Only they can afford to pay the price for the advanced, experimental procedures.

Meanwhile the poor in the U.S., like veterans, are used as gunea pigs in research studies to come up with the technology to help the rich Europeons. And the average American must pay 4 times the costs for the same meds sold in other countries because the pharmaceutical industry does not operate as a "free market industry." They do this by lobbying legislatures to protect America's advanced technology. I would rather see our technology shared for the benefit of all the world. World cooperation and world health take first place over America's pride in their technology. For those without the information to help themselves, or afford to pay for advanced technology the current government mentality of, "Let them eat cake," is no longer plausable or tolerable by a modern society.

Yes, my spelling and memory are going to the devil, but the message is understood and documented. The BBB theory is only that: An unproven theory not proven or documented. The scientific community is the best educated and are working hard again, after a 30 year hiatis of treating symptoms, and not working to understand the disease and its causes. The cure will come more quickly, thanks to people like Caroline, Peg, Joan Blessington Snyder, and others who pioneered patient advocacy groups, speaking out loudly to their congressmen, "we are mad as ****, and we're not going to take it (treating symptoms only) anymore. That, accompanied by the aging baby boom generation, will kick start the government to search for a cure. They may be a bit slow in getting it, but the beginning of the baby boom generation has just hit the 60's age category and as Parkinson's disease rises on the "cause of death" list so will the money to find a cure. Remember, we live in a Supply and Demand economy. The demand is just beginning.

vlhperry,
Sorry, I was joking about your "Substantia Niagra", that is why i put LOL in. It just struck me as very funny when we were talking about releasing the floodgates, etc. If you were offended I do agologise.
However, I don't think that a gene based theory necessarily kills all other theories, particularly when less than 5% of PD cases are attributed to genes. I don't want to have an argument, it wastes all our time. I also feel my information is documented also, I have given the refs in earlier posts. Gene theories are well documented too, but can you answer why PD is more prevalent in old age?, why does stress have an immediate catastrophic effect? My point is that we do not have a cure having spent billions, so some of the well documented "facts" must be wrong. We need more innovative research, which questions established dogma.
There is no sense in me contacting your researcher,as you suggest, he would confirm his "facts" like all researchers would.
I don't want to enter an argument on which countries do the most for PD., and whether poor Americans are used as guinea pigs for rich Europeans, it has nothing to do with a BBB theory, and will end up in the thread being banned. Let's stick to pleasant discussions which have a possibility to advance the arrival of the cure. If the BBB concept is wrong, lets prove it, as I said, "Kill or confirm it"
Hope we can avoid conflict and sorry again for quoting your "Substantia Niagra" hope you can see the funny side.
Very best wishes
Ron.
PS Taking about genes, there is a saying,
"The future of mankind is in his genes"
See the joke??

Which may be useful and which, out of respect for Ron's thread, I will post in their own....

Ron,
your interesting but your hypothesis has a hole in it.

microplasmas can bring viral infection into the brain - free radicals are then able to enter the cells, and create- dis -ease.

our brains are not leaking, but our medicine does break the BBB
in the form of dopamine, so it does work as a drug, but there may be other drugs that we are prescribed that cause it to be depleted faster.
or protein and our med's dont work because we eat proteins and take meds too close together -thus the dopamine also works as an amino acid and digests our food instead of helping us walk -stop shaking etc.
My hypothesis is that many are diagnosed incorrectly...

also - Starfield JAMA article: Barbara Starfield's JAMA article (Volume 284, No. 4, 2000), gives very large estimates of death due to medical treatment. A total of 225,000 deaths are attributed to various iatrogenic causes. This figure puts them at the 3rd highest cause of death, only after heart disease and cancer. With roughly 2.4 million US deaths in 1999, these estimates would put iatrogenic causes at approximately 9.3% of deaths.

see links there are many -here's one
http://www.wrongdiagnosis.com/mistakes/common.htm
or
http://www.wrongdiagnosis.com/news/y..._diagnosed.htm


you said

"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,

Drug Class And Mechanism:

Levodopa-carbidopa is a combination of two drugs, levodopa and carbidopa. Levodopa-carbidopa is used in the treatment of Parkinson's disease. Parkinson's disease is believed to be related to low levels of dopamine in certain parts of the brain. When levodopa is taken orally, it crosses through the "blood-brain barrier." Once it crosses, it is converted to dopamine. The resulting increase in brain dopamine concentrations is believed to improve nerve conduction and assist the movement disorders in Parkinson disease. Carbidopa does not cross the blood-brain barrier. Carbidopa is added to the levodopa to prevent the breakdown of levodopa before it crosses into the brain. The addition of carbidopa allows lower doses of levodopa to be used. This reduces the risk of side effects from levodopa such as nausea and vomiting. This combination medicine was approved by the FDA in 1988.

Prescription:Brand Name
Sinemet

Dosing: Levodopa-carbidopa is taken several times per day. It may be administered with food to reduce the likelihood of nausea. However, a high-protein diet may reduce its absorption.

Drug Interactions: The use of amantadine (Symmetrel), benztropine (Cogentin), procyclidine (Kemadrin), or trihexyphenidyl (Artane) with levodopa-carbidopa can enhance the anti-Parkinson's effects of levodopa. Droperidol, haloperidol (Haldol), loxapine (Loxitane), metoclopramide (Reglan), phenothiazines such as prochlorperazine (Thorazine); thioxanthenes as thiothixene (Navane) inhibit dopamine in the brain. These drugs, therefore, can worsen Parkinson's disease and reverse the beneficial effects of levodopa. Methyldopa (Aldomet) and reserpine also can interfere with the beneficial actions of levodopa-carbidopa and can increase the risk of side effects.

Phenytoin (Dilantin) can increases the break-down of levodopa-carbidopa, reducing its effectiveness.

Use of levodopa-carbidopa with monoamine oxidase inhibitors (MAOI's) antidepressants, for example, isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), and procarbazine (Matulane), can result in severe and dangerous elevations in blood pressure. MAOI's should be stopped 2-4 weeks before starting levodopa-carbidopa therapy.

Related Links on MedicineNet.com

http://www.thewolfeclinic.com/newsle...etter0205.html

http://healthguide.howstuffworks.com...-in-depth7.htm

http://healthguide.howstuffworks.com...-in-depth6.htm

or read about the metabolism
http://healthguide.howstuffworks.com...dictionary.htm

http://health.howstuffworks.com/defi...ive-system.htm

an article for women -pertaining

The digestive system and dysbiosis
by Marcelle Pick, OB/GYN NP

The major function of the digestive system is to break down food and provide a means by which the nutrients can be absorbed in the body. Nutrients that are liberated by this process allow the body to grow, heal and function on a day-to-day basis.

Unfortunately it is very common for this process to be disrupted (known as dysbiosis). A wide range of factors can influence how well the digestive system function — including dietary habits, medications, and emotional wellness — and most people are affected by at least one of these factors. In fact, an estimated two-thirds of women suffer from gastrointestinal problems, which often leads to malabsorption.

http://www.womentowomen.com/digestio...dysbiosis.aspx