Stem cell therapy

[halperinchen]

Has any one here tried stem cell therapy for restless legs syndrome? Any success of curing the restless leg ailment or alleviating the signs and symptoms of it? Thanks.

[LotteM]

I am nit aware of any stem ceel therapy for RLS. Do you? If so, please provide some information, if you can with links to sources. As far as I know the main hypothesis on the cause of RLS is brain iron deficiency (BID) in a certain part of the brain. But what cause the BID is not known. Stem cell therapy I think requires a precise target, special cells that are faulty and need repairing. I am not aware that applies to (the cause of) RLS. But I would be happy to learn if you know otherwise

[halperinchen in reply to LotteM]

I am just desperate with the severity of RLS and wondering if is possible to reverse the disease or alleviate the symptoms using stem cell therapy. It seems stem cell therapy is able to regenerate and rejuvenate body organs and I don't know If it also can rejuvenate our dopamine receptor defects and I 'd like to know if anyone who is familiar with this kind of treatment can shed some light on if it can help with RLS . Thanks for your response.

[Carlettejaque]

I have been asking around on here and it seems that RLS could be caused by a back problem either spinal or muscular caused by nerves being pinched or squashed. If you have or have ever had a bad back, I would recommend a sports injury therapist massager or chiropractor.

It's a less drastic treatment than stem cells and if it is a squashed nerve then stem cells won't work.

[Munroist in reply to Carlettejaque]

Hi Carlettejaque, can I just clarify that in my case I think I had RLS initially and back issues made it worse rather than caused it. However there are plenty of posts from people who say it started after back issues and indeed other traumatic experiences such as knee operations etc. Given that RLS normally has a circadian aspect I.e. gets worse at some parts of the day (normally evening), it seems that there is a brain component to the problem.

[Carlettejaque in reply to Munroist]

Yes, every case is different. It's possible that in your case you may have a compressed nerve but it didn't cause a problem until you got your back problem. But, on the other hand as you said there could also be a brain problem element to it. Nerves tell the brain something is wrong so could it still be something interfering with the nerves feeding the brain information?Looking at it logically if sufferers are getting uncontrolable movements then it would seem to be a nervous or neurological condition. What do you reckon?

[Elffindoe in reply to Carlettejaque]

Just to clarify, primary RLS is a neurological condition involving certain areas in the brain. It is partly due to a dopamine dysfunction (D2 receptor sites) and excess glutamate. Both these are neurotransmitters.

Compression of spinal nerves may possibly cause RLS type symptoms, but in this case they probably won't meet the RLS diagnostic criteria.

Spinal nerve compression may make RLS WORSE in somebody who already has primary RLS, The point being, also that primary RLS most commonly exists when there is no spinal nerve compression. It is a genetic disorder.

[MumofSam in reply to Elffindoe]

I completely agree with Elffindoe. I was born with the condition but wasn’t born with spinal problems. I do have spinal problems now, through age-related arthritis and have had surgery for spinal stenosis. That might have made my RLS worse as I now get it in the base of my spine, though the rapid spread of my RLS has also coincided with coming off Tramadol. So primary RLS isn’t caused by spinal problems though it does seem to be a cause of secondary RLS in others.

[Munroist in reply to Carlettejaque]

My own totally unqualified view is that what happens to our nerves can make a big difference to how we feel the RLS. I had PLMD well before I knew I had RLS but wasn't aware of it until conversations later in life revealed I used to "cycle" in bed, and it was partly the back issues and partly age I suspect that raised the RLS to a level where it started to impact me during the day, in particular late evenings when I wouldn't be able to sit still, and then it started to wake me up and I couldn't lie still and had to get up and move. As my back has improved the RLS has got better in the evening, but is still a pain at night.When I exercise hard and aggravate my muscles etc. RLS is worse and there are articles which suggest that exercise sensitises the nerves in muscles. However I think it's much more complex. If it was just nerve why would it be circadian, why does dopamine or methadone make a difference, why does iron supplementation make a difference, why do diet and carbs and sugar make a difference, and why is it so different for different people? Research has shown that RLS sufferers have much lower brain iron. All these things point to a more complex situation and one which has multiple triggers although what we are all desperately hoping for is someone to find the common thread and something that can be specifically treated for RLS rather than re-using medications developed for other conditions which help in some cases but in others cause more problems e.g. augmentation.

[Carlettejaque in reply to Munroist]

Yes, I'm just desperately trying to find a connection, a common thread.Everyone is different and has a unique condition. After Xmas I am going back for massage treatment. I will let you all know if it cures anything other than a bad back.

[Elffindoe in reply to Munroist]

Some excellent questions

why would it be circadian,

Part of the problem that leads to RLS is a lack of D2 dopamine receptor sites in some areas of the brain. Hence when dopamine levels get low the insufficient number of sites there are get less activated hence the RLS symptoms. The amount of dopamine varies over a 24 hour period. There are many other neurotransmitters and hormones that vary like this, melatonin, serotinin, noradrenaline, cortisol etc, to name a few. Dopamine levels in partuculat are at theur lowest at night. Thus RLS symptoms usually happen at night.

why does dopamine make a difference,

For the same reason. Because RLS symptoms occur because of a lack of receptor sites combined with low levels of dopamine then increasing dopamine levels can relieve the symptoms. Because of this levodoap is possibly the nost effective drug for RLS and can take effect in about 15 minutes. This is becasue it directly raises dopoamine levels.

Dopamine agonists however act differently, they act not by raising dopamine levels but by stimulating the receptor sites. Unfortunately, this can also raise dopamine levels as a side effect.

I don't really know why opioids help with RLS. I don't think this has been fully explored as yet. There is what is called "empirical" evidence that opioids work simply because they do work.

However, it is also known that narcotics DO affect dopamine levels.

Out of interest, it was because dopamine agonists were found to work for RLS that the dopamine theory first arose. The dopamine theory was not known until after they started being used.

Similar things have happened with other conditions e.g it was noted that when people with psychotic symptoms were given a sedating antihistamine for nausea, their symptoms improved. This eventually led to a theory that psyhosis involves excessively high levels of dopamine as the antihistamines lower dopamine.

Incidentally, that's why taking a sedating antihistamine can make RLS worse AND taking levodopa can casue psychotic symptoms.

why does iron supplementation make a difference,

This is because the dysfunction of the dopamine receptors is associated with low levels of iron in the brain. and further, that this low level comes about because of poor iron transport across the blood brain barrier.

It has also been found that there is some kind of association between serum ferritin levels and brain iron levels, althoiugh it's not a clear association. Therefore for want of a better method of assessing brain iron levels the need for iron therapy is based on serum ferritin levels. This is the idea that increasing ferritin levels will improve the transport of iron across the blood brain barrier.

There are however many other factors that can affect iron metabolism and these differ between individuals. Hence iron can help most, but not all RLS sufferers.

One of these factors is inflammation. Inflammation can interfere with iron metabolism and can raise ferritin levels for example. Hence just because some people may have high ferritin levels, it doesn't necessarily mean thit will help their RLS. Inflammation is known to be an exacerbating factor in RSL.

If there is nay inflammation in the body then it can worsen RLS. The inflammation may be detectable. e.g. as in rheumatoid arthritis, asthma etc, but it can also be chronic or sub-clincial, with no apparent signs.

Why do diet and carbs and sugar make a difference,

The chronic excessive intake of excessive carbohdrates can casue chronic inflmammation which can subsequently lead to a variety of conditions from dementia to cancer.

I'm afraid I'm not an expert on sugar and RLS. I do know that sugar, or to be more precise sugarS are carbohydrates with simple molecules which when ingested are broken down and absorbed very quickly. This can lead to a sudden influx of glucose into the blood, an insulin reaction and a condition known as reactive hypoglycaemia, which is LOW blood sugar. This may affect nerves because they require a lot of energy, usually derived from glucose and oxygen.

The other thing about diet is that some food elements are more likley to cause bowel inflammation than others. It just depends whether you eat a lot lof those foods or not. Another factor is that some people have food sensitivities. These aren't full blown allergies, but can still lead to inflammation. Common sensitivities are gluten and lactose. People differ in what sensitivities they have, if any.

Another factor is inflammatory bowel conditions, which some people have and others don't. Thgis might include IBS, SIBO, ulcerative colitis, crohns disease H Pyloribacter etc.

Bowel inflammation can particularly interfere with iron absorption in the intestines, hence iron deficiency.

There is also a relationship between chronically high blood glucose, diabetes and RLS. Thuis is becasue the execssive sugar can mean small capillary blood vessels can become blocked cutting off blood supply to peripheral nerves. Peripheral neuropathy due to other causes, (e.g. vitamin B deficiency), also makes RLS worse.

and why is it so different for different people?

That is because as you can see, there are a lot of factors affecting RLS and people varty in those factors.

In addition there are genetic factors in RLS and it isn't necessarily a single gene, so it will in poart depend on how many defective genes you inherit AND whether they are activated or not.

[Elffindoe]

Hi. I belive that as Lotte says, stem cell therapy can target specific cells. I believe it can be used for some neurological conditions, e.g. Parkinson's Disease (PD). However PD occurs in a fairly specific area of the brain, the substantia nigra.

RLS on the other hand involves a few areas in the brain and not just dopaminergic neurons, but also glutaminergic neurons.

Furthermore, the dopamine dyfunction for example occurs because of Brain Iron Deficiency (BID) and this in itself may be a result of a dysfunction in transferring sufficient iron across the Blood Brain Barrier, (BBB).

If a stem cell therapy could be developed to regenerate the dopamine receptor sites then this still doesn't correct the BID or BBB problem. The RLS would recur.

I doubt that there will ever be a stem cell therapy for RLS or for many conditions that are complex.

[ironbrain]

The circadian nature of RLS strongly points to the iron problem being the fundamental one, it seems to me (and others) – I believe Parkinson's sufferers may also be better in the morning than later. Why stem cell therapy may not be useful for RLS may perhaps be understood from why it may well help retinal problems:

sciencedirect.com/science/a... (Advantages of the eye as a target organ)

If the problem is with mitochondria within cells in parts of the brain with RLS, then, I'd guess, that's rather a lot, and complicated, to target with stem cells.

If there is a genetic tendency to RLS, I don't know if, or how, gene editing may or may not be applied to it.

[Elffindoe in reply to ironbrain]

The circadian nature is due to dopamine levels primarily, rather than iron.

[ironbrain in reply to Elffindoe]

Have you any references for this? This would tend to mean that dopamine was essentially starving itself of iron it needs for its production.

This paper describes iron's circadian nature, but doesn't say what controls it.

journals.physiology.org/doi...

I see writing of dopamine modulating circadian rhythm, but nothing so far on how that affects iron levels.

This paper might perhaps be slightly relevant, but is not free:

nature.com/articles/s41575-...

[Elffindoe in reply to ironbrain]

Hi, thanks for the links.

Fascinating.

I must admit that after reading the first article which is quite complex that I'm not quite sure whether it demonstrated circadian variation in brain iron levels. I'll try reading it again.

For now, let's assume it does.

What I find confounding about the study is that it compares two groups of mice. One group is starved of iron and the other isn't. I assume the starvation is mean't to mimic what happens in RLS.

However where both groups of mice were genetically similar, humans with RLS have a genetic factor. Hence I'm not sure if the results can be applied to humans.

Also I note that the study entirely focuses on iron, not dopamine. Dopamine is mentioned just once.

Looking at other studies. There is clearly a correlation between iron levels and RLS severity. Circadian variations in iron levels could therefore play a part in RLS.

However, that's not the whole picture, because the factors that directly, or primarily trigger RLS are dopamine and glutamate levels.

Whether circadian variations in these happen independently of changes in iron levels, I haven't been able to discover.

There is a connection between iron levels and dopamine and glutamate.

The link below gives a possible explanation for this which identifies adenosine as the connection.

. sciencedirect.com/science/a...

Note, it isn't actually changes in dopamine levels that causes RLS, rather it's due to a dopamine receptor site dysfunction. Changes in dopamine levels only explain why RLS is worse at night not why it occurs in the first place.

Other things which have to be noted are that whereas taking levodopa (which raises dopamine levels) can stop RLS symptoms in about 15 minutes and dopamine agonists can prevent RLS symptoms in hours, iron on the other hand does not appear to have such an immediate effect. This is because in RLS there are problems with iron crossing the blood brain barrier.

[ironbrain in reply to Elffindoe]

Dopamine is produced in an interaction between iron and the amino acid tyrosine. So, a lack of iron ultimately leads to a lack of dopamine.

At the synapse, is there not some form of regulatory process? – it's not just straight getting the dopamine across, but something involving feedback. My guess, therefore, is that levodopa, the precursor to dopamine, simply results in flooding the synapse beyond control, while, as you say, iron itself has problems with the BBB.

Ultimately, I would think that if we essentially have circadian "sub-clocks" all over the place, one or more of these could be involved in iron levels and hence dopamine.

I understand there are "morning people" and "evening people". I think I'm probably more of the former nowadays – not sure that's always been the case. But I wonder what would make dopamine have a circadian nature other than iron levels. Is the fact that we start off bright in the morning and then wind down throughout the day enough? Distractions, becoming absorbed in something interesting, do, of course, stave off RLS symptoms. Could we have become so psychologically ingrained with a disparagement that gradually worsens towards evening to have developed the condition? Glutamate might increase as a result of a desire to overcome this lower mental state.

Just some of my thoughts!

[Elffindoe in reply to ironbrain]

Hello again.

Firstly just to clarify RLS is NOT due to a lack of dopamine. In fact, many people with RLS have an excess of dopamine.

The dopamine aspect of RLS is due to a dysfunction of dopamine receptor sites especially D1 sites and D2 sites. RLS is associated with a lack of D2 receptor sites.

As a simple anaology.

Imagine you want to cover a wall with paint by throwing the paint at the wall. For this to work, the wall needs to be sticky,

In this analogy the paint is dopamine and the stickiness is the number of D2 receptor sites.

With a normally sticky wall you can throw a "normal" amount of paint at it because most of it will stick. The wall will become easily covered.

If the wall isn't that sticky, then a lot of the paint will just fall off and hence the wall is less likely to get covered.

This will be at its worst when you run out of paint (low dopamine levels).

One way of dealing with this is to throw even more paint at the wall, increasing the likelihood of more sticking. Another way is to make the wall more sticky. In RLS this is the dopaminergic treatment of RLS.

The problem with increasing dopamine levels in RLS, where levels may already be high may lead to the "downregulation" of D2 receptor sites - the wall becomes even less sticky! So even more dopamine is needed, which again leads to even less D2 receptor sites -p thsi results in augmentation.

In addiiton an excess of dopamine can lead to "upregulation" of D1 receptor sites which has the opposite effect of the D2 sites.

Circadian variations in iron keveks may lead to variations in doioamine production. However, that's not the whole picture. Dopamine firstly is present in many parts of the brain and performs different functions in those parts.

Examples

A lack of dopamine due to nerve cell degeneration in the substantia nigra leads to parkinons; diseas.

A lack of dopamine in the pre-frontal cortex is associated with ADHD

An excess of dopamine in the pre-forntal cotex is associated with schizophrenia

A lack of dopamine in the "reward" centres is associated with depression and an excess with addictive or impulsive behaviour.

There are mechanisms I believe where dopamine levels in particular areas of the brian are regulated in response to the need for dopamine in that area.

The problem with dopaminergic therapy for RLS (like any allopathic medicine) causes problems because it goes all over the place. i.e. in the naology ot doesn't just target the RLS wall, but all the other walls. Hence complications such as Impulse Control Disorder and psychotic symptoms can occur.

Note that dopamine, a neurotransmitter acts in conjunction with many other neurotranmitters and their has to be synchronisation between them, serotonin being one of these for example. Otherwise circadian disruption occurs in such phenomena as "jet lag".

The regulation of circadian rhythms is, as you'd expect is very complicated. There is a "master clock" in the suprachiasmatic nucleus (SCN). There are however also rhythms which are regulated outside the SCN, (sub clocks)

The main factors which affect ALL circadian rhythms are -

The light-dark cycle - as part of this, there are light sensitive receptors that send nerve impulses to the SCN and the pineal gland. IN the dark the pineal gland releases melatonin which promotes sleep.

Activity levels - periods of activity and less activity can regulate the rhythms. Enabling greater alertness and energy levels at the time of increased activity.

Eating -

The whole aim of these rhythms in evolution is that we are more alert and have more energy when we are awake, which used to be during the light hours when we are more active and eat.

Unfortunately, the devlopment of artifical lighting, earlier incandescent lighting and nowadays full spectrum lighting can lead to the disruption of natural circadian rhythms and such disorders as insomnia. and even decreased immunity.

It does appear that dopamine levels are regulated by something but in turn dopamine levels regulates other rhythms. Hence iron is not the only factor affecting dopamine levels.

NOTE : since RLS is not due to a lack of dopamine then normal daily variations in dopamine levels are not going to affect anybody who does not have a genetic predisposition to the condition.

There is evdicne that low iron not only affects dopamine levels, it can also lead to a a lack of D2 receptor sites and this is why iron deficiency is one of the causes of RLS along with its effect on adenosine,

[ironbrain in reply to Elffindoe]

I have read that dopamine levels are found to be generally around normal in RLS sufferers. I thought this was because of the regulatory mechanism at the synapses that tends to try to maintain dopamine homeostasis on the receptor side. I shall have to read up again and possibly a bit further.

My understanding is that RLS results from not enough dopamine passing through the receptor, whether a problem with receptors (too few) or not enough dopamine on the transmitter side (generally iron deficiency). PD is a result of dead neurons in dopamine circuits. I think this roughly agrees with most of what you wrote.

Despite searches, I've not yet found out the turnover of dopamine receptors: how quickly they can be created; how long they last.

[Elffindoe]

I can't give a link or reference, but dopamine levels in RLS tend to be higher than normal. You may notice in the previous link I gave, it inducates RAISED dopamine in RLS.

I can't remember the mechanism for this however I think it may be partly due to poor uptake by receptors (see below) and or regulatory mechanisms attempting to compensate for the dopamine not being effective.

Its also affected by low adenosine.

It's not a matter of enough dopamine passing through receptor sites. It doesn't pass through, it merely enters like a key in a lock. This causes a reaction in the receptor cell membrane.

The real problem is there aren't enough receptor sites available. Hence a weak response, plus the dopamine has nowhere to go. (See above).

Iron deficiency, as I think I wrote before interferes with the development of receptor sites, in infancy..

Thus

Iron deficiency = reduced receptor sites = reduced dopamine uptake and response = excess dopamine plus RLS.

Since higher dopamine higher levels can partly remedy this situation (see my wall anology), anything that lowers dopamine levels can make it worse. E.g. lower levels at night, the effect of sedating antihistamines and dopamine antagonists, which block the receptor sites.

PD is a totally different situation. PD is due to the death of dopaminergic neurons. They die and aren't replaced.

RLS doesn't mean losing whole neurons, only receptor sites.

I'm not 100% certain, but I believe that there is NO "turnover" of receptor sites which disappear and are replaced.

I think it may be comparable to other body parts. For example if you're born with legs. Except for disease or traumatic/surgical amputation they dont just disappear and if they do, they don't grow back again.

They may be damaged however and in the case of D2 sites they can be downregulated, i.e. become unavailable = not work.

They can recover from this following removal of whatever's causing the downregulation e.g. levodopa or DAs.

However, there is some evidence that there can be permant damage to sited, especially afyer augmentation.

This explains why alpha 2 ligands may not be effective in people who previously had augmentation. important then that ligands be the FIRST treatment for RLS.

Don't forget that it's not just dopamine dysfunction that causes RLS, it's also glutamate excess.

See the link I previously gave.

[ironbrain]

It looks as if neuroreceptors are formed from proteins generated according to genes (in the usual way?).

"By maintaining lower dopamine levels in the brain, dopamine receptors can start returning to higher, normal levels. Increasing the number of dopamine receptors to normal levels reduces impulsivity and anhedonia symptoms."

hazeldenbettyford.org/educa...

[Elffindoe in reply to ironbrain]

Note that it's receptor sites returning to normal levels, NOT dopamine levels. This seems to be what happens in practice. Somebody suffering augmentation can relieve this by stopping the cause of it, levodopa or a dopamine agonist. When the number of D2 receptor sites return to "normal" then augmentation will subside.

However, note that in somebody with primary RLS, the "normal" number of receptor sites is still not enough, that's why they have the condition in the first place. So although augmentation symptoms may disappear, the person STILL has RLS.

There is also some evidence that following augmentation there is some permanent damage in which case although some receptor sites will return to function others will not.

It's noted that alpha 2 delta ,ligands taken as the first medication for RLS are as equally effective as dopamine agonists taken as a first medicine. However, if somebody takes a DA first and suffers augmentation, then the ligands may not be as effective.

Concerning the second part of what you write. This refers to another function of dopamine in other parts of the brain NOT the parts of the brain involved in RLS.

These other parts are known as the reward system.

Things that we find enjoyable or rewarding raise dopamine levels in the reward system. So lower levels of dopamine in this system can lead to the opposite i.e. not enjoying anything = known as anhedonia.

Drugs which (artificially) raise dopamine levels in the reward system e.g. opioids or cocaine can lead to intense enjoyment = euphoria. You could also include levodopa in this. This is because when somebody takes levodopa e.g. for parkinson's disease, it doesn't just go the parts of the brain associated with PD, it goes all over the place, including parts associated with RLS, the reward system and the pre-frontal cortex.

When the drug is removed then it takes a while for "normal" levels of dopamine to return = withdrawal effects and parts of these effects can be anhedonia, causing depression.

This can happen in DAWS.

If high dopamine levels in the reward system are greatly increased by drugs such as opioids or cocaine, there is some evdidence that this can cause permananet damage and dopamine levels never rise again to what they were before. Ex-drug addicts can therefore experience long term anhedonia.

Just to correct what appears to bea bit of an error, it isn't low dopamine levsl that cause impulsivity, it's high levels.

It has long been known, as first described by a pyschobiologist called Skinner that behaviours which lead to the expereince of reward are more likely to be repeated. This is the basis of "operant conditioning" a technique used to train animals, (and some humans).

Hence in humans, any behaviour which becomes associated with an increase in dopamine levels is more likely to be repeated. This is the basis of compulsive or addictive behaviour. This is why drug addiction is caused by narcotics.

This is also why dopamine agonists can cause Impulse Control Disorders such as addictive shopping, gambling, eating or hypersexuality.

This "behavioural" component of addiction combined with longer term anhedonia in ex drug addicts can lead to "cravings" which can last for years and even though somebody may get rehabilitated or "dried out" they are prone to returning to their previous habits, again and again.

Drug addiction is a health condition not a criminal act and it's not a matter of choice.

The other aspect of giivng levodopa or dopamine agonists is that it can increase dopamine kevels in the pre-frontal cortex of the brain, Whilst this might actually help somebody with ADHD it can cause psychotic symptoms in people with PD or RLS, these include hallucinations.

[ironbrain]

I'm reading, in RLS, the current theory is that low brain iron leads to an increase in tyrosine hydroxylase that leads to increased dopamine production.

pubmed.ncbi.nlm.nih.gov/194...

"… the decrease in D2R density most probably represents an adaptation, down-regulation, secondary to an increased dopamine release."

books.google.co.uk/books?id...

So, do we need to look beyond a circadian brain iron variation, albeit that glutamate, genes, and whatever, may exacerbate it or make us more prone to it?

The increased presynaptic dopamine causes an overregulation (downregulation) in D2 receptors – mechanism we understand yet? Why does L-Dopa work?