another jig saw piece? Cholinergic system

[eve]

I've come across an interesting article on the Dutch MS forum. It's about this study:

Abstract

Hippocampal pathology was shown to be extensive in multiple sclerosis (MS) and is associated with memory impairment. In this post-mortem study, we investigated hippocampal tissue from MS and Alzheimer's disease (AD) patients and compared these to non-neurological controls.

By means of biochemical assessment, (immuno)histochemistry and western blot analyses, we detected substantial alterations in the cholinergic neurotransmitter system in the MS hippocampus, which were different from those in AD hippocampus.

In MS hippocampus, activity and protein expression of choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, was decreased, while the activity and protein expression of acetylcholinesterase (AChE), the acetylcholine degrading enzyme, was found to be unaltered.

In contrast, in AD hippocampus both ChAT and AChE enzyme activity and protein expression was decreased. Our findings reveal an MS-specific cholinergic imbalance in the hippocampus, which may be instrumental in terms of future treatment options for memory problems in this disease.

http://www.ncbi.nlm.nih.gov/pubmed/21691765

I was not familiar at all with the colinergic system so I had a little read - up. Anyway, to make a long story short - I also came across this:

The central cholinergic system exercises important neuromodulatory functions on cerebral circuits related to cognitive and behavioral integration, as well as on vasomotor control related to cerebral blood flow adjustments.

http://www.demneuropsy.com.br/detalhe_artigo.asp?id=125

I have loads of brainfog at the moment and I know there's a lot of clever people around here - maybe worth having a look into?

[ThisIsMA]

This is very intriguing! However I too have cog fog issues and in addition am very tired right now, so I'm not much help (at least not until after I get a good night's sleep).

But thank you for posting this. I hope someone will look into it further for us. It does seem like it could be a piece of the puzzle.

[eve]

I ran the article tru google translate:

Chemical interference with memory system in MS


It is possible that the memory problems of MS patients are caused by decreased production of the substance acetylcholine. With drugs you would do something about.

About half of all MS patients suffer from memory problems. A brain region that is of vital importance for the formation of new memory is called the hippocampus. The "cholinergic system plays an important role. This system includes several substances, including acetylcholine, involved in communication between brain cells and ensure that memory can be formed. Research shows that in MS patients a disturbance of the cholinergic system. It is possible that medications that affect the cholinergic system, improve memory.


It is already known that in Alzheimer's disease is a disruption of the cholinergic system. VUMC Amsterdam scientists wonder if there is something similar happening in MS and therefore the hippocampus of deceased patients and healthy people are compared. They had the hippocampus of 15 MS patients, 10 Alzheimer's patients and 10 healthy controls collected.


The researchers first looked if there was any hippocampal demyelination. None of the Alzheimer's patients and healthy controls showed demyelination in the hippocampus. Twelve of the fifteen-hippocampal MS were fully or partially demyelinated

Then it measures the amount of choline acetyltransferase (ChAT) activity. Chat is responsible for the production of acetylcholine. They saw a statistically demonstrable reduction of ChAT in the hippocampus of MS patients and Alzheimer patients. There was no difference between hippocampal and those not were demyelinated.

Also, researchers looked at the VU to the amount of the enzyme acetylcholinesterase (AChE). AChE causes acetylcholine is broken again. There was a decrease of AChE in the hippocampus of Alzheimer's patients but not in those of MS patients. Again there was no difference between hippocampal and those not were demyelinated.


The authors of the study conclude that there is a disruption of the cholinergic system in MS patients, but not comparable to the disturbance as seen in Alzheimer patients. It is possible that the memory problems of MS patients are caused by decreased production of acetylcholine. A possible therapy would be to reduce the amount of AChE which reduces acetylcholine is broken. There have been tests done in animals and a small number of MS patients, this therapy seems to have a beneficial effect on memory functions.

Bron: Kooi EJ, Prins M, Bajic N, Beliën JA, Gerritsen WH, van Horssen J, Aronica E, van Dam AM, Hoozemans JJ, Francis PT, van der Valk P, Geurts JJ.- Department of Pathology (Neuropathology), VU University Medical Center, Amsterdam, The Netherlands

Acta Neuropathologica 2011 Jun 21. [Epub ahead of print]

I also had a look at acetylcholine - it turns out this substance can be found in great abundance in ... bee stings. I kid you not.

I also found that vitamine B6 plays a vital role in processing acetylcholine. I think most of us would agree B6 is one of the vitamins MSsers profit from.

Also came across this interesting study:

http://www.ncbi.nlm.nih.gov/pubmed/20655720

Vitamin D3 restores altered cholinergic and insulin receptor expression in the cerebral cortex and muscarinic M3 receptor expression in pancreatic islets of streptozotocin induced diabetic rats.

Kumar PT, Antony S, Nandhu MS, Sadanandan J, Naijil G, Paulose CS.
Source

Molecular Neurobiology and Cell Biology Unit, Centre for Neuroscience, Cochin University of Science and Technology, Cochin, Kerala 682 022, India.
Abstract

Nutritional therapy is a challenging but necessary dimension in the management of diabetes and neurodegenerative changes associated with it. The study evaluates the effect of vitamin D(3) in preventing the altered function of cholinergic, insulin receptors and GLUT3 in the cerebral cortex of diabetic rats.

Muscarinic M3 acetylcholine receptors in pancreas control insulin secretion. Vitamin D(3) treatment in M3 receptor regulation in the pancreatic islets was also studied. Radioreceptor binding assays and gene expression was done in the cerebral cortex of male Wistar rats. Immunocytochemistry of muscarinic M3 receptor was studied in the pancreatic islets using specific antibodies.

Y-maze was used to evaluate the exploratory and spatial memory. Diabetes induced a decrease in muscarinic M1, insulin and vitamin D receptor expression and an increase in muscarinic M3, α7 nicotinic acetylcholine receptor, acetylcholine esterase and GLUT3 expression.

Vitamin D(3) and insulin treatment reversed diabetes-induced alterations to near control. Diabetic rats showed a decreased Y-maze performance while vitamin D(3) supplementation improved the behavioural deficit. In conclusion, vitamin D(3) shows a potential therapeutic effect in normalizing diabetes-induced alterations in cholinergic, insulin and vitamin D receptor and maintains a normal glucose transport and utilisation in the cortex.

In addition vitamin D(3) modulated muscarinic M3 receptors activity in pancreas and plays a pivotal role in controlling insulin secretion. Hence our findings proved, vitamin D(3) supplementation as a potential nutritional therapy in ameliorating diabetes mediated cortical dysfunctions and suggest an interaction between vitamin D(3) and muscarinic M3 receptors in regulating insulin secretion from pancreas.

[ThisIsMA]

Great find! That's incredible about the bee stings...

Here is an excerpt from Wikipedia's page on the Cholinergic System:

Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin. It prevents fat deposits in the liver and facilitates the movement of fats into the cells.

I wonder if supplementing with lecithin might be helpful?

Also, if we are deficient in acetylcholine, which the article you posted said we are, then according to the above wikipedia article we would have trouble with normal processing of fat. I wonder if that is why the low saturated fat intake Swank diet may be effective?

[cheerleader]

Hi Eve--
I've been very interested in the hippocampus, since this UCLA study on depression, stress, cortisol and hypocampal atrophy in MS came out in 2010.

The researchers examined three sub-regions of the hippocampus region ― CA1, CA3 and the dentate gyrus area of the hippocampal region called CA23DG (CA stands for cornu ammonis). They imaged 29 patients with relapsing remitting multiple sclerosis and compared them with 20 healthy control subjects who did not have MS. They also measured participants' cortisol level three times a day; cortisol is a major stress hormone produced by the HPA axis that affects many tissues in the body, including the brain.

In addition to the difference between MS patients and healthy controls, the researchers found that the multiple sclerosis patients diagnosed with depression showed a smaller CA23DG sub-region of the hippocampus, along with excessive release of cortisol from the HPA axis.
"Interestingly, this idea of a link between excessive activity of the HPA axis and reduced brain volume in the hippocampus hasn't received a lot of attention, despite the fact that the most consistently reproduced findings in psychiatric patients with depression (but without MS) include hyperactivity of the HPA axis and smaller volumes of the hippocampus," Sicotte said

http://www.sciencedaily.com/releases/20 ... 145533.htm


What I found most interesting was the release of cortisol and a heightened or hyper-active HPA axis response. (This is why stress is so harmful to pwMS. Cortisol is a major endothelial disrupter and vasoconstrictor. It messes with nitric oxide.) Cortisol and the stress response also mess with the cholinergic system...cortisol activates the response, but what happens in chronic stress? Cholinergic uticaria, or hives, are known to be caused by stress.

Considerable data have emerged which strongly indicate that the septohippocampal cholinergic system is involved in the adaptive response to stress. Neurotransmitter regulatory mechanisms in cholinergic synaptic terminals of this part of the limbic system undergo adaptive changes in response to stress and recover slowly after stress. The initial stress-induced response is characterized by activation of hippocampal cholinergic terminals within minutes, as indicated by a rapid and transient elevation in high affinity choline uptake and increased newly synthesized acetylcholine release. The response of this cholinergic system to stress is influenced by both neuronal and hormonal stimuli. Among the several neuronal systems converging in the septum, terminals of the dopaminergic mesolimbic system have been found to be selectively involved in the early response to stress. Pharmacological interference with dopaminergic neurotransmission, with agonist and antagonist treatments, revealed that changes in the tonic inhibitory influence of septal dopaminergic terminals can modulate the response of hippocampal cholinergic terminals to stress. A similar activation of hippocampal cholinergic terminals as after short-term stress was observed after treatments with a large dose of either adrenocorticotropic hormone or corticosterone. Furthermore, glucocorticoids and not adrenocorticotropic hormone can directly enhance acetylcholine release, but only from excited terminals. This indicates that stress-induced activation of the septo-hippocampal system may occur secondary to, but not directly by, increased levels of pituitary-adrenocortical hormones. Yet, it is possible that under stressful conditions the increased glucocorticoid levels may modulate the activity of the stimulated hippocampal cholinergic terminals. Together the findings support the notion that the stress-induced response of the septo-hippocampal cholinergic system represents an integrated output of converging neuronal and hormonal stimuli which convey signals of stress to this limbic brain region.

http://www.ncbi.nlm.nih.gov/pubmed/3615747

I guess this just brings up more questions....is it a heightened stress response which causes this disregulation in the MS brain, or does the disregulation come first?

Stress reduction and ways to limit the flood of cortisol seems to be an effective practice for those with MS...I know my husband has benefitted from meditation and relaxation. He used to be a type A workaholic, but is more relaxed now. Certainly, more research ahead! Good find--
cheer

[MegansMom]

This is even further interesting because the Hippocampus is extremely vulnerable to hypoxic injury.it's considered one of the most easily damaged Brain parts. And since "CCSVI caused hypo-perfusion/hypoxia " may be intermittent and chronic it's a definite fit of another piece of a very complex puzzle.

[cheerleader]

This is even further interesting because the Hippocampus is extremely vulnerable to hypoxic injury.it's considered one of the most easily damaged Brain parts. And since "CCSVI caused hypo-perfusion/hypoxia " may be intermittent and chronic it's a definite fit of another piece of a very complex puzzle.

Thanks for the reminder, Cat...I knew this all looked familiar. Been doing this too long, sometimes forget what I wrote or looked at
Here's a note where I wrote about hypoxia, hippocampal atrophy and the activation of a hyper HPA response...
link to post

The study I linked was looking at CO2 poisoning...
cheer

[eve]

This is all really interesting..and links going back to 2009 !! I'll have a read tomorrow (it's evening here already and I'm not very bright, at night... ) Very interesting points brought up!

I'm gonna try and find out a bit more about the '" vasomotor control related to cerebral blood flow adjustments." because that really made me go and pay attention.

[Thekla]

very interesting stuff---7 years ago, the nutritionist that I was consulting with had me taking choline. It was granular and I thought it smelled a bit like eggs so I mixed it with a spoonful of egg salad every day, It was one supplement that I felt made a difference at the time.

I think the bee stings mention is intriguing. I had thought the histamine response was the explanation there, but maybe not.

[Bethr]

Very interesting thread!
When I started reducing my iron levels in early 2010, I was taking Choline/Inositol caps, because inositol is an iron chelator.
I didn't stay on them more than 3 months though, and didn't notice any improvement, but I was so up and down it would be hard to notice. My improvements centred directly around the phlebotomy timings ultimately. I'm feeling really well, and getting on with life, my memory is back in pretty good form, no more switched round words, fumbling to find words, getting into a room and not knowing why I'm there, and I'm taking on more responsibilities and getting organised again.

BUT after reading this I think I'll go back to taking the rest of the bottle and see how I feel. I'm totally clean, take no supplements or drugs, so we'll see how I feel a few months down the track.

I do react to many things, which is why I stay clean, can't take any hormones, alcohol, some types of local anaesthetics. Zinc made me feel ill. But I'll give this a go again, and report back.

[Bethr]

Inositol: A Necessary Nutrient






Inositol is recognized as part of the B-Complex vitamins. It works closely with Choline as one of the primary components of the cell membrane. The human body contains more inositol than any other vitamin except Niacin (1). It is found in large quantities in the spinal cord nerves, the brain, and the cerebral spinal fluid. It is also needed for growth and survival of cells in bone marrow, eye membranes, and the intestines. It also encourages hair growth and can help prevent baldness.

Like Choline, Inositol helps to move fat out of the liver, and helps prevent serious liver disorders, as well as disorder involving high cholesterol. Serotonin and acetylcholine, two neurotransmitters, both depend upon Inositol, and it supplementation therefore can assist in the reduction of depression and panic attacks (2). Loss of Inositol from nerve cells is the primary reason for Diabetic neuropathy, so Inositol supplementation can assist in improving this condition. Phytic acid, the plant source of Inositol, has been shown to have anticancer properties, which may be one reason why a high-fiber diet protects against many cancers (3).

Inositol also has a prominent calming effect on the central nervous system, so it is sometimes helpful to those with insomnia. Studies on brain waves have shown that it has an effect similar to that of Librium or Valium. It can gradually lower blood pressure, and can be helpful in cases of schizophrenia, hypoglycemia, and those with high serum copper and low serum zinc levels.

Because it stimulates muscles of the alimentary canal, Inositol is helpful in cases of constipation. It can also induce labor contractions in pregnant women.

Most sources state that Inositol is not essential in the human diet. If it is a fundamental ingredient of cell membranes and is necessary for proper nerve, brain, and muscle function, how can it NOT be essential? Cell function is impaired when inositol is not present. Perhaps it is seen as not necessary in the diet because it can be synthesized by the intestinal flora. The action of the intestinal bacteria liberates inositol from phytic acid, which is found in citrus fruits, whole grains, nuts, seeds and legumes. The same kind of statement is made in reference to the amino acids. The ones which the body manufactures are considered "non-essential" amino acids. But I believe this is incorrect terminology. All the amino acids ARE essential to bodily functions, it's just that some are made by the body, so we don't have to concentrate on how much we eat. That doesn't mean they aren't essential to the body's functioning, and so the same is true of inositol.

However, just because the body can manufacture a certain nutrient doesn't mean that it necessarily provides all that is needed in every circumstance. In certain disease states, certain nutrients may be required in greater quantities than the body can produce, which is why it is also found in foods. My belief is, if it's found in food, then we need to consume it, otherwise why would it be there?

Daily dosages include:

As a general rule, if you have none of the specific problems listed in this article, it is generally thought that the dosage of Inositol should be the same as that of Choline daily.

For liver support - 100 to 500 milligrams daily
For depression or panic attacks - 12 grams
For diabetes, 1,000 to 2,000 milligrams (4)
For blood pressure - one gram in the morning and one gram at night (5).

Nutritional sources for Inositol:

Beef brains and heart, cabbage, citrus fruits, raisins, whole grains, lecithin, and unrefined molasses.

[Bethr]

Here's a statement against taking inositol:

Among these are inositol hexaphosphate, more commonly known as phytate. This substance binds to minerals such as iron, calcium, magnesium, and zinc in the gastrointestinal tract, significantly reducing their absorption by the body(10-12). The last thing most people need is to impair the assimilation of such nutrients, all of which are essential for healthy cardiovascular function, and many of which are already woefully inadequate in the average American diet(13-15)."

Suits me though Zinc makes me ill, so does iron. The less the better for me. But maybe not for everyone!

[eve]

Bethr, the mentioning of Niacin in your posting blew my mind - Niacin is one vitamin I really, really benefit from - but not in the brain fog department.

I found this on the wiki page on lecithin:

A proven benefit and suggested use for lecithin is for those taking niacin to treat high cholesterol. Niacin treatment can deplete choline, necessitating an increased amount of lecithin or choline in the diet.

http://en.wikipedia.org/wiki/Lecithin

I needed to stock up on supplements today anyway, so I'll go and get some lecithin. Great posting.

[eve]

I am really quite intugued by Cheer's posting about cortisol production.
I suffer from psoriasis as well as MS. Psoriasis als has a link with cortisol production.

Funny thing is both my neurologist and my dermatoligist call my MS/psoriasis a-typical.

Found this article while reading up and cortisol and psoriasis:

Cure of Psoriasis and Arthritis when Addison's Disease Was Detected
Marcus Lind*
Department of Medicine, NU Hospital Organization, Uddevalla, Sweden
*Dr. Marcus Lind, MD, PhD, Department of Medicine, NU Hospital Organization, SE–451 80 Uddevalla (Sweden), Tel. +46 522 15239, E-Mail lind.marcus@telia.com

Abstract
Introduction
Corticoid therapy is well-known to improve the symptoms of psoriasis. Addison's disease is an autoimmune disease which leads to a loss of cortisol production in the adrenal glands. This case report describes a patient with wide-spread psoriasis for 34 years who was cured when Addison's disease was detected and substitution to reach normal biological cortisol levels was introduced.


Case Report
A 59-year-old man was diagnosed with Addison's disease. He had been tired for several years and had had difficulties in continuing his work. His brother had Addison's disease and recommended him to make a screen for the disease. Synacthen test diagnosed Addison's disease with a clear deficiency of cortisol production. After substitution with hydrocortisone the patient's constitution improved rapidly and he felt no longer tired during work. At the same time, all skin lesions of psoriasis disappeared as well as aches in several joints, both symptoms having been present for a couple of decades. Previously, salves of cortisol had been used to reduce the symptoms of psoriasis, but now, 1–2 years later, after the treatment of Addison's disease, no symptoms in the skin or joints have reoccurred.

Conclusions
This report illustrates that Addison's disease, although a rare condition, should be kept in mind before treatment of psoriasis is started. Especially if other symptoms such as fatigue are present, a screening test of serum cortisol in the morning should be liberally made. The report also illustrates a need of examining corticoid levels in patients with psoriasis compared to the general population.
Key Words: Psoriasis, Addison's disease, Cortisol,

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988843/

Apperently there's cortisol tests and treatments that can be done. Wonder if i could get my neuro to check my levels...

[eve]

I started taking lecithin coz of this thread. Now I love to do sudoku's but could only master 2 and 3 stars (difficulty). I would have to scribble down possibilities on the side for the 3 stars otherwise I would lose track. And I would mess up terribly if I was tired.
Now I do 3 stars without scribbling and I can solve 5 star sodoku's. I havent noticed anything else though, I still feel cogfogged, but this does surprise me, as I am quite fatigued. I have done sudoku's for a number of yrs and never improved so I'm inclined to credit the lecithin...