ALS - A Different Approach

MarkNH

New member
A Better Theory of ALS. Part One.
In the previous Blog on ALS, I stated, not suggested, that a chronically low NF-kappaB level in muscle might be THE factor that predisposed muscle to deteriorate and cause motor neuron loss. In the last four days, I have accumulated at least 100 scientific articles that suggest otherwise. There is an old saying in science: ?Don?t fall in love with your own theories because they are probably wrong.? My former theory about chronically low NF-kappaB levels and ALS is almost certainly wrong.

Low NF-kappaB levels, brought on by muscle fatigue or environmental toxins, might indeed cause muscle injury, but muscle injury and ALS are not the same thing. The scientific papers that I have recently located argue, directly and indirectly, that chronically elevated NF-kappaB levels are the problem in muscle deterioration and motor neuron loss.

I found one article that opened up my mind and provided me with a direction for future article searches. In this scientific paper, scientists investigated the difference between motor neurons that atrophied and those that didn?t in human ALS cases. What they found electrified me, to say the least. Apparently, the presence of calcium binding proteins in the viable motor neurons protected them from death. Calcium binding proteins bind and sequester free calcium ions, thereby protecting them from causing too much damage in cells, especially vulnerable motor neurons. Calcium binding proteins like calbindin D-28k and parvalbumin are similar to proteins like ferritin, which bind a sequester iron, and metallothionen, which binds and sequesters zinc and copper. In the absence of these binding proteins, free metal ions can become immediately toxic to cells.

Calcium binding proteins are under the genetic control of activated vitamin D3, a hormone called calcitriol. This is a prescription drug. Basic vitamin D3 is made in the skin upon exposure to certain wavelengths of ultraviolet light. Vitamin D3 can be purchased as a supplement in most health food stores. Vitamin D3 can be converted to active vitamin D3, calcitriol, in different tissues of the body. It is still dogma in some textbooks that vitamin D3, made in the skin, is first activated to 25-vitamin D3 in the liver and further converted to calcitriol, 1,25-vitamin D3, in the kidneys. This is completely wrong. Many, many tissues possess the enzymes that allow basic vitamin D3 to be converted to the active form, and this is a critical point.

They say discovery favors the prepared mind. Well, I know a ton about vitamin D3 because its absence is a factor in the development of cancer. Most people have no vitamin D3 in their diet (it is only present in fatty fish) and they do not get exposed to enough ultraviolet light to make their own. In the US, milk is supplemented with vitamin D3 but not enough to do much good if this was a person?s only source of the hormone. Vitamin D3 is present in milk, because milk contains calcium that will NOT be absorbed in the intestines if calcium binding proteins are not present. Vitamin D3, the activated form, stimulates the synthesis of calcium binding proteins in the body. This is its primary job.

In ALS, the presence or absence of calcium binding proteins directly, and I do mean directly, influences the ability of motor neurons to withstand activation by the neurotransmitter glutamate. The presence of these proteins also spares normal motor neurons from death induced by antibodies found in ALS patients that bind and activate L-channel calcium transporters. Interestingly, activated vitamin D3 directly regulates the synthesis of calcium binding proteins in motor neurons.

Let?s review some past history for clarity. In genetically engineered mice, SOD-1 mutations, commonly found in cases of familiar ALS, were introduced only into motor neurons or astrocytes, cells that protect motor neurons from death. If the mutation is expressed only in these cells, the mice do not develop ALS. These studies concluded that the other cells in the body, those that did not possess the SOD-1 mutation, protected the motor neurons from death, perhaps by a secreted factor. That factor may be activated vitamin D3, calcitriol.

Interestingly, when a mouse genetically engineered to over-express parvalbumin, a calcium binding protein normally under the control of activated vitamin D3, was mated to a mouse harboring the ALS SOD-1 mutation, the babies of this union had a substantially reduced incidence of motor neuron death and delayed disease onset.

The enzyme that converts 25-vitamin D3 to the fully active form, 1,25 vitamin D3, is called 25-hydroxyvitamin D3 1alpha-hydroxylase. This enzyme is found in many cells of the body, including neurons and microglial cells (astrocytes are a form of glial cell). It is highly likely that astrocyles and glial cells in general make activated vitamin D3 which is released to provide protection for motor and other neurons.

As I previously stated, glial cells protect neurons from toxic products and other agents that can damage their ability to function. In addition to stimulating the synthesis of calcium binding proteins, activated vitamin D3 also does the following in the nervous system.

It activates glial cells to synthesis nerve growth factor.

It inhibits the expression of inducible nitric oxide synthase in the CNS. Nitric oxide and its byproducts such as peroxynitrite are closely associated with the development of inflammatory diseases in the nervous system.

It blocks the ability of glucocorticoids to inhibit nerve growth factor synthesis.

It increased the level of glutathione (GSH) in astrocytes resulting in a substantial reduction of nitrite production, thereby acting as a detoxification factor.

It activates glial cell line-derived neurotrophic factor synthesis.


Vitamin D3 also stimulates maturation of the skin cells resulting in enhanced barrier function. I mention this because skin problems are often associated with advanced cases of ALS.

Activated vitamin D3 is clearly a neuroprotective factor in the nervous system as a whole.

OK, what is the fundamental problem with ALS? To start, most people do NOT have a sufficient amount of inactive vitamin D3 in their bodies. Even people who live near the equator and are therefore exposed to an optimal level of UV light wear shirts most of the day. If we don?t wear long sleeve shirts, we work indoors where UV light is not present or we use massive amounts of sun screen because we are afraid of skin cancer or dry skin. Vitamin D3 is only found in fatty fish in the diet. Therefore, you can safely assume that most people in the world, especially those who live far from the equator, are grossly deficient in this most important, yet easily ignored vitamin.

But this is only half the story. The presence of inactive vitamin D3 does nothing if it cannot be converted to active vitamin D3. This requires an enzymatic conversation that can be done in microglial cells, and in many other cells of the body, including skin. Remember the genetic factor NF-kappaB that I discussed before? NF-kappaB inhibits the synthesis of the enzyme that converts inactive to active vitamin D3. Therefore, cells that suffer from chronic NF-kappaB activation cannot convert inactive to active vitamin D3. Interestingly, NF-kappaB also interferes with the ability of the vitamin D3 receptor to active the genes under its control. Chronically elevated levels of the genetic factor NF-kappaB completely neutralize both the synthesis and binding of vitamin D3 in the body.

Vitamin D3 is necessary for proper skeletal muscle development. In its absence, muscle myoblasts do not differentiate properly into normal muscle fibers. It is interesting to speculate that even minor muscle injuries will not heal properly in the absence of activated vitamin D3. Activated vitamin D3 also apparently maintains the function of type II muscle fibers, thereby preserving muscle strength and preventing falls, especially in the elderly. In one Japanese study, the scientists found a direct correlation between low circulating concentrations of 25-vitamin D3, the direct precursor of activated vitamin D3, and the small diameters of type II muscle fibers. They concluded that a combination of low muscle activity and vitamin D3 deficiency were contributing factors to hip fractures due to falls. Apparently, vitamin D3, which does not increase overall muscle strength, does improve neuromuscular function as evidenced by improved reaction time and balance.

In a recently published study, ALS patients were tested against normal controls for motor fatigue. The authors concluded that a reduction in muscle fiber conduction velocity was a contributing factor to the pathology of muscle fatigue in ALS, and that decreased type II fast motor unit muscle fiber activity was a contributing factor to motor fatigue.

There has never been a human study that used activated vitamin D3 in an attempt to alleviate the muscle fatigue in ALS. And even if there were, the results would be inconclusive. Certainly ALS folks need to supplement their diets with vitamin D3, but they need to do much more, as will be discussed in the next Blog.

Reducing the activation of NF-kappaB is a key factor in reversing the muscle fatigue and tissue damage associated with ALS. NF-kappaB does inactivate vitamin D3 in the body, but it also DIRECTLY stimulates muscle fiber breakdown by a variety of methods that have nothing to do with vitamin D3 homeostasis.

These problems can be addressed using natural medicines.

From Kurosawa Natural Medicine Blog
 
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barbara

Pioneer Founding member
Natural meds

This is interesting in that natural medicines are encouraged. The stem cell clinic where I went is big on supplements and vitamins. Some clinics are, some are not. I do feel there is a growing trend in this country at least to acknowledge that many supplements and vitamins can play a role in keeping us well and even keeping us younger. Do you take D3 and if so, how does one know how much to take?
 

MarkNH

New member
Part 2a

ALS and Vitamin D3
In certain areas of Japan, Guam and other far east countries, the inordinately high incidence of ALS in certain isolated populations was attributed to imbalances in the intakes of calcium, magesium and aluminum. Aluminum was considered the main toxic agent and for awhile set off a panic that the use of aluminum cooking utensils could lead to ALS and Alzheimer's Disease. I think aluminum toxicity is a minor player in these neurological diseases.

In time, researchers found out that it wasn't the absolute amount of calcium or magnesium ingested that was important. It was the ratio between calcium and magnesium. Calcium and magnesium have much in common. The uptake of both ions from the intestines is controlled largely by vitamin D3. Many enzyme systems require both calcium and magnesium for activity. Other enzyme systems are calcium activated and magnesium inhibited and vice versa. Under situations of low magnesium update, calcium ions have greater access into cells, such as motor neurons. If calcium ions are not properly regulated by magnesium antagonists and calcium binding proteins, they can create tremendous problems in almost all tissues. Such is the case in ALS.

The following article refers to calcium ions as the Darth Vader of ALS. Its a good review of the problem.

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11465925

Some of the most interesting studies on ALS have concentrated on the biochemical differences between atrophied and normal motor neurons at autopsy. Interestingly, motor neurons that did not atrophy during the course of the disease contained normal amounts of the calcium binding proteins parvalbumin and calbindin-D28K. The atrophied motor neurons contained low levels of these proteins. This is a critical observation because glutamate, the motor neuron neurotransmitter, stimulates calcium uptake. There have been many theories over the years that excessive glutamate activity, and therefore increased calcium uptake, is responsible for motor neuron death. However, the studies on calcium binding proteins suggest that even normal stimulation of motor neurons by glutamate could induce calcium toxicity if these calcium binding proteins were not present to sequester and therefore buffer the influx of calcium ions.

The following articles discuss the low content of calcium binding proteins in atrophied motor neurons.

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7998770

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9021258

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7766841

The study above concludes that only parvalbumin is decreased, while other calcium binding proteins are normal in atrophied motor neurons. Other studies have found all calcium binding proteins to be decreased in these cells.

The study that follows is a fun one. There is no question that many people with ALS harbor antibodies that bind and activate the calcium channels in motor neurons. Whether these antibodies are responsible for the sporadic form of the disease or merely a consequence of prior damage remains to be seen. Regardless, these antibodies make the clinical picture worse since they can activate calcium uptake into normal motor neurons.

In this study, the scientists took the gene for calbindin-D28K and put it into a retrovirus. They then infected a specific motor neuron cell line that is very sensitive to death by ALS antibodies. When this retrovirus integrated the calbindin gene into the DNA of these cells, they became very resistant to cell death by ALS antibodies. If they inhibited the expression of the introduced calbindin gene, the sensitivity to ALS antibody toxicity returned. Cool study.

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8692898

The following study is also very informative. The scientists developed a special strain of mouse that overexpressed the calcium binding protein parvalbumin in their motor neurons. When these mice were subjected to injury induced cell death in their motor neurons, twice as many motor neurons in the genetic strain of mouse survived the injury over normal mice.

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14698753

This study shows that motor neurons respond to activated vitamin D3 by expressing parvalbumin and calbindin-D28K. This is a critical observation since it proves that motor neurons do in fact have receptors for activated vitamin D3.

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9452309

Now we are going to talk about astrocytes, the cells that protect motor neurons and other neurons against toxic byproducts derived from oxygen and nitrogen radicals.

In this study, an enzyme necessary for the production of GSH or glutathione in astrocytes was specifically induced by activated vitamin D3. GSH is specifically involved in the elimination of oxygen radicals and nitric oxide. This study is VERY important because excessive nitrite and superoxide production can result in the formation of peroxynitrite, an incredibly nasty molecule that can kill astrocytes and motor neurons alike. Remember the Blog on inosine? Well a breakdown product of inosine, uric acid, is a natural inhibitor of peoxynitrite. Activated vitamin D3 is an even more important inhibitor of peroxynitrite because by increasing the concentration of GSH in astrocytes it inhibits the production of peroxynitrite in the first place.

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10428085

Neurotropin-3 or NT-3 is a neural growth factor that is made in astrocytes and glial cells. Once made, the hormone is secreted from the astrocytes and activates neurons, including motor neurons, protecting them from cell death. Activated vitamin D3 stimulates the synthesis of NT-3 in astrocytes.

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8635562

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7703399

In ALS, the amount of NT-3 in motor neurons was found to be decreased at autopsy.

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9125388
 

MarkNH

New member
Part 2b

This next paper is a little complicated but it's extremely important. When motor neurons bind muscle cells, they release acetylcholine into the muscle thereby stimulating muscle contraction. When a person is injected with the cosmetic drug Botox, the toxin in Botox prevents motor neurons from releasing acetylcholine, thereby effectively paralyzing the muscle for a protracted period of time. In this study, NT-3 was found to increase the amount of acetylcholine released into the muscle. This suggests that a reduction in NT-3 synthesis, secreted from muscle, decreases the efficiency of motor neuron activation of the muscle. This means that muscle can actually enhance motor neuron efficacy by inducing the motor neurons to release more neurotransmitters. If the amount of secreted acetylcholine is too low to meet the metabolic demand, muscle weakness will occure, especially after excercise.

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9065506

Voluntary excercise increases the level of NT-3 in the spinal column. This effect may have nothing to do with the vitamin D3 status of the tissues. It does suggest, however, that a lack of excercise can make any form of muscle weakness much worse by a reduced synthesis of NT-3.

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14499950

This paper shows that NT-3 enhances nerve regeneration and improves recovery of muscle fibers after injury. The take home message is that NT-3, made in both astrocytes and muscle, enhance motor neuron activity. There is no published evidence that activated vitamin D3 increases the synthesis of NT-3 in muscle. Apparently, no one has looked.

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9348287

We aren't going to discuss the affect of vitamin D3 on skeletal muscle, because the subject is too extensive. Take it for granted that activated vitamin D3 does indeed bind skeletal muscle and regulate numerous genes. In the absence of vitamin D3 binding, muscles become week. More on this topic another time.

One more topic. Some ALS folks suffer from elevated calcium levels in their blood. This is a significant observation. In the absence of sufficient activated vitamin D3, calcium cannot be absorbed properly from the intestines. The low calcium in the blood triggers the release of parathyroid hormone from the base of the brain. PTH stimulates bone cell breakdown and the release of bone calcium to make up for the dietary deficiency. PTH is NOT a harmless hormone. Besides breaking down bone and other horrors, it stimulates the uptake of calcium into motor and other neurons. Chronic PTH secretion is more common than appreciated, according to a study I referenced in another Blog. It may not be clinically high enough to be detected, but its high enough to cause problems over a prolonged period. A proper dietary consumption of BOTH vitamin D3 supplements and calcium, preferably from diary AND supplements, should inhibit PTH secretion. Chronic PTH secretion due to poor activated vitamin D3 availability could be a MAJOR factor in the cause of ALS. Apparently, there is nothing in the scientific literature on this topic. There should be.

http://www.ncbi.nlm.nih.gov/entrez/queryd.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2236103

In summary, there is no question that vitamin D3, calcium and magnesium play a role in the development of ALS. There are no doubt other factors involved, but these problems can be addressed easily and immediately.

Please follow the protocol in the MS and vitamin D3 Blog a few days ago. Make certain to take magnesium sulfate in the form of Epsom salts each day. Use 1/2 teaspoon in juice, preferably tomato since it kills the taste of the magnesium.
 
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