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
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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