Blocking PUFA metabolism may treat Amyotrophic Lateral Sclerosis (ALS)

[haidut]

The disease ALS needs no introduction. It is perhaps the most dreaded disease in current/former athletes as it is currently considered incurable, invariably lethal, and is known to strike athletes in much higher rates than the general population. Medicine claims that about 10% of the ALS cases are familial/generic/inherited, though there is no solid evidence to support that claim (e.g. no ALS gene has been identified so far). Even so, the remaining 90% of ALS cases are acknowledged to be environmentally-driven, yet medicine claims that the cause is unknown. As usual, nothing can be further from the truth. Numerous animal studies have demonstrated that the disease is of mitochondrial origin, and that administration of pro-mitochondrial substances such as copper can reverse the pathology in those animal models. There is an ongoing human clinical trial with copper supplementation, but the results are not available yet. Other studies have all but proven that "oxidative" (actually, reductive is the proper word) stress is a known driving factor of the disease and that PUFA metabolites through the COX (e.g. prostaglandins) and/or LOX (e.g. leukotrienes) pathways are the main drivers of said "oxidative" stress. Conversely, blocking COX/LOX was shown to be very therapeutic in animal models with ALS and to extend the lifespan of the sick animals to the point of matching the lifespan of the healthy animals. In other words, animal studies have already demonstrated that blocking PUFA metabolism can effectively cure ALS or at least make it a non-deadly chronic condition similar to arthritis. Based on those animal studies, the article below reports that a Phase I human clinical trial with a LOX inhibitor was just successfully completed, and now Phase II is under way. Unfortunately, despite this good development that would undoubtedly benefit ALS patients, nobody is discussing the elephant in the room - i.e. the presence of PUFA in our tissues, which is entirely of dietary origin (e.g. we cannot synthesize PUFA ourselves). So, instead of chasing downstream toxic metabolites of PUFA (which always runs the rusk of not addressing 100% of the causal factors), one could attempt to treat (and prevent) ALS by dietary PUFA restriction. Coincidentally, the symptoms of vitamin E - a functional PUFA antagonist and a known COX/LOX inhibitor - deficiency include progressive muscle atrophy, paralysis and eventual death. In other words, systemic deficiency in the main dietary PUFA antagonist results in a lethal condition with symptoms identical to those of ALS. Other interventions that work along similar anti-PUFA pathways include saturated fats (duh!), aspirin - a known COX (and partial LOX) inhibitor - as well as progesterone, androgens, vitamins D/K, thyroid, magnesium, flavones/flavanones, glycine/gelatin, etc.

https://accp1.onlinelibrary.wiley.com/doi/10.1002/cpdd.1203

ALS Study Results Clear Way to Test Utreloxastat on Patients | ALS...

Utreloxastat, an investigational therapy for ALS, was safe and displayed promising pharmacological properties in study of healthy people.

alsnewstoday.com

"...The nerve cells that control muscle movement, called motor neurons, are lost in ALS, leading to symptoms of muscle weakness that affect motor function, speaking, swallowing, and eventually, breathing. A central mechanism behind motor neuron loss is oxidative stress — cell damage caused by an excess of highly reactive oxygen-containing molecules generated by normal cellular processes. Oxidative stress increases the production of an enzyme called 15-lipoxygenase (15-LO), triggering several processes known to contribute to motor neuron death. Utreloxastat is designed to block the action of 15-LO, reducing further oxidative stress, preventing motor neuron death, and slowing or preventing disease progression. So far, promising preclinical studies in multiple animal models have supported the therapy’s further evaluation in human clinical trials."

 

[GTW]

Desaturase and elongase enzymes don't generate PUFA? Surprising news.
And biochemistry holds that particular cell membrane PUFA are essential for life. More paradoxes!

 

[Sitaruîm]

Desaturase and elongase enzymes don't generate PUFA? Surprising news.
And biochemistry holds that particular cell membrane PUFA are essential for life. More paradoxes!

What about the enzymes delta 6 and delta 5 desaturase?

 

[mostlylurking]

The disease ALS needs no introduction. It is perhaps the most dreaded disease in current/former athletes as it is currently considered incurable, invariably lethal, and is known to strike athletes in much higher rates than the general population. Medicine claims that about 10% of the ALS cases are familial/generic/inherited, though there is no solid evidence to support that claim (e.g. no ALS gene has been identified so far). Even so, the remaining 90% of ALS cases are acknowledged to be environmentally-driven, yet medicine claims that the cause is unknown. As usual, nothing can be further from the truth. Numerous animal studies have demonstrated that the disease is of mitochondrial origin, and that administration of pro-mitochondrial substances such as copper can reverse the pathology in those animal models. There is an ongoing human clinical trial with copper supplementation, but the results are not available yet. Other studies have all but proven that "oxidative" (actually, reductive is the proper word) stress is a known driving factor of the disease and that PUFA metabolites through the COX (e.g. prostaglandins) and/or LOX (e.g. leukotrienes) pathways are the main drivers of said "oxidative" stress. Conversely, blocking COX/LOX was shown to be very therapeutic in animal models with ALS and to extend the lifespan of the sick animals to the point of matching the lifespan of the healthy animals. In other words, animal studies have already demonstrated that blocking PUFA metabolism can effectively cure ALS or at least make it a non-deadly chronic condition similar to arthritis. Based on those animal studies, the article below reports that a Phase I human clinical trial with a LOX inhibitor was just successfully completed, and now Phase II is under way. Unfortunately, despite this good development that would undoubtedly benefit ALS patients, nobody is discussing the elephant in the room - i.e. the presence of PUFA in our tissues, which is entirely of dietary origin (e.g. we cannot synthesize PUFA ourselves). So, instead of chasing downstream toxic metabolites of PUFA (which always runs the rusk of not addressing 100% of the causal factors), one could attempt to treat (and prevent) ALS by dietary PUFA restriction. Coincidentally, the symptoms of vitamin E - a functional PUFA antagonist and a known COX/LOX inhibitor - deficiency include progressive muscle atrophy, paralysis and eventual death. In other words, systemic deficiency in the main dietary PUFA antagonist results in a lethal condition with symptoms identical to those of ALS. Other interventions that work along similar anti-PUFA pathways include saturated fats (duh!), aspirin - a known COX (and partial LOX) inhibitor - as well as progesterone, androgens, vitamins D/K, thyroid, magnesium, flavones/flavanones, glycine/gelatin, etc.

https://accp1.onlinelibrary.wiley.com/doi/10.1002/cpdd.1203

ALS Study Results Clear Way to Test Utreloxastat on Patients | ALS...

Utreloxastat, an investigational therapy for ALS, was safe and displayed promising pharmacological properties in study of healthy people.

alsnewstoday.com

"...The nerve cells that control muscle movement, called motor neurons, are lost in ALS, leading to symptoms of muscle weakness that affect motor function, speaking, swallowing, and eventually, breathing. A central mechanism behind motor neuron loss is oxidative stress — cell damage caused by an excess of highly reactive oxygen-containing molecules generated by normal cellular processes. Oxidative stress increases the production of an enzyme called 15-lipoxygenase (15-LO), triggering several processes known to contribute to motor neuron death. Utreloxastat is designed to block the action of 15-LO, reducing further oxidative stress, preventing motor neuron death, and slowing or preventing disease progression. So far, promising preclinical studies in multiple animal models have supported the therapy’s further evaluation in human clinical trials."

Dyspnea, Air Hunger, and Molecular Oxygen Consumption- Hormones Matter

Dyspnea is applied to breathlessness at rest and when it is greater than expected with the degree of exertion.

www.hormonesmatter.com

"There is a serious lethal disease known as Amyotrophic lateral sclerosis (sometimes known as Lou Gehrig’s disease) that leads to chronic respiratory failure from failure of the diaphragm (the large muscle that separates the chest cavity from the abdominal contents and used in breathing). This is a major driver of dyspnea and mortality. In this disease, energy expenditure is known to be often abnormally high and this may be an important observation. If energy expenditure exceeds its production, the deficit must be a cause of the dysfunction.

Energy Synthesis Versus Expenditure​

I live in a retirement home and of course it is not uncommon to see people being pushed around in a wheelchair and being treated with nasal oxygen. The question that always occurs to me is whether the sole administration of oxygen is considered to be effective. The mechanism of oxidation requires oxygen of course, but proper fuel (glucose) and vitamin B complex are both necessities. If the patient is consuming a normal diet, the glucose will be available but there is generally nothing to indicate whether an adequate supply of B complex is part of that diet. Often sick people do not eat very well and I would insist on a supplement of B complex to such an individual if I were in charge.

Although ALS is relatively rare, if energy expenditure exceeds synthesis as the underlying cause, perhaps a method of accelerating its synthesis might be a logical approach and there is some precedent for approaching it this way. Without going into the technical details, redox (reduction/oxidation) is the technical word used to describe the essential reactions of oxidation in the synthesis of energy and I came across two manuscripts that suggest the need for research into thiamine metabolism in this disease.

Why Thiamine?​

In our book “Thiamine Deficiency Disease, Dysautonomia and High Calorie Malnutrition“, we describe the case of an eight-year-old child who had suffered from chronic asthma from the age of four years. She was so allergic to virtually any mattress that she had to sleep on a plastic lawn chair. The bronchial tubes are closed and opened under the influence of the autonomic nervous system (ANS), so asthma is really an example of dysautonomia (abnormal action of the ANS). This means that the bronchial tubes shut down abnormally, making breathing exquisitely difficult. The controls of the ANS in the brain are energy dependent and dysautonomia results from lack of energy in those control centers. The signaling mechanisms become distorted. Since thiamine sits astride the chemistry of energy production, this girl was given large doses of thiamine to which she responded dramatically. It is an example of drawing a logical deduction from understanding the actions of the brain when oxidative metabolism is compromised. I am not suggesting that large doses of thiamine would be beneficial to all cases of asthma, but I am suggesting that an imbalance of nervous control is responsible for a lot of poorly understood disease."
-end-

In other words, animal studies have already demonstrated that blocking PUFA metabolism can effectively cure ALS or at least make it a non-deadly chronic condition

I've read that PUFA blocks thiamine function. Perhaps supplementing high dose thiamine overrides this problem? Taking some niacinamide 3-4 times/day would be helpful too.

Desaturase and elongase enzymes don't generate PUFA?

I think that it's important to understand that "PUFA" is usually considered to be the Omega 6's and the Omega 3's. The body does make unsaturated Omega 9, aka the Mead acid which is anti-inflammatory. Anti-Inflammatory Omega -9 Mead Acid (Eicosatrienoic acid) – Functional Performance Systems (FPS)

 

[joaquin]

@mostlylurking
What thiamine do you prefer? I've been opening up a capsule of benfotiamine and taking about 1/4 each morning with a high fat meal for absorption?

 

[mostlylurking]

@mostlylurking
What thiamine do you prefer? I've been opening up a capsule of benfotiamine and taking about 1/4 each morning with a high fat meal for absorption?

I take a gram of thiamine hcl 2Xday. I use the pure bulk powder from bulksupplements.com. I was unable to tolerate TTFD thiamine because of a glutathione deficiency. I have not tried benfotiamine. I have also tried a sublingual B-1, thiamine mononitrate but after a week I went back to the high dose thiamine hcl. I'm following Dr. Costantini's protocol. I've experienced very good results from this protocol.

 

[joaquin]

@mostlylurking I tried sulbutiamine once but gave me insomnia and mild headache. I'm certain I have thiamine defiency because of drinking so much coffee over the years.

 

[mostlylurking]

@mostlylurking I tried sulbutiamine once but gave me insomnia and mild headache. I'm certain I have thiamine defiency because of drinking so much coffee over the years.

Dr. Costantini warned that taking thiamine after 3:00pm can give you insomnia. He said taking the last dose before 3:00pm improves sleep quality. Thiamine lowers blood sugar and lowered blood sugar will increase adrenaline and cause insomnia.

I take one dose before lunch and the second dose around 3:30pm. My sleep is good.

 

[Motorneuron]

The disease ALS needs no introduction. It is perhaps the most dreaded disease in current/former athletes as it is currently considered incurable, invariably lethal, and is known to strike athletes in much higher rates than the general population. Medicine claims that about 10% of the ALS cases are familial/generic/inherited, though there is no solid evidence to support that claim (e.g. no ALS gene has been identified so far). Even so, the remaining 90% of ALS cases are acknowledged to be environmentally-driven, yet medicine claims that the cause is unknown. As usual, nothing can be further from the truth. Numerous animal studies have demonstrated that the disease is of mitochondrial origin, and that administration of pro-mitochondrial substances such as copper can reverse the pathology in those animal models. There is an ongoing human clinical trial with copper supplementation, but the results are not available yet. Other studies have all but proven that "oxidative" (actually, reductive is the proper word) stress is a known driving factor of the disease and that PUFA metabolites through the COX (e.g. prostaglandins) and/or LOX (e.g. leukotrienes) pathways are the main drivers of said "oxidative" stress. Conversely, blocking COX/LOX was shown to be very therapeutic in animal models with ALS and to extend the lifespan of the sick animals to the point of matching the lifespan of the healthy animals. In other words, animal studies have already demonstrated that blocking PUFA metabolism can effectively cure ALS or at least make it a non-deadly chronic condition similar to arthritis. Based on those animal studies, the article below reports that a Phase I human clinical trial with a LOX inhibitor was just successfully completed, and now Phase II is under way. Unfortunately, despite this good development that would undoubtedly benefit ALS patients, nobody is discussing the elephant in the room - i.e. the presence of PUFA in our tissues, which is entirely of dietary origin (e.g. we cannot synthesize PUFA ourselves). So, instead of chasing downstream toxic metabolites of PUFA (which always runs the rusk of not addressing 100% of the causal factors), one could attempt to treat (and prevent) ALS by dietary PUFA restriction. Coincidentally, the symptoms of vitamin E - a functional PUFA antagonist and a known COX/LOX inhibitor - deficiency include progressive muscle atrophy, paralysis and eventual death. In other words, systemic deficiency in the main dietary PUFA antagonist results in a lethal condition with symptoms identical to those of ALS. Other interventions that work along similar anti-PUFA pathways include saturated fats (duh!), aspirin - a known COX (and partial LOX) inhibitor - as well as progesterone, androgens, vitamins D/K, thyroid, magnesium, flavones/flavanones, glycine/gelatin, etc.

https://accp1.onlinelibrary.wiley.com/doi/10.1002/cpdd.1203

ALS Study Results Clear Way to Test Utreloxastat on Patients | ALS...

Utreloxastat, an investigational therapy for ALS, was safe and displayed promising pharmacological properties in study of healthy people.

alsnewstoday.com

"...The nerve cells that control muscle movement, called motor neurons, are lost in ALS, leading to symptoms of muscle weakness that affect motor function, speaking, swallowing, and eventually, breathing. A central mechanism behind motor neuron loss is oxidative stress — cell damage caused by an excess of highly reactive oxygen-containing molecules generated by normal cellular processes. Oxidative stress increases the production of an enzyme called 15-lipoxygenase (15-LO), triggering several processes known to contribute to motor neuron death. Utreloxastat is designed to block the action of 15-LO, reducing further oxidative stress, preventing motor neuron death, and slowing or preventing disease progression. So far, promising preclinical studies in multiple animal models have supported the therapy’s further evaluation in human clinical trials."

can mitolipin speed up the process?