Inhibiting Hypoxia Biomarker (HIF-1) Reverses Parkinson Disease

[haidut]

Ray has written a lot about HIF-1 and its role in cancer and heart disease. It looks like this biomarker of hypoxia is implicated in the energetic deficits underlying Parkinson disease. Blocking HIF-1 reversed the Parkinson pathology.
Caffeine, methylene blue, aspirin and CO2 all inhibit the activation of HIF-1.

http://www.pnas.org/content/early/2015/ ... 2.abstract

"...Remarkably, knockdown of HIFα restores neuronal function without affecting the primary mitochondrial defect. Mitochondrial retrograde signaling is therefore partly responsible for neuronal pathology. Knockdown of HIFα also restores function in Drosophila models of Leigh syndrome and Parkinson’s disease. Our results demonstrate that mitochondrial retrograde signaling has a key role in neuronal homeostasis and that manipulation of retrograde signaling may have therapeutic potential in mitochondrial diseases and Parkinson’s. "

http://www.thelatestnews.com/fruit-flie ... s-disease/
"...A new study carried out at the King’s College London identified a new gene in fruit flies called HIFalpha (hypoxia inducible factor alpha), which could prove an effective target treatment for deactivating the gene in humans that cope with neurodegenerative diseases such as Parkinson’s and Leigh syndrome as the HIFalpha gene is also found in humans. These new findings could lead to new preventative treatments for such diseases in the future. Parkinson’s disease is a condition that is affecting 7-10 million people worldwide and each year 60,000 new Americans are diagnosed with Parkinson’s. The current “toll” that Parkinson’s does is estimated at $25 billion per year in the US alone."

 

[Sheila]

Dear Haidut, thank you for posting this.
Could hyperventilation that prevents proper O2 utilisation stimulate HIF-1?
If so, could correcting breathing, (eg. optimisation of CO2) as well as the molecules you suggested, improve HIF-1 induced damage?
The high rates of supplementation that have been found helpful in disease states like Parkinsons suggest some form of blocking that can be overcome in some with high doses (900mg B1 for example, 100mg allithiamine, very high dose CoQ10 etc) but not in others. Would you care to speculate on the blocking mechanisms here and what might be core to say B1 utilisation? Could it be 'just' hypoxia that damns and dams everything else downstream?
I am sorry if these are stupid questions but when high dose supplementation of several 'known assisters' doesn't work, it suggests a more basic problem, a lower level that is not being addressed.
I am most grateful for any time you can spend to enlighten me.
Sheila

 

[haidut]

Dear Haidut, thank you for posting this.
Could hyperventilation that prevents proper O2 utilisation stimulate HIF-1?
If so, could correcting breathing, (eg. optimisation of CO2) as well as the molecules you suggested, improve HIF-1 induced damage?
The high rates of supplementation that have been found helpful in disease states like Parkinsons suggest some form of blocking that can be overcome in some with high doses (900mg B1 for example, 100mg allithiamine, very high dose CoQ10 etc) but not in others. Would you care to speculate on the blocking mechanisms here and what might be core to say B1 utilisation? Could it be 'just' hypoxia that damns and dams everything else downstream?
I am sorry if these are stupid questions but when high dose supplementation of several 'known assisters' doesn't work, it suggests a more basic problem, a lower level that is not being addressed.
I am most grateful for any time you can spend to enlighten me.
Sheila

Yes, lactate (from increased hyperventilation) is one of the primary triggers of HIF. Insulin resistance and thus wasting of glucose into lactate can be a primary cause. High levels of NO can block respiration and also lead to increase in HIF. Being in a reduced metabolic state vs. oxidized due to any health reasons manifests in lower NAD/NADH ratio and also increases HIF.
If regular vitamin B1 (the Hcl salt) is used then in some people it is not absorbed properly, and even it is absorbed it does not improve vitamin B1 status by converting into thiamine pyrophosphate (TPP) which is what is needed for the enzyme PDH to work and lower pyruvate/lactate. This study compared oral allithiamine with IV regular thiamine and found that only the oral allithiamine and IV thiamine improved the red blood cell thiamine status. Oral regular thiamine had absolutely no effect.
http://www.ncbi.nlm.nih.gov/pubmed/978282

Incidentally, the human study with thiamine for Parkinson also used IM route:
https://raypeatforum.com/community/threads/thiamine-b1-reverses-parkinson-disease-in-humans.8305/

In the past, human studies with oral thiamine Hcl for conditions such as Alzheimer and alcoholic dementia have used up to 8,000mg daily. I think it comes down to absorption and conversion into TPP. For someone who is in poor health taking oral thiamine will probably not be optimal due to absorption and poor conversion into TPP (ATP is needed for that). So, for those people I think taking oral allithiamine and some thyroid may be the only feasible option short of IV/IM in a clinical setting.

 

[Sheila]

Dear Haidut
You are most kind to take this time to reply to me, thank you.
In studying this disease state and its effect on people, I have come to the tentative conclusion that PD is an umbrella 'label' and that the causes - what and where function is broken - can be slightly or very different. Thus some will respond to allithiamine, or IV/IM thiamine but some won't. In this case, I suspect 'metabolism' is broken at a deeper level than B1 (in any form) can compensate for, so will research further into hypoxia which feels like a deeper level approach. A TSH of 0.5 put me off considering Thyroid but I see now that this thinking may have been incorrect, conversion at the liver level has to be cactus. Nothing about this person is hyper! I may have put the cart before the horse.
Glucose + 02 + T3 = ATP + water + CO2 is the aim, and if CO2 is lacking, O2 is present but unavailable, lactate will be the response just as in cancer.
If T3 is MIA also, and lactate is produced, I suspect no amount of TPP activated PDH will help because if you like it's tinkering at the edges in non-responsive cases. There appear to be degrees of brokenness here, maybe it the same for all diseases where the results of supplementation are inconsistent. The subjects are not all the same, but have all the same label.
Again, thank you for your time. If I have written anything really dumb, do let me know!
Sheila

 

[haidut]

Dear Haidut
You are most kind to take this time to reply to me, thank you.
In studying this disease state and its effect on people, I have come to the tentative conclusion that PD is an umbrella 'label' and that the causes - what and where function is broken - can be slightly or very different. Thus some will respond to allithiamine, or IV/IM thiamine but some won't. In this case, I suspect 'metabolism' is broken at a deeper level than B1 (in any form) can compensate for, so will research further into hypoxia which feels like a deeper level approach. A TSH of 0.5 put me off considering Thyroid but I see now that this thinking may have been incorrect, conversion at the liver level has to be cactus. Nothing about this person is hyper! I may have put the cart before the horse.
Glucose + 02 + T3 = ATP + water + CO2 is the aim, and if CO2 is lacking, O2 is present but unavailable, lactate will be the response just as in cancer.
If T3 is MIA also, and lactate is produced, I suspect no amount of TPP activated PDH will help because if you like it's tinkering at the edges in non-responsive cases. There appear to be degrees of brokenness here, maybe it the same for all diseases where the results of supplementation are inconsistent. The subjects are not all the same, but have all the same label.
Again, thank you for your time. If I have written anything really dumb, do let me know!
Sheila

I think if lactate is overproduced, allithiamine activating PDH and riboflavin lowering LDH will help reduce that production. But lactate is not the only possible issue as you say, and it could be more of a result. So, hypoxia will generate lactate no matter how much vitamin B1/B2 is given BUT the B1/B2 should help lower it if not completely reverse it. Emodin and the naphthoquinone like vitamin K and lapachone are well known to inhibit HIF, so that may be something to try. There is a study with vitamin K reversing Parkinson symptoms in an animal model. See below.
http://www.ncbi.nlm.nih.gov/pubmed/22582012

 

[Sheila]

Dear Haidut.
I will add emodin, Pau d'arco and Vit K to your Caffeine, methylene blue, aspirin and CO2 HIF-1 inhibitors into the frame once I have acquainted myself with how they might act in this context, thank you again for your thoughtful replies in this regard.

At the moment, targeting lactate is not working but it might in less developed (broken) cases, as the trial results suggest. Some form of direct electron transfer is I think required, a spark plug if you like that will set the energy chain running again. Excuse the clumsy metaphors, it's hard for me to turn all those complex diagrams (Kreb's cycle etc) into reality (and to really be sure they are reality, we don't know SO much!) and determine what is the foundation level to target. (If there is such a thing)

In this case, use of L-dopa does little, and it might be that the reduction of endogenous l-dopa - here, at least - is an adaptation to very low energy production, even an (albeit distressing) protective mechanism. I don't think any 'body' is dumb, so often I have mistaken 'broken' for the 'latest adaptation'. It may explain then, why adding dopaminergics/B1/l-dopa does not appear to do anything and perhaps why in others, if the circuits are switched off protectively, more of these things may result in toxicity (too much B6, too much l-dopa (notoriously difficult to dose). Raising dopamine at the wrong time may be like flogging a near dead horse once more round the paddock. Not going to end well.

I'm sorry, this is, of course, all speculation, but if there is an order to dysfunction and adaptation is the compensation, I do not want to crow bar open a response only to find it snaps shut with further decline. Hence I wonder is there a deeper level to pursue, possibly via CO2, could that be a baser level entry point per my simple equation above. Maybe emodin et al above can also provide that 'spark' too whilst improved CO2 reduces the circulatory hypoxic shut down. More speculation I regret to say.
Best regards to you,
Sheila

 

[tca300]

Thanks for the post Haidut!

 

[yerrag]

@haidut lately I've been using Tyromix/StressNon/Progestene in seeing if it could increase my heart rate. I would be on 4 drops each 3x/day. I find that I see heart rate increase in the morning and lunch treatments, but towards mid-afternoon heart rate would just come down where my heart rate would just go back to baseline. If my high blood pressure is caused by plaque accumulation in the capillaries, I suspect that the limited tissue oxygenation from restricted capillaries is leading to hypoxic conditions. With the limited oxygen available, the mitochondria automatically downregulates metabolism, and this results in my heart rate being limited, despite the boost provided by the steroid hormones. In the particular case of my kidneys, this may lead to anaerobic glycolysis with lactate being produced. It may explain why my serum uric acid is high, and why my serum LDH is on slightly above range. I tested way low on my urine uric acid excretion test, and this could account for my high serum uric acid. Studies have shown that lactic acid inhibits uric acid excretion. Hypoxia lends to lactic acid production, leading to high serum uric acid.

While I work on lysing away the plaque in my capillaries (using proteolytic enzymes, among other methods), I'm considering using all the substanes you mentioned that would inhibit HIF-1 expression - caffeine, methylene blue, aspirin, and CO2.. I just ordered Oxidal today, and with CO2 I would have to force myself to use the elaborate CO2 bath contraption of Carbogenetics (which requires some supervision by a second party to avoid mishap, and is the reason why I've delayed so long in using it).

My aim really is to improve the delivery of the enzymes to the capillaries to more effectively effect lysing of plaque, and by increasing metabolism (as evidenced by increased heart rate and attendant increased blood pressure), I could do that. While plaque limits available oxygen supply, I would like to see the available oxygen used optimally as well as have a substance that can act as an electron donor in place of oxygen and I think you mentioned that methylene blue can fill that role.

I suppose that being able to inhibit HIF-1 expression only means that the effects of hypoxia are minimized, and that can be seen in lower lactic and LDH being produced, and this could be confirmed by lower serum uric acid levels made possible by higher kidney excretion of uric acid in urine. This can also be seen by an upregulation in mitochondrial metabolism, and the increased heart rate would also be seen.

I can see methylene blue to be the most helpful in this regard. Would caffeine, aspirin, and CO2 be as helpful?

 

[Hans]

@yerrag
To lower HIF you might want to look into the TCA cycle.

Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. - PubMed - NCBI
"succinate, which accumulates as a result of SDH (succinate dehydrogenase) inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha."

Another problem enzyme is fumarate hydratase (FH).
If those two enzymes are not working you get a buildup of fumarate and succinate that stabilize HIF-1a.
SDH uses vitamin B2 as a cofactor and FH uses iron as a cofactor. ROS can thus inhibit FH, so lowering elevated ROS (through uncoupling for example), if that is an issue, can be helpful.

Palmitate and oleate also appear to be beneficial at lowering HIF - Fatty Acids Prevent Hypoxia-Inducible Factor-1α Signaling Through Decreased Succinate in Diabetes

Here's a lengthy but good article that talks about B-vitamins, the mitochondria and HIF - Mito-Nuclear Communication by Mitochondrial Metabolites and Its Regulation by B-Vitamins

 

[yerrag]

@yerrag
To lower HIF you might want to look into the TCA cycle.

Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. - PubMed - NCBI
"succinate, which accumulates as a result of SDH (succinate dehydrogenase) inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha."

Another problem enzyme is fumarate hydratase (FH).
If those two enzymes are not working you get a buildup of fumarate and succinate that stabilize HIF-1a.
SDH uses vitamin B2 as a cofactor and FH uses iron as a cofactor. ROS can thus inhibit FH, so lowering elevated ROS (through uncoupling for example), if that is an issue, can be helpful.

Palmitate and oleate also appear to be beneficial at lowering HIF - Fatty Acids Prevent Hypoxia-Inducible Factor-1α Signaling Through Decreased Succinate in Diabetes

Here's a lengthy but good article that talks about B-vitamins, the mitochondria and HIF - Mito-Nuclear Communication by Mitochondrial Metabolites and Its Regulation by B-Vitamins

Glad to get your response Hans. It may be that tweaking HIF-1 wouldn't do much as I'm dealing fundamentally with hypoxia due simply to low oxygenation from plaque blocking capillary intake of oxygen.

But you may have some thoughts on whether going keto would be helpful. If I should rely on fats instead of glucose for energy, would it be reasonable to think that I won't be consuming as much oxygen for energy? I wouldn't have to resort to anaerobic glycolysis thus not producing lactic acid. The lactic acid produced inhibits kidney uric acid excretion and leads to high serum uric acid. Most of all, I'm not facing oxygen as a limiting factor in increasing metabolism. When I use progesterone currently, I feel it's not increasing my heart rate and it's probably just getting glucoronidated by the liver.

 

[yerrag]

@Hans Here's why I was thinking of increasing fat intake and decreasing carb intake, or go on a fast. If I could use less oxygen to produce energy, which means more beta-oxidation and less oxidative metabolism (or anaerobic glycolysis), I would not be pushing my already low oxygen supply at plaque-filled capillaries to exhaustion, and producing lactic acid, increasing uric acid and then deactivating nitric oxide as an end result, losing the vasodilatory effect of nitric oxide.

Inactivation of Nitric Oxide by Uric Acid

 

[Hans]

@Hans Here's why I was thinking of increasing fat intake and decreasing carb intake, or go on a fast. If I could use less oxygen to produce energy, which means more beta-oxidation and less oxidative metabolism (or anaerobic glycolysis), I would not be pushing my already low oxygen supply at plaque-filled capillaries to exhaustion, and producing lactic acid, increasing uric acid and then deactivating nitric oxide as an end result, losing the vasodilatory effect of nitric oxide.

Inactivation of Nitric Oxide by Uric Acid

Fasting could maybe help to remove plague and heal some stuff but I'm not convinced that a low carb diet is going to fix things. You LDH is elevated but that is just a sign of tissue damage somewhere in the body. Your lactate is low and you think that you're urinating it out quickly - is there maybe a urine lactate test just to be sure?
Have you tested your nitric oxide levels? So that you know if you have enough NO or not and if your vascular system is just not responding to it.

Have you re-tested your LDH after using the anti-biotics? Because bacteria and endotoxins can elevated your LDH.

 

[yerrag]

Fasting could maybe help to remove plague and heal some stuff but I'm not convinced that a low carb diet is going to fix things. You LDH is elevated but that is just a sign of tissue damage somewhere in the body. Your lactate is low and you think that you're urinating it out quickly - is there maybe a urine lactate test just to be sure?
Have you tested your nitric oxide levels? So that you know if you have enough NO or not and if your vascular system is just not responding to it.

Have you re-tested your LDH after using the anti-biotics? Because bacteria and endotoxins can elevated your LDH.

The elevated LDH isn't accompanied by high levels of hsCRP or ESR. In fact my hsCRP, at 0.8 is low, and my ESR, is at 0. This, to me, discounts the tissue destruction nature of my elevated LDH reading. My last LDH reading, at 221 u/L, is barely within range of 135-225, but is slightly above optimal range. It is for this reason that I believe the elevated LDH merely reflects higher LDH due to hypoxia in my kidney capillaries.

I checked if there's a urine lactic acid test already and there's none. As for NO levels, I only tested salivary nitric oxide with a nitric oxide strip test. It tests low, but I'm just not sure about how to interpret it, as according to Ray Peat that is a good thing but according to the maker of the test strip it's not. I don't know of a way to test it that's useful for our discussion's purpose though.

I could try fasting again to see if I could experience again lower blood pressure from the exercise. If I experience lower blood pressure, one way I could check to see if it's attributed to a relief from hypoxia would be to test my random urine uric acid as well as serum uric acid and serum LDH. Just not sure though if the serum markers would quickly reflect the change in conditions though. If the urine uric acid levels are increased, it could mean lower lactic acid production due to the suppression of the anaerobic glycolytic pathway.

If fasting would lower blood pressure because I'm relying on ketosis for energy, then I could follow up with consuming fats and abstaining from carbs for a day or two, to see if relying on beta-oxidation for metabolism could inhibit hypoxic conditions from developing in my capillaries, and thus lead to lower blood pressures as well.

 

[Hans]

https://www.sciencedirect.com/science/article/abs/pii/S0026049565800063
"The clearance of uric acid, of total ketones,and of creatinine was determined during a 10-day fast in 4 obese women and in response to an acute infusion of β-hydroxybutyrate. A brisk fall followed by a plateau of uric acid clearance was concomitant with a steady rise of plasma ketones; thereafter the changes were not uniform. This inverse relationship in the early stages of fasting was duplicated with exogenous ketosis. The inhibition of renal excretion of uric acid by the ketosis of fasting is confirmed and some mechanisms for this effect are suggested."

If fasting improves your blood pressure it's possibly via another mechanism than lowering uric acid. Fasting also lowers ROS and thus stabilises BH4 and increases NO production. Even short term fasting, such as Ramadan fasting can increase NO.

During medical fasting, the improvements in blood pressure was due to natriuresis, weight loss, sympathetic nervous system downregulation, improved insulin sensitivity, etc.

I don't think you have sympathetic nervous system dominance because then your FFA might have been elevated and you would have been insulin resistant.
Other than that, aldosterone might be elevated causing an excess of sodium retention. Did you test aldosterone and PTH?

As a side thought. Uric acid is an indicator of rapid energy consumption. 2 ADP = 1 ATP + 1 AMP. The AMP is degraded to AIP and all the way to uric acid. Excess fructose and excess glycolysis might do this. Have you had your DHEA-S tested? DHEA-S and DHEA is an inhibitor of excess glycolysis.

 

[yerrag]

https://www.sciencedirect.com/science/article/abs/pii/S0026049565800063
"The clearance of uric acid, of total ketones,and of creatinine was determined during a 10-day fast in 4 obese women and in response to an acute infusion of β-hydroxybutyrate. A brisk fall followed by a plateau of uric acid clearance was concomitant with a steady rise of plasma ketones; thereafter the changes were not uniform. This inverse relationship in the early stages of fasting was duplicated with exogenous ketosis. The inhibition of renal excretion of uric acid by the ketosis of fasting is confirmed and some mechanisms for this effect are suggested."

I can't get access so it's hard to say how this would apply in a more general sense. Still I have some comments. First, the subjects are obese and they present confounding factors. Secondly, the fall in uric acid clearance may be true, but the study should also measure the actual serum uric acid as well. For all we know, the fall in uric acid clearance could be due to a decrease in serum acid production. But if it were so, a drop is serum uric acid would be a good thing, as it would lead to the availability of nitric oxide.

If fasting improves your blood pressure it's possibly via another mechanism than lowering uric acid. Fasting also lowers ROS and thus stabilises BH4 and increases NO production. Even short term fasting, such as Ramadan fasting can increase NO.

There could be another mechanism involved in lowering blood pressure through fasting. I would first have to eliminate my first hypothesis that fasting would shift the metabolic pathway towards beta-oxidation, and reduce reliance on sugar metabolism, and this would keep my oxygen-starved capillaries from resorting to anaerobic glycolysis, where lactic acid is a byproduct, which would cascade into an increase in uric acid (due to lactic acid inhibiting uric acid excretion), and hence the inactivation of nitric acid - a vasodilatory agent.

During medical fasting, the improvements in blood pressure was due to natriuresis, weight loss, sympathetic nervous system downregulation, improved insulin sensitivity, etc.

I don't think you have sympathetic nervous system dominance because then your FFA might have been elevated and you would have been insulin resistant.
Other than that, aldosterone might be elevated causing an excess of sodium retention. Did you test aldosterone and PTH?

I've tested PTH before and it's fine, as part of checking my calcium panel of vitamin D and ionized calcium. As for aldosterone, I got results only recently and it's fine(I think):

Aldosterone 244 pg/mL (range 25.2- 392) ; I don't know what range would be optimal though.

As a side thought. Uric acid is an indicator of rapid energy consumption. 2 ADP = 1 ATP + 1 AMP. The AMP is degraded to AIP and all the way to uric acid. Excess fructose and excess glycolysis might do this. Have you had your DHEA-S tested? DHEA-S and DHEA is an inhibitor of excess glycolysis.

Haven't tested for DHEA-S. It's available but I'm sure it's expensive. Is it something I can do without? I mean, it would just confirm that I have excess glycolysis right? Something that I already assume given the hypoxic condition inside a plaque-filled capillary. And my kidney capillaries being plaque-filled is also an assumption, given there are no methods (ultrasound, MRI, CT-scan) to affordably and non-invasivally evaluate.

 

[Hans]

I can't get access so it's hard to say how this would apply in a more general sense. Still I have some comments. First, the subjects are obese and they present confounding factors. Secondly, the fall in uric acid clearance may be true, but the study should also measure the actual serum uric acid as well. For all we know, the fall in uric acid clearance could be due to a decrease in serum acid production. But if it were so, a drop is serum uric acid would be a good thing, as it would lead to the availability of nitric oxide.


There could be another mechanism involved in lowering blood pressure through fasting. I would first have to eliminate my first hypothesis that fasting would shift the metabolic pathway towards beta-oxidation, and reduce reliance on sugar metabolism, and this would keep my oxygen-starved capillaries from resorting to anaerobic glycolysis, where lactic acid is a byproduct, which would cascade into an increase in uric acid (due to lactic acid inhibiting uric acid excretion), and hence the inactivation of nitric acid - a vasodilatory agent.



I've tested PTH before and it's fine, as part of checking my calcium panel of vitamin D and ionized calcium. As for aldosterone, I got results only recently and it's fine(I think):

Aldosterone 244 pg/mL (range 25.2- 392) ; I don't know what range would be optimal though.


Haven't tested for DHEA-S. It's available but I'm sure it's expensive. Is it something I can do without? I mean, it would just confirm that I have excess glycolysis right? Something that I already assume given the hypoxic condition inside a plaque-filled capillary. And my kidney capillaries being plaque-filled is also an assumption, given there are no methods (ultrasound, MRI, CT-scan) to affordably and non-invasivally evaluate.

Yeah I don't think you have to test it though.

Just to elaborate some more on the excess ATP consumption.

Shortage of Cellular ATP as a Cause of Diseases and Strategies to Enhance ATP
"During acute energy consumption, like extreme exercise, cells increase the favorability of the adenylate kinase reaction 2-ADP -> ATP+AMP by AMP deaminase degrading AMP to IMP, which further degrades to inosine and then to purines hypoxanthine -> xanthine -> urate. Thus, increased blood urate levels may act as a barometer of extreme energy consumption."

"decreased energy consumption from maintaining the pool of IMP for salvage to AMP and then ATP, since de novo IMP synthesis requires burning seven ATPs."

"If that purine salvage process fails to salvage Hx (hypoxanthine) back into high-energy phosphate molecules (AIP, AMP, ADP, ATP), and instead, XOR degrades it to X (xanthine), then X can only be further degraded by XOR to UA (uric acid)."

"after degradation to UA, new purine molecules would need to be salvaged from dietary intake or resynthesized de novo at an energy expense of 7 high-energy phosphate bonds from 6 ATP molecules to regenerate IMP"

"Previous results suggest that serum UA is a biomarker of ATP consumption, since rapid ATP consumption can lead to purine degradation and an increased rate of UA production in humans. For example, intense muscular exercise (Hellsten et al., 1999; Stathis et al., 1994, 1999), fructose challenge (Budillon et al., 1992; Donderski et al., 2015), alcohol intake (Lieber, 1965; Schmidt et al., 2013), and high brain activity (Salvadore et al., 2010; Goodman et al., 2016) can lead to energy crisis and resultant hyperuricemia. In addition, vascular regions undergoing ischemia-reperfusion may produce increased purine degradation products; a sign that a local energy crisis has occurred."
I would like to add that converting lactate back to glucose in the liver requires 6 ATP. Proteosomal degeneration also requires a lot of ATP and can elevate uric acid.

"Another study by the same group investigated the effect of angiotensin II (AII) on matrix metalloproteinase activity (MMP) in the canine heart. AII administration increased MMP activity, as well as chamber diastolic stiffening and MMP activity, and decreased tissue bioenergetics, while treatment with an MMP inhibitor was shown to decrease the effects of AII and reduce purine loss, likely through inhibition of AMPD activity (Paolocci et al., 2006)."

They found that the best way to increase ATP and lower uric acid was with a xanthine oxidoreductase (there are natural inhibitors) plus inosine.

 

[yerrag]

They found that the best way to increase ATP and lower uric acid was with a xanthine oxidoreductase (there are natural inhibitors) plus inosine.

Thanks for sharing your research on this Hans. I'm having difficulty understanding the language of the study. I feel the author needs some lessons in simplified English lol. So this is the only part so far I can respond to.

I'm not very sure I'd like to go the route of taking xanthine oxidoreductase inhibitors being that Allopurinol is one such drug in its class that's commonly given to gout sufferers by doctors. I don't know if this is a typical example of how doctors treat gout patients, but a friend of mine takes allopurinol because of his gout condition. He without doubt has high uric acid. I asked him if his doctor ever made him take a random urine uric acid test, and he says no. This is a very simple and affordable test. It only cost me $6 to take this test and I found out that my uric acid excretion is very low (908 umol/L; ref 2200-5475). I got this result after the third time I gave a urine sample. Reason: the lab personnel seldom get requests for this test and are so unfamiliar with the procedure of having to add a preservative to keep the urine sample from getting spoiled. This means that doctors (at least in Manila) rarely use this test for their patients.

Yet, I read that very often the cause of high serum uric acid is low urine uric acid excretion rate (I should have bookmarked that research), and I wonder if that is the case, doctors should be using the random urine uric acid test as part of their diagnosis. But why aren't they? Why are they not looking at increasing urine uric acid excretion rather than simply reducing uric acid production by using Allopurinol?

It makes me wonder about this study where the authors would find that the best way to increase ATP and lower uric acid was with a xanthine oxidoreductase inhibitor and inosine. But if a shortage of ATP production is a problem related to high uric acid production, would it also make sense to enable more of oxidative metabolism so that ATP production would be more efficient and shortage of ATP be prevented? If a urine test would confirm low urine uric acid excretion, and if it can be established that high lactic acid is the cause of that, wouldn't the solution be in lowering serum lactic acid so that the effects could cascade down to lower serum uric acid? And if lactic acid production is reduced, it would most likely involve using a more efficient metabolic pathway, such as oxidative metabolism.

"During acute energy consumption, like extreme exercise, cells increase the favorability of the adenylate kinase reaction 2-ADP -> ATP+AMP by AMP deaminase degrading AMP to IMP, which further degrades to inosine and then to purines hypoxanthine -> xanthine -> urate. Thus, increased blood urate levels may act as a barometer of extreme energy consumption."

Isn't extreme exercise assocaiated with anaerobic glycolysis? Doesn't lactic acid get produced, and doesn't this lead to reduced uric acid excretion, and thus increased serum uric acid as well?

"decreased energy consumption from maintaining the pool of IMP for salvage to AMP and then ATP, since de novo IMP synthesis requires burning seven ATPs."

"If that purine salvage process fails to salvage Hx (hypoxanthine) back into high-energy phosphate molecules (AIP, AMP, ADP, ATP), and instead, XOR degrades it to X (xanthine), then X can only be further degraded by XOR to UA (uric acid)."

"after degradation to UA, new purine molecules would need to be salvaged from dietary intake or resynthesized de novo at an energy expense of 7 high-energy phosphate bonds from 6 ATP molecules to regenerate IMP"

This gets very complicated for me. I wish I had the time to study this more or have a biochemistry degree. I hope I don't have to understand this for now. But if it's important I'll go thru some Khan Academy videos to understand this.

"Previous results suggest that serum UA is a biomarker of ATP consumption, since rapid ATP consumption can lead to purine degradation and an increased rate of UA production in humans. For example, intense muscular exercise (Hellsten et al., 1999; Stathis et al., 1994, 1999), fructose challenge (Budillon et al., 1992; Donderski et al., 2015), alcohol intake (Lieber, 1965; Schmidt et al., 2013), and high brain activity (Salvadore et al., 2010; Goodman et al., 2016) can lead to energy crisis and resultant hyperuricemia. In addition, vascular regions undergoing ischemia-reperfusion may produce increased purine degradation products; a sign that a local energy crisis has occurred."

I really question the statement " serum UA is a biomarker for ATP consumption." Does it mean then that all ATP consumption results in serum UA? It's either the author is making a false statement, or English isn't his first language. Or I am totally off the mark.

But I can relate to the statement "vascular regions undergoing ischemia-reperfusion may produce increased purine degradation product" in the sense that with ischemia hypoxic conditions develop and when energy needs to be generated it is forced to go through the anaerobic glycolytic pathway, and lactic is once acid produced, leading to decreased excretion of uric acid.

I would like to add that converting lactate back to glucose in the liver requires 6 ATP. Proteosomal degeneration also requires a lot of ATP and can elevate uric acid.

This could be another reason lactate increase leads to uric acid increase, but in a manner different from inhibiting the excretion of uric acid. It still augurs well for the case that lactic acid causes uric acid to increase.

I hope I can get my friend with gout to provide me with some test results I'm asking him to take, for his sake as well as for me to verify the relationship of lactic acid to uric acid. But I'm not holding my breathe. I'd like to get his random urine uric acid, his LDH, his serum lactate, and his blood glucose level (before and after meals), and his urine pH throughout the day.

 

[Hans]

But if a shortage of ATP production is a problem related to high uric acid production, would it also make sense to enable more of oxidative metabolism so that ATP production would be more efficient and shortage of ATP be prevented?

High ATP consumption causes elevated uric acid if the purines isn't recycled fast enough. That is why a xanthine oxidoreductase inhibitor boosts ATP, because it enables better purine recycling.

But in your case it might be only a problem with the excretion of uric acid like you said and not with the production thereof. To lower lactate by dropping carbs, I would lower carbs to 200g, then 150g and no lower than 100g (although 100g might already be stressful) and see what happens to uric acid.

I also want to throw this in here: "DHEA appears promising in some forms of CVD and hypoxic pulmonary hypertension linked to COPD" - Dehydroepiandrosterone (DHEA): Hypes and Hopes

 

[yerrag]

Thank Hans. I got to read up on the adenylate kinase reaction. I get the impression that it's another way to produce ATP for energy (aside from anaerobic glycolysis, oxidative metabolism, and beta-oxidation), but only used and exhausted when ATP generation is insufficient, and that could happen with excess consumption of energy and ATP, as in extreme exercise, or that can happen also when generation of ATP is insufficient due to inefficient ATP generation.

So, it's very well a biomarker for excessive ATP consumption, but in the sense that "excessive" is a matter of energy generation is unable to keep up with energy consumption. So, it appears than the adenylate kinase pathway is a supplemental pathway, and is tapped only when such excess occurs.

So, in a healthy individual whose metabolism is optimal, where energy metabolism is very efficient and ATP generation is maximized, and who is engaging in normal activity, he wouldn't be put in a situation where he would be producing plenty of uric acid. Is this correct?

Perhaps xanthine oxidoreductase inhibitors such as allopurinol reduces uric acid production, and would be a way to keep the adenylate kinase pathway from getting exhausted, but its use is fine only as a stop-gap measure. But if the body has to regularly employ this pathway simply for normal activities, then there is something else that needs to be addressed on how the body is generating ATP for energy. A doctor could keep a patient on regular use of allopurinol, or he could address the issue of inefficient metabolic pathways that necessitate the use of the adenylate kinase pathway.

As for DHEA, I'll check to see if it's not to expensive a test and get one done if so. This excerpt from the article is relevant to my case: "DHEA modulates cardiovascular signalling pathways and exerts an anti-inflammatory, vasorelaxant and anti-remodelling effect. Its low levels correlate with increased cardiovascular disease and all-cause mortality. "

I'll go ahead and get started with changing my macronutrient makeup in my food intake and see how a lower carb component and a higher fat component can help. Today I finished a water fast and already saw higher heart rates while blood pressure changed only slightly. I had to stop when my blood sugar dropped to 60, to which I began to feel a little light-headed. I then ate 4 teaspoons of peanut butter (a sweet blend) and a glass of whole milk. An hour later, my heart rate shot up to 87 from 77 (end of fast), both of which were higher than my heart rate of 67 when not fasting.

I interpret the higher heart rate as indicating that the mitochondria can upregulate its energy generating activity when oxygen availability is less of a constraint. And it's perhaps due to my reliance less on sugar metabolism for energy amd more on fat metabolism, allowing for the limited oxygen supply from clogged capillaries to not be exhausted as quickly.

My blood pressure also went down, and I see this as possibly being a case of less lactate, less uric acid, and more available nitric oxide for vasodilation.

Of course, this means little yet and I have to really put this to the test with a week-long trial at least.

 

[yerrag]

@Hans I got this quote from my diagnostic lab-

DHEA (RIA) - P8,000 = $160
DHEAS (CMIA) - P2,500 = $50

Would the DHEAS test be useful?