PDK inhibitors

[AdamS]

After reading the below abstract about the PDK4 inhibitor Diisopropylamine Dichloroacetate, I got excited again about PDK inhibitors. I have a few questions:

• Are there any PDK inhibitors we can test out or is safety/availability a problem?
• Do you think that PDK inhibitors could help improve symptoms in ME patients? If not, why?

Severe influenza is characterized by cytokine storm and multiorgan failure with metabolic energy disorders and vascular hyperpermeability. In the regulation of energy homeostasis, the pyruvate dehydrogenase (PDH) complex plays an important role by catalyzing oxidative decarboxylation of pyruvate, linking glycolysis to the tricarboxylic acid cycle and fatty acid synthesis, and thus its activity is linked to energy homeostasis. The present study tested the effects of diisopropylamine dichloroacetate (DADA), a new PDH kinase 4 (PDK4) inhibitor, in mice with severe influenza. Infection of mice with influenza A PR/8/34(H1N1) virus resulted in marked down-regulation of PDH activity and ATP level, with selective up-regulation of PDK4 in the skeletal muscles, heart, liver and lungs. Oral administration of DADA at 12-h intervals for 14 days starting immediately after infection significantly restored PDH activity and ATP level in various organs, and ameliorated disorders of glucose and lipid metabolism in the blood, together with marked improvement of survival and suppression of cytokine storm, trypsin up-regulation and viral replication.

I've listed a few PDK inhibitors, I couldn't find many initially but will add to the list when I have more time.

PDK1

• Phenyl Butyrate http://www.sciencedirect.com/science/article/pii/S0928098717302129
• AZD7545
  
• Dichloroacetic Acid (DCA)

PDK2

• ??

PDK4

• Diisopropylamine Dichloroacetate https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035290/

Thanks, Adam

 

[Jesse2233]

I believe DCA is available OTC

 

[Tunguska]

This study combined two of the ones you listed, and they synergized: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551558/

Differential inhibition of PDKs by phenylbutyrate and enhancement of pyruvate dehydrogenase complex activity by combination with dichloroacetate
Pyruvate dehydrogenase complex (PDHC) is a key enzyme in metabolism linking glycolysis to tricarboxylic acid cycle and its activity is tightly regulated by phosphorylation catalyzed by four pyruvate dehydrogenase kinase (PDK) isoforms. PDKs are pharmacological targets for several human diseases including cancer, diabetes, obesity, heart failure, and inherited PDHC deficiency. We investigated the inhibitory activity of phenylbutyrate toward PDKs and found that PDK isoforms 1-to-3 are inhibited whereas PDK4 is unaffected. Moreover, docking studies revealed putative binding sites of phenylbutyrate on PDK2 and 3 that are located on different sites compared to dichloroacetate (DCA), a previously known PDK inhibitor. Based on these findings, we showed both in cells and in mice that phenylbutyrate combined to DCA results in greater increase of PDHC activity compared to each drug alone. These results suggest that therapeutic efficacy can be enhanced by combination of drugs increasing PDHC enzyme activity.

Similarly it's the combinations with other protocols I'm interested in trying, rather than PDK inhibitors alone. Get them to complement each other. The way I see it PDK inhibitors can make sense to into any scenario if used right.

There's conflicting information about the other forms of butyrate, but in this one, Sodium Butyrate also had desirable effects (but in other studies it increased PDK instead - so I'm not certain about this one): https://www.ncbi.nlm.nih.gov/pubmed/28123081

Histone Deacetylase Inhibitors Protect Against Pyruvate Dehydrogenase Dysfunction in Huntington's Disease.
[...] Exposure to SB also suppressed hypoxia-inducible factor-1 (HIF-1α) stabilization and decreased the transcription of the two most abundant PDK isoforms, PDK2 and PDK3, culminating in increased PDH activation in mutant cells. Concordantly, PDK3 knockdown improved mitochondrial function, emphasizing the role of PDK3 inactivation on the positive effects achieved by SB treatment. YAC128 mouse brain presented higher mRNA levels of PDK1-3 and PDH phosphorylation and decreased energy levels that were significantly ameliorated after SB treatment. Furthermore, enhanced motor learning and coordination were observed in SB-treated YAC128 mice. These results suggest that HDACIs, particularly SB, promote the activity of PDH in the HD brain, helping to counteract HD-related deficits in mitochondrial bioenergetics and motor function.

I don't know if this going through mTor or not.

There's something to the Erk pathway and epidermal growth factor: https://www.ncbi.nlm.nih.gov/pubmed/21852536 but I haven't read this

There was also stuff in the Fluge & Mella thread but I completely forgot. I wasn't as interested at the time. I'm kind of tired so if I misinterpreted something please point it out.

 

[junkcrap50]

That paper about the H1N1 mice and DCA inhibiting PDK, as well as a couple other papers by the same authors , are incredibly interesting. And I believe deserve more review by the community here than were giving in the Fluge & Mella PDH thread.

 

[Tunguska]

After reading the below abstract about the PDK4 inhibitor Diisopropylamine Dichloroacetate, I got excited again about PDK inhibitors.

I skimmed through your article (nice find by the way):

The results also showed that diisopropylamine dichloroacetate (DADA), which is the active component of pangamic acid [21] and commercially available as a Liverall (Daiichi Sankyo Co., Tokyo, Japan) for over 50 years for the treatment of chronic liver diseases, is a safe inhibitor of PDK4. DADA selectively and effectively inhibited PDK4, resulting in significant restoration of PDH activity as well as various metabolic disorders, such as ATP levels in various organs, and improved glucose, lactate and β-hydroxybutyric acid levels in the blood.
[...]
Among the known synthetic inhibitors of PDK [28], such as dichloroacetate (DCA), AZD7545 and radicicol, the pyruvate analog DCA is the most common classic inhibitor for PDK isoforms
[...]
DADA concentrations at which the reaction rates are suppressed by 50%, were 50.9 µM against PDK4 and 636.0 µM against PDK2. These values were almost identical to those of DCA against PDK4 and PDK2, respectively
[...]
DCA also has symptomatic adverse reaction of peripheral neuropathy [23], [60], [61]. In the present study, DADA, a new PDK4 inhibitor, inhibited PDK4 and PDK2 with potency similar to DCA (Table 3). DADA was originally obtained from apricot nuclei and called pangamic acid or “vitamin B15” [21] and has been used as a safety treatment option for hepatic injury and nonalcoholic fatty liver diseases [62] without symptomatic peripheral neuropathy or other adverse effects.

Edit: Ah wait it was posted here: http://forums.phoenixrising.me/inde...-encephalopathy-cfs.48446/page-20#post-802851

 

[alex3619]

I would like to know if there are any patients here who have already tried these or similar treatments, and what the outcomes were.

 

[Jesse2233]

From a PR member who tried DCA back in 2014:

I was trying DCA and it actually seemed to work well for the fibro and CFS. However, I am not sure whether or not it was the cause of some of my stomach pain and nausea. I just had some tests and my pancreatic enzymes have been very low for quite awhile, so that could have caused some of my problems. I got some digestive enzymes and am thinking about going back on it for awhile to see if the enzymes fixed the stomach problems. I also have some Zofran. I did get my liver and kidney function tested while I was on it, and they were both normal, so it did not affect either. I was worried about this since I read some reports that it was hard on both the kidneys and liver.

I will let you know if the stomach pains are related or not in a week or two. A lot of things make me nauseous and hurt my stomach. If you have a stronger less queasy stomach than mine, I would say go for it. I think it will be worth it. I bought it from Amazon under pet cancer meds (same stuff, but way cheaper).

@Hip and his friend tried it as well

Unfortunately either the DCA or the interferon suppositories (more likely) that I just started taking last week triggered a bout of neurologically-caused depression (which I often suffer from anyway), and I am trying to get over this before trying any more DCA. I don't like to test new drugs or supplements when I am in any way feeling less healthy than normal, just as a precaution.

Someone I know who's been trying DCA over the last few days has seen no positive effects so far on her ME/CFS.

 

[AdamS]

@Tunguska Thanks for posting this...

DADA was originally obtained from apricot nuclei and called pangamic acid or “vitamin B15”

Just ordered some Vit B15/Pangamic Acid...will let you know how I get on. Not expecting anything but will try anything really.

 

[Tunguska]

@Tunguska Thanks for posting this...
Just ordered some Vit B15/Pangamic Acid...will let you know how I get on. Not expecting anything but will try anything really.

Yeah my first thought was "great this might be accessible" but then I remembered pangamic acid supplements have a terrible reputation: https://en.wikipedia.org/wiki/Pangamic_acid

Safety
Positive results from mutagenicity analysis via the Ames test of compounds commonly found in preparations labelled "pangamic acid" including diisopropylamine dichloroacetate, diisopropylamine,[4] dichloroacetate,[5] as well as dimethylglycine mixed with sodium nitrite[2] suggests there may be concern for the development of cancer with the use of these substances.

Legal status
The United States Food and Drug Administration has recommended seizing any chemicals advertised as pangamic acid and restraining the importation and interstate shipment of pangamic acid on the grounds that pangamic acid and pangamic acid products are unsafe for use and have no known nutritional properties.[6] Pangamic acid's distribution in Canada has been prohibited by the then-named Canadian Food and Drug Directorate.[3]

@Hip and his friend tried it as well

He wrote me he didn't plan on trying it again for the time being... kinda speaks for itself... I'm scared of trying DCA because I've had neuropathy before of the worst kind, and DCA is super expensive. But DADA sounds alright, assuming you can get the real thing.

I think the best results have been from super high-dose thiamine, a few posters, Lynn, Sidereal, etc. had great experiences with that, albeit temporary. But there are just as many if not more failures including me.
http://forums.phoenixrising.me/inde...ent-story-focus-on-thiamine-deficiency.24059/
The thread is titled "thiamine deficiency" but they were taking 1500mg+ so more than likely it's just the therapeutic effect(s), betting on PDH/PDK or something in glycolysis anyway. I'm not sure if it did anything for people's PEM though (this plays into my belief it might be more useful during activity although it should help a little anytime [but also that it may be better in combinations]).

 

[Tunguska]

It's predictable, that if PI3K/Akt is significantly inhibited, that PDK inhibitors won't do much because glycolysis will have little substrate to work with, and worse because most will have some type of side effect or another, so all you get is the side effects with none of the benefits.

I think some people might have to take an Akt and/or mTor activator in order for PDK inhibitor to work at all, or reliably. The exception would be those who already have high pyruvate levels, they probably don't need it at least not at first.

It will also worsen ROS from mitochondria so that's a possible source of problems, and you might have to take a ROS scavenger like NAC, ALA or vit C.

Point is I think if it doesn't work alone, I wouldn't give up right away.

 

[Jesse2233]

So if one has high pyruvate levels, a PDK inhibitor might work on its own?

 

[Tunguska]

Yeah, I think it could work alone, at least temporarily.

You might have other issues that would become limiting soon after starting though. (it's also not a guaranteed sign that Akt is working well, since it's a balance between production and consumption, rather than on/off)

 

[AdamS]

It's predictable, that if PI3K/Akt is significantly inhibited, that PDK inhibitors won't do much because glycolysis will have little substrate to work with, and worse because most will have some type of side effect or another, so all you get is the side effects with none of the benefits.

I think some people might have to take an Akt and/or mTor activator in order for PDK inhibitor to work at all, or reliably. The exception would be those who already have high pyruvate levels, they probably don't need it at least not at first.

It will also worsen ROS from mitochondria so that's a possible source of problems, and you might have to take a ROS scavenger like NAC, ALA or vit C.

Point is I think if it doesn't work alone, I wouldn't give up right away.

Do you know of any AKT/mTOR activators? Sure I read somewhere that aminos like Leucine/Glutamine can stimulate mTORC1, I took some Leucine last night actually, no idea if it helped though.

 

[Tunguska]

Do you know of any AKT/mTOR activators? Sure I read somewhere that aminos like Leucine/Glutamine can stimulate mTORC1, I took some Leucine last night actually, no idea if it helped though.

A lot of the mTor activators in this thread http://forums.phoenixrising.me/index.php?threads/how-can-we-stimulate-mtor.49892/page-10#post-841424 also increase Akt, most of them afaik. These may already relieve PDH on their own to a certain degree through mechanisms that nandixon explained.

Akt activators that don't increase mTorC1 are things like ALA and rapamycin, or more generally some of the AMPK activators but you have to look each of them up to see if they increase or lower Akt. (Akt also can relieve PDH a little on its own dep. on circumstance but I no longer think you can count on this)

 

[Tunguska]

Also the nitric oxide boosters often involve Akt, mTor and/or AMPK activation so they are good candidates to look at.

 

[eljefe19]

@Tunguska I felt pretty sure I was improving 2-3 days into starting Rapamycin but I'm a week in now at 1mg and the last two days have been pretty standard PEM. Suffice to say I'm not feeling any tremendous relief from Akt activation. I shouldn't have by now shouldn't I? I've now tried several Akt activators without any great results.

 

[Tunguska]

@Tunguska I felt pretty sure I was improving 2-3 days into starting Rapamycin but I'm a week in now at 1mg and the last two days have been pretty standard PEM. Suffice to say I'm not feeling any tremendous relief from Akt activation. I shouldn't have by now shouldn't I? I've now tried several Akt activators without any great results.

Maintaining Akt is a requirement for things to work, but it's not quite sufficient, that's what I've been coming to. It would be fast relief, yes. During periods of recovery - or most of the day - I lean heavily toward using Akt+/mTorC1+, which has some action toward inhibiting PDK on its own (see nandixon posts). To exploit Akt+/mTorC1- properly I think maybe you have no choice to add a separate PDK inhibitor (there could conceivably be yet something else I haven't found yet). That said, I'm not suggesting combining rapamycin with DCA, it sounds dangerous.

I was hoping maybe rapamycin had a magic undocumented effect that inhibited PDK (disease-specific or not) separately, but that's wishful thinking.

 

[AdamS]

I can't say i've had any noticable effect from any supplement or drug i've tried other than alcohol, even after 1-2 pints i'm almost normal again. In fact, i've managed nights out recently fueled by alcohol, it even pulled me out of a crash. There must be something in this...blunting B Cell secretion or microglial activity, it's not a long term solution because hangovers suck but nice instant relief nonetheless. Naviaux talks about personalised treatment based on metabolomics, I wonder if this translate to symptomatic relief or just make the tests look better? Perhaps ME does take a long time to recover from, even with the right treatment, this is certainly the case from most Valcyte/Rituximab stories. I'm desperate to find something that we can try (as we all are), i'm gutted Rapamycin didn't work out for you @eljefe19 as that seemed to show promise!

 

[Jesse2233]

i'm gutted Rapamycin didn't work out for you @eljefe19 as that seemed to show promise!

Likewise, though maybe it requires a somewhat longer trial

 

[Tunguska]

I can't say i've had any noticable effect from any supplement or drug i've tried other than alcohol, even after 1-2 pints i'm almost normal again. In fact, i've managed nights out recently fueled by alcohol, it even pulled me out of a crash. There must be something in this...blunting B Cell secretion or microglial activity, it's not a long term solution because hangovers suck but nice instant relief nonetheless. Naviaux talks about personalised treatment based on metabolomics, I wonder if this translate to symptomatic relief or just make the tests look better? Perhaps ME does take a long time to recover from, even with the right treatment, this is certainly the case from most Valcyte/Rituximab stories. I'm desperate to find something that we can try (as we all are), i'm gutted Rapamycin didn't work out for you @eljefe19 as that seemed to show promise!

Do you try combinations much? There are almost no supplements that work alone on me except opioids and ALA and it's only to a degree.

Dr. Davis expects a solution that targets the blood factor to be a single drug, but nothing that I'm talking about is targeting that blood factor; so conversely I expect all these things we're looking at to work [best] in combinations.

@eljefe19 Remember there might be a disconnect between the short-term relief and the disease-modifying aspects if rapamycin has any which might occur after longer time, unfortunately there's absolutely no evidence for it, so who knows. I would agree that Akt activation alone is not helping you, but who knows what else the drug is doing or not doing. There's also that question of how much you're actually absorbing (see comment on the rapamycin thread).