Brain Kynurenine and BH4 Pathways: Relevance to the Pathophysiology and Treatment of Inflammation-Driven Depressive Symptoms

nerd

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Vancassel S, Capuron L and Castanon N (2018) Brain Kynurenine and BH4 Pathways: Relevance to the Pathophysiology and Treatment of Inflammation-Driven Depressive Symptoms. Front. Neurosci. 12:499. doi: 10.3389/fnins.2018.00499

Abstract
The prevalence of depressive disorders is growing worldwide, notably due to stagnation in the development of drugs with greater antidepressant efficacy, the continuous large proportion of patients who do not respond to conventional antidepressants, and the increasing rate of chronic medical conditions associated with an increased vulnerability to depressive comorbidities. Accordingly, better knowledge on the pathophysiology of depression and mechanisms underlying depressive comorbidities in chronic medical conditions appears urgently needed, in order to help in the development of targeted therapeutic strategies. In this review, we present evidence pointing to inflammatory processes as key players in the pathophysiology and treatment of depressive symptoms. In particular, we report preclinical and clinical findings showing that inflammation-driven alterations in specific metabolic pathways, namely kynurenine and tetrahydrobiopterin (BH4) pathways, leads to substantial alterations in the metabolism of serotonin, glutamate and dopamine that are likely to contribute to the development of key depressive symptom dimensions. Accordingly, anti-inflammatory interventions targeting kynurenine and BH4 pathways may be effective as novel treatment or as adjuvants of conventional medications rather directed to monoamines, notably when depressive symptomatology and inflammation are comorbid in treated patients. This notion is discussed in the light of recent findings illustrating the tight interactions between known antidepressant drugs and inflammatory processes, as well as their therapeutic implications. Altogether, this review provides valuable findings for moving toward more adapted and personalized therapeutic strategies to treat inflammation-related depressive symptoms.

How is this relevant?

One of the unsolved questions of the metabolic trap theory is why and how it happens and what mechanism(s) participate in the relapsing process. This study gives one possible explanation, i.e. a biopterin dysbalance and BH4 deficiency respectively. It might be possible that pathogens suppress the IDO activity directly, but I think this will be limited to certain cell types. But how can a fraction of cells cause such wide systemic issues? The scarcer a metabolic process is, the more susceptible it is to localized pathogenicity. The biopterin cycle is relatively localized to nerves and nerve liquids. It is also connected to the folate and methylation cycles. When BH4 "runs dry" at a certain locality, tryptophan can accumulate and cause the substrate inhibition of IDO1, which will not only block kynurenine synthesis but will also make the tryptophan hydroxylase more susceptible to psychological triggers and nitrosative stress.

One approach to alleviating this aspect of the pathology is the use of sepiapterin to increase the biopterin buffer. Of course, tryptophan should be avoided as a supplement. 5-HTP would be the preferable choice for serotonin support. Niacin supplementation could partially compensate for the localized intracellular deficiency. Considering that tryptophan only becomes a problem when it accumulates in a cell, LNAAs and BCAAs can support the diffusion and efflux of accumulated tryptophan from cells (10.1007/BF00238470).

It's a fitting explanation for why PEM happens. However, from my personal experience with remission, I don't think that we really push ourselves back into the trap by a lack of pacing or by psychological triggers once we are in remission. There must be something else going on. Either the normalized metabolic function triggers the lytic signaling of a virus, or another metabolite accumulates and causes the BH4 and/or tryptophan pathways to jam again.
 

junkcrap50

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I think you'll need certain mammalian cell lines for BH4 testing. And the model isn't adaptable because there is no endpoint for CFS/ME unless you know how to induce it in these cells.
I'm referring to Ron Davis's newest video he released recently where he discusses the newest experiments on the metabolic trap he's testing. He has been able to model and recreate the metabolic trap of tryptophan and IDO1/IDO2 in Candida cells and will be adding drugs to the cells to see if it reverses the trap.

You still may be right as BH4 may work from a wider non-direct process than the focused model Davis is using.
 

percyval577

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5-HTP would be the preferable choice for serotonin support.
Would though, as it sadly does not cross the brain blood barrier. This makes it, btw, also rather impossible that the serotonin in chocolate accounts for the supposed good effect of chocolate on nerves. It might though be to a small fraction that other stuff needed for the synthesis of serotonin then crosses the BBB more densely, as the synthesis in the periphery is less needed.

Thanks for the paper and the relevance (which I like to agree to).
 

Learner1

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not available outside hospitals in my country, unfortunately
There are 2 generics that came out in the US in the past 6 months - one from Par Pharmaceuticals and the other from Dr.. Reddys.

They are only available from 7 specialty pharmacies in the US. One can buy them directly if insurance won't pay. I priced out Kuvan, the research chemical version and Ecological Formulas Pteridin, and they were all about the same price, with Kuvan being a stabilized version.
inflammation-driven alterations in specific metabolic pathways, namely kynurenine and tetrahydrobiopterin (BH4) pathways, leads to substantial alterations in the metabolism of serotonin, glutamate and dopamine that are likely to contribute to the development of key depressive symptom dimensions
Depletion of BH4 will lead to low levels of neurotransmitters. Kuvan raised my chronically low dopamine levels, however, I was not depressed before that.
Of course, tryptophan should be avoided as a supplement. 5-HTP would be the preferable choice for serotonin support
5-HTP should also be avoided as a supplement. It triggered the IDO metabolic trap in me, which took 18 months of hyperbaric oxygen to reverse.
Niacin supplementation could partially compensate for the localized intracellular deficiency.
Niacin can reverse methylation..it is not a very efficient way to make more ATP, depends on a lit of steps working correctly. Much more efficient to take sublingual NAD+.
It's a fitting explanation for why PEM happens.
They have had nothing to do with PEM for me. Resolving the IDO trap, making more kynurenine but increasing pyridoxal-5-phosphate (B6) and taking Kuvan have definitely helped increase energy but none is a cure for ME/CFS or a cure for PEM. Glutathione, ALA, and BCAAs help avoid or reverse PEM.
@Learner1 saw great improvements by adding Kuvan (BH4) to her regimen. I am trialing it now.
Kuvan increased nitric oxide production, increasing ability to exercise, increasing activity level by 30% and lowering my high blood pressure, as well as Increasing dopamine and reducing peroxynitrites. Benefits have been sustained over 14 months.
 
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nerd

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I'm referring to Ron Davis's newest video he released recently where he discusses the newest experiments on the metabolic trap he's testing. He has been able to model and recreate the metabolic trap of tryptophan and IDO1/IDO2 in Candida cells and will be adding drugs to the cells to see if it reverses the trap.

You still may be right as BH4 may work from a wider non-direct process than the focused model Davis is using.
I think it's bakers' yeast and not Candida. I'm not sure if and how a BH4 metabolism exists in yeast, but his current study design would have to be reversed from the IDO perspective to the BH4 perspective to show the causality of BH4.

saw great improvements by adding Kuvan (BH4) to her regimen. I am trialing it now.
It will only increase the buffer though, and not improve recycling. And unfortunately, BH4 precursors/variants are difficult to get. In Germany, you need to have genetic BH4 deficiency for a prescription of Sapiopterin. I think it can alleviate the trap but if you skip on pacing, it will hit even harder due to increased free radical production the grater the biopterin imbalance/blockage and BH2 accumulation.

Would though, as it sadly does not cross the brain blood barrier.
I don't think there is any consensus on this topic yet (10.1038/s41386-017-0003-7).

5-HTP should also be avoided as a supplement. It triggered the IDO metabolic trap in me, which took 18 months of hyperbaric oxygen to reverse.
The only explanation for this, as far as I can tell, is BH4 again. If you already have a biopterin dysbalance and low BH4 levels, adding neurotransmitter precursors to your diet, no matter if it is tyrosine or tryptophan or 5-HTP, will increase the load on BH4 recycling. It's very well possible that this sends you back into the trap. 5-HTP itself isn't the reason for this though. It's BH4 and an overload of BH4 utilization via tryptophan + dysfunctional recycling of BH4 via the folate+methylation cycle. If your methylation is overburdened, as it is common for CFS/ME, presumably by the overmethylation from the glycolysis-histone pathway, your homocysteine levels would be exhausted eventually and your folate recycling would also block efficient BH4 recycling. SAMe would resolve this on the shorthand, but on the long hand, the overmethylation has to be eliminated by reducing glycolysis, by reducing insulin and blood glucose peaks, e.g. by a well-formulated keto diet that adjusts for potential electrolyte deficiencies. Of course, this wouldn't be necessary if the immunological+metabolic trigger for the glycolysis issue was addressed.

Niacin can reverse methylation.
Only excessive levels. I would take it only with SAMe since it causes additional methylation load to catalyze Niacin. But Niacin has a wide variety of feedback mechanisms we might not be even aware of (NAD+-dependant). You might be correct in that NAD+ could evade the methylation issue and thus is to be preferred (in non-excessive levels).

They have had nothing to do with PEM for me.
I can't say that I'm fully convinced by the presumed severity of the metabolic trap theory either. But at least this would associate the metabolic trap theory with the wider pathological picture of CFS/ME. It is one explanation.

Kuvan increased nitric oxide production, increasing ability to exercise, increasing activity level by 30% and lowering my high blood pressure, as well as Increasing dopamine and reducing peroxynitrites. Benefits have been sustained over 14 months.
I wish I could try it. I wish I had a doctor who would be willing to prescribe me anything.
 
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Hoosierfans

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I took straight BH4 in the past and it might confirm @nerd ‘s suspicion as it made me immediately worse.
I’ve heard of several folks having a bad reaction to the supplement BH4. I don’t understand all of it but my weak understanding was that the supplement versions tend to be unstable.

I had some sample Kuvan to try about 6 weeks ago and at 20 mg / day it would absolutely help my hysterical crying level anxiety and depression for a couple hours, then wear off. I was taking 10 mg 2 x day. Other days I got a slight mood boost.

My doc and I are going to play w dosage. Given that I was on Effexor for over a decade, my neurotransmitters and receptors are probably very wonky. So he’s given me permission to go up to 100 mg / day. In studies on autism, they used up to 1000 mg / day. At least for issues like autism, anxiety, depression there isn’t any consensus on what is effective dosing so if one would try it for anything you could start at what Learner has used (20 mg / day) and then play w dosing under a docs supervision.
 

Hoosierfans

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I think it can alleviate the trap but if you skip on pacing, it will hit even harder due to increased free radical production the grater the biopterin imbalance/blockage and BH2 accumulation.
Can you explain further??? So is there something I should be taking / doing along w the Kuvan to keep it working properly / avoid an imbalance??
 

nerd

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Can you explain further??? So is there something I should be taking / doing along w the Kuvan to keep it working properly / avoid an imbalance??
I wish there was a study on the biopterin metabolism of CFS/ME patients to clarify if it is just a dysbalance or if there is something actively exhausting BH4 (and BH2 altogether). Neurotransmitters naturally exhaust BH4 but this is normally balanced with the biopterin synthesis. Now, if there is something like an IDO trap, any tryptophan localized in certain cell types would actively exhaust BH4. I assume that the lack of kynurenine or Niacin will also trigger somehow the utilization of tryptophan. I mean, if there is a Niacin-signaled feedback mechanism for the blockage, there might also be a Niacin-signaled feedback mechanism for the utilization of tryptophan. But this is purely speculative. But I guess this is something that Prof. Ron Davis and his team will look into. What happens to the healthy yeast cultures' IDO metabolism when they add different amounts of Niacin? I'm not sure if yeast Niacin/NAD+ metabolism is completely projectable to human cells though.

One plausible causality and locality for the complete exhaustion of biopterins would be endothelial NOS and a CR6-interacting factor 1 deficiency (10.1016/j.freeradbiomed.2011.03.010; 10.1038/s41598-020-57673-9). This could be triggered by SIRT1 signaling due to Niacin/NAD+ deficiency (10.1089/ars.2016.6719; 10.1016/j.cmet.2014.04.001). Another factor would be the variance of ammonia from the methylation cycle/cystathionine. You see, it's a vicious circle. Where to begin the correction? Maybe all at once? How to really fix the overmethylation so that homocysteine levels are normal without taking any additional methylation supplements? All I can imagine is taking SAMe, B6, and avoiding B12 deficiency. We could try thinking one step further and the glycolysis-histone connection and how a keto diet could fix this, but I think this is getting off-topic because it's about the methylation blockage primarily.

I don't think there is anything else until all causes for BH4 deficiency are known. I mentioned all the things you could do, e.g. taking 5-HTP instead of Tryptophan, BCAAs or LNAAs, taking Niacin+SAMe or better Niacin metabolites.
 
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Second star to the right ...
Considering that tryptophan only becomes a problem when it accumulates in a cell, LNAAs and BCAAs can support the diffusion and efflux of accumulated tryptophan from cells (10.1007/BF00238470).
Hi @Mary .... am tagging you into this thread because of your good experiences with BCAAs, and the possibility that some of this info might be of interest to you, or maybe help connect some dots ...
 

Learner1

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Taking 5-HTP isnd tryptophan are not advisable.

LNAA include tryptophan, tyrosine, phenylalanine, and the branched-chain amino acids (BCAA; leucine, isoleucine and valine). The transporter is saturable and competitive, so that raising the blood (or plasma or serum) concentration of one LNAA raises the brain uptake of that LNAA, and reduces those of the others.
Tryptophan is not advisable. Tyrosine may be useful.

Niacin may be counterproductive. NAD+ us more direct without as much downside. So can SAMe. May be more useful to take methionine or TMG.

BCAAs and glutathione can reduce/avoid/reverse PEM.
 

Hoosierfans

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Taking 5-HTP isnd tryptophan are not advisable.


Tryptophan is not advisable. Tyrosine may be useful.

Niacin may be counterproductive. NAD+ us more direct without as much downside. So can SAMe. May be more useful to take methionine or TMG.

BCAAs and glutathione can reduce/avoid/reverse PEM.
As you and I have chatted about, I started BCAAS last week. Am taking 7.5 g 3 x day. They appear to be helping a little bit. I may add some Tyrosine after a couple of weeks on the Kuvan...see if it makes any change.

BTW, for anyone that knows, is there a way to get tested for the IDO genes? To know if it’s an issue for me? I heard Ron say that every patient they tested had the defect...but my ME / CFS is a bit atypical (I meet the old criteria for DX bit not the more stringent criteria as I don’t experience PEM).
 

nerd

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Tryptophan is not advisable. Tyrosine may be useful.
Neurotransmitter precursors are always competing, also competing for BH4. Tyrosine could be useful for dopamine and hypothyroidism while 5-HTP could be useful for serotonin production. Tryptophan is also an LNAA but it could contribute to the IDO trap, this is why I wouldn't take it, in addition to quality issues that are only known for tryptophan but not for 5-HTP so far. However, I don't see why 5-HTP wouldn't be advisable. I know that there are some potential factors to consider in the brain, i.e. 5-HT receptors and their role in cardiovascular regulation, but I'm not sure yet how this might be affected in CFS/ME patients. Why do you think is 5-HTP not advisable?

Niacin may be counterproductive.
I agree. Excessive doses could be counterproductive.

So can SAMe. May be more useful to take methionine or TMG.
Here I disagree. I'm quite sure it is SAMe that get's depleted and not its precursors. How can SAMe be more counterproductive than its precursors? Feel free to share your theory in the separate post that I opened about the methylation cycle:
What is your understanding of the methylation cycle trap or blockage?

BCAAs and glutathione can reduce/avoid/reverse PEM.
I'd be interested in how you understand that they can reverse PEM? What's their mechanism of action?

@nerd Have you considered speaking to Ron Davis about your ideas?
I haven't. It sounds like he's already in the process of finding IDO regulators either way. And I think it's worth looking into it. I'm not sure how much of a difference BCAAs can really make in affected cells and if this will be significant enough. But I'm also a bit hesitant with IDO regulation because there will be the contrary side where unaffected cells' IDO will be upregulated. And how much this will be the case and how many side effects this will cause depends on the effective concentration in affected cells. I hope affected cells will be sensitive enough to the agent so that unaffected cells won't overproduce kynurenine and exhaust tryptophan (i.e. toxic concentration).

BTW, for anyone that knows, is there a way to get tested for the IDO genes? To know if it’s an issue for me?
Unless they publish(ed) the affected SNPs, it will be difficult to tell even with a test. I asked for a particular SNP (i.e. rs4503083) in their last video update without an answer. Maybe they're still working on it and don't want to spread misinformation unless it's verified. There are different ways to get your genome sequenced. The complete way is full-genome sequencing (FGS) 30x - 100x. It's offered by Nebula Genomics and Dante Labs. 23andme and other microarray providers offer cheaper sequencing but it's inaccurate and only cherry-picking pre-selected SNPs, which might not include the SNPs you're looking for. I think there are also other ways if your insurance covers it but this depends on your country.