8 replies to this topic

[Mind_Paralysis]

As previously posted, I am working on a thesis regarding the possible connection between amino-acid metabolism and the pathology of ADHD - similar to how some research is indicating that amino-acid metabolism plays an important role in the pathology of other mental disorders.

 

And now I've actually got a first, preliminary draft! : D Mostly just a basic hypothesis and various references towards a potential connection, but at least there's something.

 

Would any of you be interested in checking it out, and giving me your feedback? I'd love to hear it.

 

I'm especially keen to hear what everyone thinks about the latest connection I uncovered: that a possible mode of action for the experimental ADHD -medication Metadoxine could be the modulation of Tryptophan metabolism! : )

 

 

The Role of Kynurenic Acid in Attention Deficit Hyper-activity Disorder

By Ninjorstinkor

 

My recent studies have led me to believe that there might be a common recurring genetic polymorphism within variations on ADHD that involves problems with the processing or synthesis of Tryptophan into Kynurenic Acid – and the subsequent effect of a hyper-active

NMDA-network, leading both to cognitive deficits (primarily in executive function), and problems with compensation for deficits within the dopaminergic circuitry.

 

My basis for the hypothesis is that it in a seemingly elegant way binds together recent theories regarding the involvement of the NMDA-network in various CNS-disorders, as well as the efficiency of Memantine, a

non-competitive NMDA-antagonist in treating ADHD, with the observations of alterations with Tryptophan-metabolism in ADHD, and the potential therapeutic value of Ketogenic diets in the treatment of ADHD, as well as the observed disruptions of Circadian Rhytms within individuals afflicted with ADHD.

It all leads back to Kynurenic Acid – and its relationship to the

NMDA-network and the metabolism of Tryptophan.

 

 

A potential method of treatment could be supplementation with compounds which inhibit kynurenine hydroxylase – primarily the compound Nicotinylalanine.

 

Roberto Pelliciari of Italian neuroscience research had a patent for the use of Nicotinylalanine in the treatment of a wide variety of CNS –disorders, however he and his colleagues were unable to procure funding from pharmaceutical companies to start the development and testing of NAL and derivatives for the use in CNS-disorders.

 

 

Points of contentment:

Testing - HOW? Genetic? Biopsy? Plasma-levels?

Cons - what are the risks and the conflicting evidence?

 

 

 

Source references:
-----------------------------

1- Altered tryptophan and alanine transport in fibroblasts from boys with attention-deficit/hyperactivity disorder (ADHD): an in vitro study

http://www.ncbi.nlm....51/?tool=pubmed
 

2- Attention-deficit hyperactivity disorder (ADHD) and glial integrity: S100B, cytokines and kynurenine metabolism - effects of medication

http://www.behaviora.../content/6/1/29

 

3- Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels.

http://www.ncbi.nlm....pubmed/22105622

 

4- Melatonin Effects in Methylphenidate Treated Children with Attention Deficit Hyperactivity Disorder: A Randomized Double Blind Clinical Trial

http://www.ncbi.nlm....les/PMC3428643/

5- Ketogenic diet increases concentrations of kynurenic acid in discrete brain structures of young and adult rats - Springer

http://link.springer...0702-011-0750-2

 
6- Cerebral Synthesis and Release of Kynurenic Acid: An Endogenous Antagonist of Excitatory Amino Acid Receptors

http://www.jneurosci.org/content/10/9/2965.full.pdf

 

7- Kynurenines in CNS disease: regulation by inflammatory cytokines

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915289/

 

8- The ketogenic diet causes a reversible decrease in activity level in

Long-Evans rats.

http://www.ncbi.nlm.nih.gov/pubmed/16750194

 

9- Effect of the ketogenic diet on the activity level of Wistar rats.

http://www.ncbi.nlm....pubmed/15585674

 

10- Ketogenic diet increases concentrations of kynurenic acid in discrete brain structures of young and adult rats

http://link.springer...2/fulltext.html

 

11- Inhibitors of kynurenine hydroxylase and kynureninase increase cerebral formation of kynurenate and have sedative and anticonvulsant activities.

http://www.ncbi.nlm.nih.gov/pubmed/7969905

 

12- Nicotinylalanine increases the formation of kynurenic acid in the brain and antagonizes convulsions.

http://www.ncbi.nlm.nih.gov/pubmed/1431895

 

 

Connections between mGlur receptors and hyper-active NMDA-network:

-------------------------------------------------------------------------------------------

DCG-IV selectively attenuates rapidly triggered NMDA-induced neurotoxicity in cortical neurons.

http://www.ncbi.nlm.nih.gov/pubmed/8713457

 

Metabotropic glutamate receptors negatively coupled to adenylate cyclase inhibit N-methyl-D-aspartate receptor activity and prevent neurotoxicity in mesencephalic neurons in vitro.

http://www.ncbi.nlm.nih.gov/pubmed/7746273

-------------------------------------------------------------------------------------------

The effect of transient increases in kynurenic acid and quinolinic acid levels early in life on behavior in adulthood: Implications for schizophrenia.

http://www.ncbi.nlm.nih.gov/pubmed/24091034

“When rats were subsequently behaviorally tested as adults, those previously treated with kynurenine exhibited decreased social behavior and locomotor activity. In contrast, attentional function and fear conditioning were not affected.”

Possible connection to the proposed positive effects of Metadoxine on attention – pyrrolidone carboxylate in Tryptophan metabolism

Effect of pyrrolidone carboxylate (PCA) and pyridoxine on liver metabolism during chronic ethanol intake in rats.

http://www.ncbi.nlm..../pubmed/7499060

 

 

[jack black]

Finally got to read this. Cool stuff. Will try to research it and digest some more.

[jack black]

I reaserched it more and came across this review: http://journal.front...2014.00012/full

 

It not an easy read, but does't seem to confirm the OP's theory. Or does it?

 

BTW, depression is associated with higher levels. If ADHD (low levels) has comorbid depression, should that take care of ADHD? I don't think so.

Edited by jack black, 08 July 2016 - 03:36 AM.

[jack black]

 

BTW, depression is associated with higher levels. If ADHD (low levels) has comorbid depression, should that take care of ADHD? I don't think so.

 

I reread the paper and I realized I misunderstood the depression part. Kynurenine is increased (and the neurotoxic quinolinic acid), but not kynurenic acid (that is decreased). So, scrap that part.

 

In the meantime, I read this study: http://www.ncbi.nlm....pubmed/26542774

and realized that you are right, even thought the K/T ratio is normal to slightly increased, the kynurenic acid is slightly decreased and even more importantly, the kynurenic acid to quinolinic acid ratio is on a low side.

 

 

This may explain why the NMDA antagonists help some in ADHD.

 

Interesting info on the vitamins (remember my post on B6?) and self-treatment with nicotine.

 

This is in keeping with the first study that you referenced that shows problems with tryptophan transport. The alanine transport connection to autism is very interesting too.

 

Strong work and sorry for the initial skeptical response.

Edited by jack black, 27 July 2016 - 12:08 AM.

[Finn]

Memantine is also D2 agonist, and there seems to be some evidence that D2 agonists might have therapeutic potential for ADHD

 

https://en.wikipedia...8D2_receptor.29

Memantine acts as an agonist at the dopamine D2 receptor with equal or slightly higher affinity than to the NMDA receptors.

 

 

Behind this link links to both open access PMC access version and ScienceDirect version of the article, for those who have access, generally PDF format of ScienceDirect article's is better than PDF format of PMC articles, I think

http://www.ncbi.nlm....pubmed/19840852

D2 dopamine receptor subtype-mediated hyperactivity and amphetamine responses in a model of ADHD.

 

 

There are a limited number of D2-like dopamine receptor agonists available for use in humans including pergolide (Permax), ropinirole (Requip), and pramipexole (Mirapex). None are particularly selective for a specific dopamine receptor subtype (Kvernmo et al., 2008). These drugs are most commonly used in the treatment of Parkinson disease (Foley et al., 2004), but are currently used only in exceptional circumstances to treat ADHD plus comorbid conditions. For example, ropinirole and pergolide improve the symptoms of ADHD in children treated with these agonists for restless leg syndrome (Konofal et al., 2005; Walters et al., 2000). 

 

 

However, in light of the similarities between the mechanism of action of psychostimulants and dopamine agonists, and considering that other non-stimulant medications with similar mechanisms, including tricyclic antidepressants, norepinephrine reuptake inhibitors and adrenergic agonists, are options for managing ADHD, D2 dopamine receptor specific agonists are obvious candidates. It is likely that with the development of compounds with high specificity, side effects will become more manageable, making D2 dopamine receptor agonists a viable option for the treatment of ADHD.

 

 

Ropinirole and pergolide are D2 agonists but not NMDA-antagonists. 

 

Atomoxetine (Strattera) is also NMDA-antagonist, but there is positive evidence for ADHD for pretty much any established psychiatric drug with NRI compotent, atomoxetine's dominance in ADHD treatment compared to other drugs with NRI component is probably due to it being purer NRI than most other drugs with NRI component, and being the first NRI that was pushed for ADHD treatment by a company, though NMDA antagonism could have additional positive effect.

 

http://www.ncbi.nlm....les/PMC2874851/

 

Atomoxetine acts as an NMDA receptor blocker in clinically relevant concentrations

 

I think it yet to be determined whether D2 agonism or NMDA antagonism of memantine contributes more to it's role as ADHD treatment.

 

 

https://en.wikipedia...ptake_inhibitor

 

 

As one can see from the list, most "pure" NRIs have ended up in the graveyard of failed antidepressants. 

 

Reboxetine and atomoxetine are only "pureish" NRIs on the market, probably atomoxetine managed to capture the markets because Eli Lilly was the first company to push a "pureish" NRI as ADHD treatment. Also atomoxetine has SRI compotent, but not so strong that it would increase serotonin levels significantly, just to make it possibly more serotonin neutral than reboxetine. Reboxetine also has SRI component, but since it is so much stronger NRI than SRI, it seems to decrease serotonin levels possibly through increased NE levels affecting a2 receptors and thus decreasing serotonin.

 

http://www.nature.co...l/1395936a.html

http://www.nature.co...ml#figure-title

http://www.nature.co...ml#figure-title

 

Apparently because of the SRI component, someone removed atomoxetine in May 2016 from wikipedia's pure NRI list but, didn't add it to "NRIs with activity at other sites" list, even if you think it is not pure enough, it is kinda strange not to add it to the other list, any established wiki-editers here who want to suggest correction of adding it at least to the other list?

Edited by Finn, 27 July 2016 - 08:36 AM.

[Mind_Paralysis]

 

 

BTW, depression is associated with higher levels. If ADHD (low levels) has comorbid depression, should that take care of ADHD? I don't think so.

 

I reread the paper and I realized I misunderstood the depression part. Kynurenine is increased (and the neurotoxic quinolinic acid), but not kynurenic acid (that is decreased). So, scrap that part.

 

In the meantime, I read this study: http://www.ncbi.nlm....pubmed/26542774

and realized that you are right, even thought the K/T ratio is normal to slightly increased, the kynurenic acid is slightly decreased and even more importantly, the kynurenic acid to quinolinic acid ratio is on a low side.

 

 

This may explain why the NMDA antagonists help some in ADHD.

 

Interesting info on the vitamins (remember my post on B6?) and self-treatment with nicotine.

 

This is in keeping with the first study that you referenced that shows problems with tryptophan transport. The alanine transport connection to autism is very interesting too.

 

Strong work and sorry for the initial skeptical response.

 

 

No need to apologize, scepticism is the basis of all scientific discovery! = )

I must admit that in my burnt-out state I didn't quite understand your last post - while trying to understand your point I got stuck in a kind of action-loop, hence no reply.

EXCELLENT that you brought out the charts! I've been looking for those, actually - so cheers for postin'!

 

 

@Finn:
You bring up some excellent points, and I shall try to adress them fully, either debunking or adding them to the conflicting-evidence section: i.e that my observations may have some faults.

But for now, I shall have to clean my appartment! = ) I'm moving, and the landlord demands results.

[jack black]

while reading about DL Phenylalanine I came accross this interesting tidbit from:

 

http://www.drugbank....DB02556#targets

 

 

Targets:

Kynurenine--oxoglutarate transaminase 1

Catalyzes the irreversible transamination of the L-tryptophan metabolite L-kynurenine to form kynurenic acid (KA).

 

Is this what I think it is? DL Phenylalanine can increase kynurenic acid? It certainly feels like a miracle drug while I'm on it.

Edited by jack black, 04 August 2016 - 11:25 PM.

[sativa]

Regarding kynurenic acid, and ways of alrering its formation/break down see this thread:

www.longecity.org/forum/topic/61506-a-greatly-overlooked-factor-for-cognitionclarity-kynurenic-acid-glycinesarcosine-users-read/

Regarding memantine, its also a strong alpha 7 nicotinic antagonist, which will initially hamper cognition but when alpha 7 upregulates, cognition will improve. This will likely perhaps be different depending on ones brain chemistry.

[jack black]

Regarding kynurenic acid, and ways of alrering its formation/break down see this thread:

www.longecity.org/forum/topic/61506-a-greatly-overlooked-factor-for-cognitionclarity-kynurenic-acid-glycinesarcosine-users-read/
 

 

Thanks for the link. I scanned that discussion it was mostly how to decrease and not increase KYNA (correct me if I'm wrong). Besides, The OP merely copied some entries from Wiki and threw in his own take that seems off target:

 

 

KYNA does have a very important purpose. It inhibits the convulsive and excitotoxic effects of too much glutamate transmission. However its metabolites like quinolinic acid cause brain fog in the body.

 

One has to keep in mind that quinolinic acid is not a KYNA metabolite, but an alternative metabolic chain. Same with kynurenine, it's not the same thing as KYNA and has a different action on excitotoxity. But it's an easy mistake to make, as I made it myself at the beginning of this thread (so don't feel too bad). The paper I linked at the beginning of this thread is actually very informative about complexities of KYNA metabolism (except for the ADHD part), but I had to read it twice for that to stick.

Edited by jack black, 05 August 2016 - 03:57 PM.