Depression: the molecular aspects of oxidative/nitrosative stress/tryptophan catabolites

[nanonug]

https://www.ncbi.nlm.nih.gov/pubmed/28951145

Abstract
Depression is the most common mental disorder in the world. It is estimated that 350 million people suffer from depression worldwide. Depressive disorders will have become the second most frequent health problem globally by the year 2020, just behind ischemic heart disease. The causes of depressive disorders are not fully known. Previous studies showed that impaired tryptophan catabolites pathway, oxidative and nitrosative stress may play an important role in the pathogenesis of depression. Patients with depression have lower plasma levels of superoxide dismutase and glutathione peroxidise in comparison to controls. Moreover, depressed patients are characterized by decreased plasma levels of zinc, coenzyme Q10, albumin, uric acid, vitamin E and glutathione. Abnormal nitric oxidative production and nitric oxide synthase activity are also associated with depression. A dysfunction of the tryptophan catabolites pathway, indicated by increased levels of tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase, is also involved in the development of depression. Furthermore, increased levels of kynurenine and quinolinic acid might cause depression. Moreover, studies to date indicate that 8-oxyguanine, malondialdehyde, and 8-iso-prostaglandin F2α may serve as possible biomarkers. Additionally, regulation of defective mechanisms may provide a promising direction for the development of new and effective therapies.

 

[Wishful]

No surprise to me. My personal observations convinced me that the TRP-IDO pathway was involved with my suicidal moods; quinolinic acid in particular. Other research shows a link between QUIN and suicidal moods.

 

[NotThisGuy]

No surprise to me. My personal observations convinced me that the TRP-IDO pathway was involved with my suicidal moods; quinolinic acid in particular. Other research shows a link between QUIN and suicidal moods.

what did you do against that?

 

[Wishful]

I minimized my intake of tryptophan and niacin, and the suicidal moods stopped sometime after that. I don't think that niacin was causing the suicidal moods. I think that the lack of dietary niacin was forcing my cells to produce more of the enzyme that converts QUIN to niacin, so adding dietary niacin would make them produce less of that enzyme, meaning higher levels of QUIN staying around causing trouble. Avoiding dietary TRP simply reduced the amount that could be converted to QUIN.

Another posting I read today, with a link ( https://www.healthrising.org/blog/2018/04/03/a-metabolic-trap-for-chronic-fatigue-syndrome-me-cfs/ ) to new findings about a 'metabolic trap', mentions problems with TRP to NAD (with QUIN and niacin as intermediate metablolites) metabolism. That agrees with my hypothesis of ME/CFS...which of course, doesn't mean much given that I'm not a biologist, but it still makes me happy.

 

[NotThisGuy]

@Wishful Wait im confused.
Did you reduced niacin now or did your increased it?

 

[Wishful]

Reduced my intake of it. Something like breakfast cereal, which is really high in niacin, would make my symptoms worse and possibly cause suicidal moods.

The body produces niacin from TRP, with QUIN as one intermediate step. If ME/CFS causes elevated QUIN, then avoiding niacin in your diet should help convert excess QUIN to niacin, reducing the availability of QUIN to cause symptoms (it's a NMDA receptor agonist).

From the wiki page on quinolinic acid: Within the brain, quinolinic acid is only produced by activated microglia and macrophages. That fits with ME/CFS My guess is that at least some of the suicidal moods--and maybe depression--that ME/CFS victims suffer, is due to QUIN. I thought I was suicidal because of how ill I felt and how there didn't seem to be any hope for improvement. I was surprised to find that it was instead just a simple biochemical imbalance. We do need QUIN, but only the right amount.

 

[NotThisGuy]

@Wishful
yeah thats the confusing part.
you didn't actually do anything to slow down the IDO or TDO pathway.
It is upregulated with stuff like TNF-a and IFN-y, blood sugar problems etc.
And I think the meaning behind this is to produce NAD+.
Avoiding tryptophan seems like a terrible idea in the long run if this pathway was the problem. That would mean that either a) your body cant produce NAD+ anymore and therefore cells would die or b) your body takes the tryptophan from somewhere else in your body. Especially b) would mean an increase in depression since you wouldn't produce enough serotonine anymore, because the IDO and TDO enzymes are still upregulated. ok, maybe the low serotonine depression doesn't feel like the NMDA depression and the later one is your greater problem.

I mean dont get me wrong, Im very glad you found something that helped. But to be honest it doesnt sound like an upregulated kynurenine pathway was the cause for your suicidal thoughts in the first place.

Did you actually do some lab work for the metabolites 5-HIAA, Quinolinic and Kynurenic?

 

[Wishful]

I couldn't find any way to modify the IDO pathway. I'd like to try 1-methyltryptophan or 7-chlorokynurenine, just to see what happens, but neither are available for home experiments.

My TDO pathway doesn't seem to be involved. Taking 5-HTP didn't have an effect, nor did serotonin reuptake modifiers. Despite trying to avoid dietary TRP for months (maybe years), I never managed to notice any effect from deficiency. The body must have a huge storage capacity for TRP, and I was obviously getting adequate NAD+ from somewhere. Also, I never really considered myself to be depressed in the clinical sense. Chemically-driven suicidal, yes, but not clinically depressed.

I did manage to get a blood test for KYN/TRP ratio, expecting it to be high. It turned out to be lower than normal. Researching deeper into that showed that kynurenines don't cross the BBB very well, so the test wasn't meaningful for measuring cerebral KYN/TRP ratio. Getting the test done on CSF was too unlikely to bother even trying.

A blood cytokine profile did show elevated MIPS-1 alpha and beta. While that doesn't prove that picolinic acid was elevated, it is what would be expected from elevated picolinic acid, and would also explain my chronic mildly elevated Tsh. What the serum level means in terms of cerebral levels in unknown to me.

My physical exertion triggered PEM has a consistent 24 hr delay. IFN-g also increases significantly 24 hrs after physical exertion. Given my responses to TRP, I assumed that IFN-g elevated IDO was responsible for my feeling worse 24 hrs after activity. This was before I knew about ME/CFS or PEM. Now I guess that IFN-g might be an important factor in PEM.

My suicidal moods very definitely strongly correlated with extra TRP or niacin, so I remain convinced that the TRP-IDO pathway was involved. The fact that my other symptoms still increase with a rise in TRP transport across the BBB adds to that conviction. I haven't encountered anything to counter that hypothesis, or any alternative hypotheses for the suicidal moods that makes any sense for me.

I haven't tried large doses of TRP or niacin for years, for the very sensible reason that experimenting with suicide-inducing chemicals is just not sensible.