Quercetin is an iron chelator, is bioavailable and crosses the blood-brain barrier

l

Quercetin is a very effective iron chelator. Supplemental quercetin is bioavailable increasing blood levels dose-dependently. Quercetin also crosses the blood-brain barrier. Quercetin is being investigated for use in the treatment of Parkinson’s disease.

If iron chelators work in Parkinson’s there should be some positive effect with supplemental quercetin. I very much doubt there will be. See the page on Parkinson’s disease. If quercetin does not work in the treatment of Parkinson’s disease then the narrative that treatment of Parkinson’s disease requires iron chelation has to be re-thought. I would avoid supplementing with quercetin until there are definite clinical studies to the effect that quercetin in the real world ameliorates symptoms of Parkinson’s disease which I think will be never.

Quercetin is found in fruits and vegetables. Querectin found in foods could have benefcial effects. Like other antioxidants, when obtained from food, quercetin could have beneficial effects.

Morning coffee

l

Many studies report coffee as having beneficial effects and a couple of cups of coffee drink only in the morning could have beneficial effects. A meta-analysis indicates that there is at inverse relationship between coffee/caffeine and risk of Parkinson’s disease. A weakness of the forgoing meta-analysis is that the meta-anaylsis focuses on caffeine. Studied indivduals, however, were drinking coffee with is much different than taking caffeine pills. A meta-analysis indicates that moderate coffee intakes is associated with decreased cardiovascular risks. There are, however, increased risks for schizophrenia where there is heavy use of coffee. Where there is heavy use of coffee, coffee most likely is not drunk only in mornings.

Difficulties with coffee can arise given coffee is drunk throughout the day. Coffee inhibits iron absorption in a concentration-dependent fashion. Polyphenols in coffee inhibit iron absorption. A couple of cups of coffee drunk only in the morning would have minimal effects on iron metabolism. Coffee drunk throughout the day could have very adverse effects on iron metabolism.

Iron chelators and Parkinson’s disease – always full of promise

A search for “iron chelation” and “Parkinson’s” pulls up 460 cites in PubMed. Given iron chelators worked in Parkinson’s disease that would be outstanding. Iron chelation in Parkinson’s disease, however, always seems to be full of promise but there have been no payoffs in terms of treatment. There are many, many ways available to chelate iron. Quercetin is for example a quite effective iron chelator. Polyphenols are quite effective iron chelators. Deferiprone, which an iron chelator, has been tried in Parkinson’s disease. Deferirone is not significantly effective in the treatment of Parkinson’s disease.

Why haven’t iron chelators worked by now in Parkinson’s disease? Perhaps because iron chelators can’t work in Parkinson’s disease. There could be difficulties with iron in Parkinson’s disease but those difficulties could be due dysregulations of iron metabolism rather than due to iron being toxic per se.

Parkinson’s disease, alpha-synuclein and iron

Alpha-synuclein aggregates are present in Parkinson’s disease. mRNAs of alpha-synuclein have iron-responsive elements in 5′ untranslated regions. Iron-responsive elements in mRNAs of iron regulated proteins bind iron regulatory proteins (IRP1 and IRP2) affecting stabililites of transcripts of iron regulated proteins. Iron levels can affect alpha-synuclein levels, however, apparently there is an asymmetry as to how iron affects alpha-synuclein levels. Iron chelators decrease alpha-synuclein levels though added iron does not increase alpha-synuclein levels. With alpha-synuclein homeostasis dysregulated via a dysregulated iron metabolism, rather than via high levels of alpha-synuclein per se, alpha-synuclein aggregates could form.

I wrote a paper on Parkinson’s disease, which addresses iron dysregulation in Parkinson’s disease, that was published in the International Journal of Neuroscience. The title of the paper is A novel treatment strategy to prevent Parkinson’s disease: focus on iron regulatory protein 1 (IRP1)

Iron and α-synuclein in Parkinson’s disease

synuclein protein in Parkinson’s disease

Alpha synuclein mRNA has an iron responive element in the 5′ untranlated region. Iron responive elements in the 5′ untranlated region of mRNA when bound by iron responsive protein 1 (IRP1) or iron responive protein 2 (IRP2) destabilize transcripts of iron-regulated proteins. Increasing iron levels would decrease levels of IRP1 and IRP2 and increase levels of alpha synuclein which is held to be very bad.

Alpha synuclein can act as a ferrireductase reducing iron 3+ to iron 2+. Overexpressing human α-synuclein in nigral dopaminergic neurons demonstrated a correlation between α-synuclein expression and ferrireductase activity, however, in Parkinson’s patients there is a reduction of ferrireductase activity in brains.

What if the key fact about alpha synuclein in Parkinson’s patients is alpha synuclein aggregates form only after decreases in ferrireductase activity in Parkinson’s patients. High, constant but normal iron levels where iron levels are tightly regulated throughout the day could keep ferrireductase activity constant throughout the day preventing alpha synuclein aggregates from forming.

Supplemental iron from iron carbonyl could keep iron levels constant keeping ferrireductase activity of alpha synuclein constant preventing alpha synuclein aggregates from forming. There is no significant differences in serum iron levels between controls and Parkinson’s patients. There are serious difficulties with iron in PD patients but these difficulties could stem from a loss of iron homeostasis which could be re-regulated by iron from iron carbonyl given three times a day.

This idea would, of course, have to be tested in rats before being tested in humans

Supplementing with free antioxidants in more than RDA amounts is worse than useless

Many illnesses, such as schizophrenia, Alzheimer’s disease, Parkinson’s disease and bipolar disorder are associated with oxidant stress. Yet, increasing levels of free antioxidants by supplementing with more than RDA amounts of vitamin E, beta-carotene and vitamin C does not treat these illnesses.

Increasing levels of free antioxidants via supplmentation could be much worse than useless. Before iron can be absorbed iron must be reduced from Fe3+ to Fe2+. Antioxidants like vitamin C, vitamin E , beta-carotene and quercetin could one way or other promote the reduction of Fe3+ to Fe2+ in the gastrointestinal tract which would increase absorption. The goal, however, is to delay iron absorption as long as feasible.

There is oxidant stress in lots of illnesses but this could be due to dysregulation of selenoproteins and dysregulation of iron metabolism which would not be fixed by increasing levels of free antioxidants with supplemental vitamin C, vitamin E , beta-carotene, quercetin etc.

Supplementing with free antioxidants could be associated with very subtle but serious mineral dysregulations which would basically be undiagnosable.

Deficiencies in vitamin D in schizophrenia, bipolar disorder, Alzheimer’s disease and Parkinson’s disease

Low levels of vitamin D are associated with schizophrenia, bipolar disorder Alzheimer’s disease and Parkinson’s disease. Vitamin D is a fat soluble vitamin. Bile acids are required for fat absorption. Taurocholic acid is a bile acid that is a conjugate of cholic acid with taurine. Taurochenodeoxycholic acid is a bile acid formed in the liver by conjugation of chenodeoxycholic acid with taurine. Taurine increases absorption of vitamin D.

There are low levels of vitamin D in schizophrenia, bipolar disorder, Alzheimer’s disease and Parkinson’s disease due to dysregulation of taurine synthesis in these illnesses attendant on dysregulation of the transsulfuration pathway which synthesizes L-cysteine from which taurine is synthesized.

Supplementation with vitamin D in these illnesses heretofore has not helped much as difficulties in fat absorption have not been addressed. Taurine, which regulates calcium homeostasis besides aiding in fat absorption, taurine would be taken with vitamin D, vitamin K and calcium carbonate to address low levels of vitamin D where there are chronic illnesses. Vitamin K is also a fat soluble vitamin whose abosoprtion could be impaired by low levels of taurine.

Polyphenols, homocysteine, Parkinson’s disease and Alzheimer’s disease

High homocysteine levels indicate the transsulfuration pathway (homocysteine to L-cysteine) is dysregulated. Taurine is synthesized from L-cysteine. Taurine is needed to form various bile acids. Bile acids are needed for fat absorption.

Polyphenols can increase beta-oxidation which can lead to serious difficulties if there are difficulties in fat absorption which are likely if there are high homocysteine levels.

Many illnesses for which polyphenols have been postulated to be treatments are associated with high levels of homocysteine, however, where there are high homocysteine levels there could be difficulties in fatty acid absorption. Increasing levels of polyphenols, which increase beta-oxidation, would be contradicted where there are difficulties in fatty acid absorption and metabolism.

Polyphenol supplements are frequently suggested as treatments for Alzheimer’s disease and Parkinson’s disease, however, both Alzheimer’s disease and Parkinson’s disease are associated with high homocyteine levels whereby there could be difficulties in fatty acid absoption. Polyphenol supplements could worsen Alzheimer’s disease and Parkinson’s disease. In the treatment of Alzheimer’s disease polyphenols have been full of promise but have failed to deliver effective treatments.

Caffeine pills have nowhere near the same effect as coffee. There must be more to the effects of coffee than caffeine and that something more is the polyphenol contents of coffee and the effect of those polyphenols on beta-oxidation.

Inflammation, taurine and essential fatty acids in schizophrenia, Parkinson’s disease and Alzheimer’s disease

Inflammation is associated with schizophrenia, Parkinson’s disease and Alzheimer’s disease. A point I have strongly stressed is that the transsulfuration pathway is dysregulated in many neurological illnesses. With the transsulfuration pathway dysregulated there will de decreased levels of L-cysteine which is synthesized via the transsulfuration pathway. Decreased levels of l-cysteine will lead to decreased levels of taurine. Taurine is synthesized from L-cysteine. The bile acid, taurocholate, is synthesized from taurine. With low levels of taurine, essential fatty acids are not absorbed sufficiently. Inflammation in schizophrenia, Parkinson’s disease and Alsheimer’s disease could be due to low levels of taurine which leads to failures to absorb sufficient fatty acids with inflammation resulting.

Taurine chloramine which is synthesized from taurine is also an important immunomodulatory.

Adverse affects from polyphenol extracts could appear to be various mysterious allergies or hypersensitivities

Polyphenol extracts are everywhere. Natural flavors are polyphenol extracts. Sodas contain polyphenols from natural flavors. Various plant oils contain concentrated polyphenols. Various supplements are marketed on the very basis that such supplements contain polyphenols, for example quercetin, pycnogenol and resveratrol. Coffee and tea contain polyphenols. Almost all frozen foods will contain natural flavors. Polyphenol extracts are a major difficulty.

This is starting to sound about as bad as ‘electromagnetic hypersensitivity’ in terms of being able to escape the difficulty. Cases of ‘electromagnetic hypersensitivity’ could in fact be adverse reactions to polyphenol extracts and concentrated polyphenols.

Adverse reactions to polyphenols are not immune responses. A difficulty with polyphenols is that polyphenols bind to iron. Polyphenols binding to iron in the gut could lead to inactivation of aconitase 1 in the gut which could have systematic effects.

I have been very strongly stressing the effect of polyphenols on iron absorption, however, there are likely other difficulties with polyphenols for individuals. Polyphenols increase beta-oxidation. If the there are difficulties in fatty acid absorption and fatty acid metabolism increases in beta-oxidation due to polyphenols can not be sustained with difficulties then arising. Even with no difficulties in fatty acid absorption and fatty acid metabolism polyphenol laden drinks should not be drunk throughout the day. Limiting coffee to two cups of coffee drunk in the morning away from iron supplements could be a safe way to drink coffee.