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.
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 relationshipbetween 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. Coffeeinhibits 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.
A search for “iron chelation” and “Parkinson’s” pulls up 460 cites inPubMed. 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.
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.
Friedreich’s ataxia is a genetic disease, where there are expansions of GAA trinucleotide repeats in intron 1 of both frataxin alleles. Gait and limb ataxia, dysarthria and loss of lower limb reflexes are clinical features Friedrich’s ataxia.
Mice models of Friedreich’s ataxia have been developed in which the gene for frataxin in is mutated, where the mice exhibit a progressive Friedreich’s ataxia-like pathology. Frataxin binds ironwhich assists in iron-sulfur cluster biogenesis.
Giving mice, with ataxia due to mutations in genes for frataxin, iron from iron carbonyl by gavage three times a day could be a treatment for such an ataxia as iron carbonyl given by gavage three times a day could tightly regulate iron utilization, making iron constantly available thereby making the frataxin protein less required or even redundant. As the iron chelator, desferal decreases expressiot of frataxin, carbonyl iron given by gavage three times a day to mice could also increase expression of the gene for frataxin.
As deferiprone, an iron chelator, can worsen ataxia in patients with Friedreich’s ataxia iron carbonyl given three times a day to humans could be part of a treatment for Friedreich’s ataxia. Prior to any clinical trials in humans, carbonyl iron, given by gavage three times a day from birth to mice with mutated frataxin genes, would have to stop a Friedreich’s ataxia-like pathology from developing and/or treat in mice, a Friedreich’s ataxia-like pathology after mice with mutated frataxin genes develope a Friedreich’s ataxia-like pathology.
Iron increases glutamate secretion by increasing cytosolic aconitase activity. The synthesis of isocitrate by cytosolic aconitase is the the first step in a three step synthesis of glutamate. Glutamate, arising from increases in cytosolic aconitase due to increases in iron, is secreted via the cystine/glutamate antiporter where at the same time cystine is imported into cells increasing glutathione levels in cells.
With iron supplementation in schizophrenia via iron carbonyl taken three times a day there could be increased glutamatergic neurotransmission via increases is secreted glutamate where at the same time there would be increases in cystine in cells and thereby increases in glutathione levels in cells. Supplementation with iron from iron carbonyl could be part the treatment of schizophrenia.
Amyloid precursor protein (APP) mRNA has an iron response element (IRE) in the 5′ untranslated region. Iron regulatory 1 (IRP1) and and iron regulatory protein 2 (IRP2) when bound to the IRE in the 5′ untranslated regiondestablize transcripts of iron regulated proteins. IRP1 and IPR2 when bound to the IRE in amyloid precursor protein mRNA decrease translation of APP. Iron decreases levels of IRP1 and IRP2. A point of iron chelators in Alzhemeir’s disease is by decreasing iron levels to increase levels of IRP1 and IRP2 thereby decreasing transcripition of APP.
APP is the precusor of amybloid beta protein. Amyloid betacan form plaques which are associated with Alzheimer’s disease. Iron chelators by decreasing APP levels would decrease levels of amyloid beta protein which was thought for decades to be a very good thing. Very effective treatments for Alzheimer’s appeared imminent.
A very serious difficulty arose. Drugs that reduce levels of amyloid beta do not treat or slow the progression of Alzheimer’s disease.
APP can looked at from a different angle. Amyloid precursor protein when ablatedincreases iron retention in cells by decreasing iron export. Loss of tight control of APP translation not high levels of APP could be what is causing iron retention in neurons.
What I have been arguing is that IRP1 is dysregulated in a range of neurological illnesses, such as Alzheimer’s and that this can lead to iron accumulation in neurons and cell death. Tight control of iron levels, not reducing iron levels via iron chelation, could be part of a treatment for various neurological illnessse such as Alzheimer’s disease.
A meta-analysis indicate that serum iron is significantly lower in Alzheimer’s patients than in controls. Supplmental iron carbonyl given three time a day could be part of a treatment for Alzheimer’s disease. The goal, of course, would not be high iron levels but rather tightly regulated levels of IRP1 and IRP2. Iron homeostasis could be upset in Alzheimer’s disease which is a much different way of loooking at iron than ‘iron is toxic’ in Alzheimer’s disease.
Alpha synuclein mRNAhas an iron responive element in the 5′ untranlated region. Iron responive elementsin 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 patientsthere 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 differencesin 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
Iron deficiency may alter dopaminergic transmission in the brain. This study investigated whether iron metabolism is associated with negative symptoms in patients with first-episode psychosis. The study enrolled 121 patients with first-episode schizophrenia spectrum disorder, whose duration of treatment was 2 months or less. Negative symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) and Clinician-Rated Dimensions of Psychosis Symptom Severity (Dimensional) scale of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Prominent negative symptoms were defined as moderate or severe negative symptoms on the Dimensional scale of the DSM-5. Iron deficiency was defined as a serum ferritin ≤ 20 ng/mL. Patients with iron deficiency were significantly more likely to have prominent negative symptoms (45.2 vs. 22.2%; p = 0.014) and a higher PANSS negative symptoms score (p = 0.046) than those with normal ferritin levels. Patients with prominent negative symptoms had significantly lower ferritin levels (p = 0.025). The significance of these results remained after controlling for the duration of illness and other confounding variables. Our finding of an independent association between iron deficiency and negative symptoms in patients at the very early stage of illness implies that iron dysregulation has an effect on negative symptoms in patients with schizophrenia. The possibility of therapeutic intervention with iron should be further investigated.
I have been argunig in this blog that there are high IRP1 levels in schizophrenia due to difficulties in iron-sulfur cluster formation whereby cytosolic aconitase switches to IRP1. As ferritin mRNA has an iron response element in the 5′ untranslated region high levels of IRP1 will decrease ferritin levels.
Iron overload in various regions of the brain has been postulated to be involved in the pathological mechanism of Alzheimer’s disease. Iron overload in the brain may very well be involved in the etiology of Alzheimer’s disease but iron overload in the brain in Alzheimer’s disease would not be due to too much iron in the diet.
A meta-analysis indicates that serum iron levels are significantly lower in Alzheimer’s disease patients than in healthy controls. Another meta-analysis also indicates that serum iron is significantly lower in patients with Alzheimer’s disease than in healthy controls.
Loss of control over iron metabolism rather that just ‘too much iron’ could be why iron can have negative effects in Alzheimer’s disease. Treatment in AD would demand that control be regained over iron metabolism. Iron chelators have been proposed as a treatment for Alzheimer’s disease. Iron chelators, however, would not be useful in terms of regaining control over iron metabolism. Iron chelators could have negative effects in AD.