Iron And Copper - Causal Or A Result?
Some researchers are looking at iron and copper as possible causal factors in Parkinson's. But limiting the ingestion of iron and copper from whole foods likely does little to alter iron or copper "behaving badly" in the brains of healthy people.
Similarly, the trace amounts found in a natural, whole plant foods diet are not something that can or should be avoided by people even with neurological diseases! Indeed, Nature has put iron and copper in trace amounts in food for a purpose. In fact, the brain is naturally rich in iron. It is reported that iron
deficiency is the most prevalent nutritional problem in the world today, with up to 5 billion people affected.141
However, taking iron supplements is a different story. Studies have shown an almost two-fold increase in Parkinson's patient who took daily iron supplements.142 With what we now know about mitochondrial damage, the iron supplements did not cause Parkinson's, of course, but can play a key role in the progression of the disease once in progress. This would be akin to the fact that systems are damaged to handle the body's natural manufacture and handling of glutamate. Consuming free glutamates in the diet also play a key role in the progression of the disease.
Undeniably, iron overload is seen in many neurological diseases, including Parkinson's. Excess iron has been associated with brain lesions, also seen in neurological diseases. In addition, the excess iron has been associated with the toxicity of mercury and other metals in the brain.143 Parkinson's disease, in fact, is
141 John Beard. Iron Deficiency Alters Brain Development and Functioning. The Journal of Nutrition. 2003 Supplement.
142 KM Powers et al. Parkinson's disease risks associated with dietary iron, manganese and other nutrient intakes. Neurology (2003) 60:1761-1766.
143 Miyasaki K et al. Hemochromatosis associated with brain lesions - a disorder of trace metal-binding proteins and/or polymers? J Neuropathol Exp Neurol. 1977 Nov;36(6):964-976.
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characterized by specific brain lesions (areas of damage) found in substantia nigra and other subcortical nuclei, namely Lewy bodies, made up of aggregates of alpha-synuclein. a-synuclein functions, in part, to regulate dopamine transporter
activities.
Recently, researchers have found that where there is accumulation of a-synuclein, there is a decrease in Complex I activity in the mitochondria in Parkinson's disease brains.144
In a 1986 study "Iron, A New Aid in the Treatment of Parkinson Patients"
Birkmayer and Birkmayer state: "Intravenously applied iron - in form of a ferri-ferro-complex exhibited a considerable benefit for all (Parkinson's) patients treated so far. They regained a remarkable mobility". 145 This would suggest, of course, that iron is actually deficient because of a damaged mitochondria's inability to
"traffic" it properly.
Of course metal ions do participate in oxidative stress seen in Parkinson's and other neurodegenerative diseases. In fact, metal ion chelators have shown therapeutic value in ameliorating oxidative stress. The safest chelators, however, appear to be dietary chelators which have been shown to negate and even reverse the role of metal ions in oxidative stress.146 These dietary chelators are included in the supplements and diet sections.
Indeed, the mitochondria is a "trafficker" of iron, or as some have put it, the mitochondria is not just about energy transduction, but it is also a focal point of iron metabolism.147 When the mitochondria is damaged, iron would be trafficked improperly, would elevate where it normally does not belong, and would
144 Devi et al. Mitochondrial import and accumulation of a-synuclein impair complex I in human
dopaminergic neuronal cultures and Parkinson disease brain. Journal of Biological Chemistry, 283, 9089-9100. 2008.
145 Birkmayer and Birkmayer. Iron, a New Aid in the Treatment of Parkinson Patients. J Neural Transm (1986) 67: 287-292
146 Theresa Hague et al. Dietary chelators as antioxidant enzyme mimetics: implications for dietary intervention in neurodegenerative diseases. Behavioural Pharmacology (2006) 17:425-430.
147 Richardson DR et al. Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol. Proc Natl Acad Sci USA. 2010 Jun 15;107(24):10775-82.
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participate in oxidative reactions. Here again we can see that it is the underlying problem of mitochondrial damage leading to excess iron that needs to be
addressed.
Frataxin is a protein that in humans is encoded by the FXN gene. Frataxin is found in the mitochondrion. When frataxin homologue YFH1 is missing in yeast strains, there is an accumulation of iron in the mitochondria which then damages the mitochondria. 148
When frataxin is mutated, there is iron overload. In deficiency of frataxin/YFH1, researchers have identified 14 proteins which are selectively oxidized as well as decreased superoxide dismutase activity, which promotes protein oxidative damage as seen in neurological diseases. The addition of copper and manganese to the culture medium restored SOD activity, preventing both oxidative damage and inactivation of magnesium-binding proteins. Recovery of mitochondrial enzymes required the addition of manganese, and cytosolic enzymes were recovered by adding copper. It is the reduced SOD activity that contributes to the toxic effects of iron accumulation.149
In a 2009 study from the University of Washington, researchers report on the mutations and deletions in the mitochondrial genome saying the losses in stability correlate with a reduction in the mitochondrial membrane potential. They state that analysis of cells undergoing this instability showed a defect in iron-sulfur cluster biogenesis, which requires normal mitochondrial function.150 This is certainly not the only study to find that defects in the biogenesis of iron-sulfur clusters arise as a consequence of mitochondrial dysfunction, and that this increases genetic instability.
148 Francoise Foury and Driss Talibi. Mitochondrial Control of Iron Homeostasis - A Genome Wide Analysis of Gene Expression Yeast Frataxin-Deficient Strain. JBC Papers December 8, 2000.
149 Irazusta V et al. Yeast frataxin mutants display decreased superoxide dismutase activity crucial to promote protein oxidative damage. Free Radic Biol Med 2010 Feb 1;48(3):411-420.
150 Veatch JR et al. Mitochondrial dysfunction leads to nuclear genome instability via an iron-sulfur cluster defect. Cell 2009 Jun 26;137(7):1247-58.
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A 2010 study was done to determine the mechanisms of iron exit from the "ferritin cage" in the mitochondria. Ferritin is a protein found inside of cells that stores iron and releases it as needed. The researchers describe how twenty-four subunits of ferritin combine to form a circular protein cage around up to 4,500 atoms of iron.
They say that there are two models with regard to how iron exits the ferritin cage, and is reutilized. The first model has to do with the lysosomes degrading the
protein ring causing iron to exit, and the second model has to do with "pores" at the junctures where the ferritin proteins join to create the ring, and iron being released through those pores. The study says that some of the fundamental functions of iron protein are still unclear. They say "...it is not known how cytosolic ferritin is
degraded, how stored iron is released." They do point to increased protein degradation, and that blocking protein degradation prevented iron mobilization from cytosolic ferritins. With regard to excess iron being released, we know that mercury degrades proteins. Nowhere in the study is mercury mentioned, however.
With regard to a normal biological amount of iron being released, it appears lysosomes may very well do the job of controlled protein degradation in order for the iron to release.151
So it isn't that iron is a toxin like mercury to be avoided or eliminated at all costs.
It is that damaged mitochondria leads to a "misdistribution" of iron. A 2010 study sums it up: "Iron concentrations can rise to toxic levels in mitochondria of
excitable cells". They say "iron chelation is probably inappropriate for
disorders associated with misdistribution of iron within selected tissues or cells."152 Iron would most definitely appear to be a result of Parkinson's, not a cause.
Not Simply A Dopamine Deficiency
Earlier I said that Parkinson's is no longer best defined as simply a dopamine
"deficiency". A damaged mitochondria results in toxic elements that cause
151 Yinghui Zhang et al. Lysosomal Proteolysis Is the Primary Degradation Pathway for Cytosolic Ferritin and Cytosolic Ferritin Degradation Is Necessary for Iron Exit. Antioxidant & Redox Signaling (2010) Vol 13, No 7. 999-1009.
152 Kakhlon O et al. Iron redistribution as a therapeutic strategy for treating diseases of localized iron accumulation. Can J Physiol Pharmacol. 2010 Mar;88(3):187-96.
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dopaminergic neurons to die. Because most doctors don't seem to know that
Parkinson's is not just a "dopamine deficiency" the patient goes to neurologist and gets a prescription for L-dopa/Carbidopa and little more. The doctor doesn't even mention the mitochondria, doesn't ask about the patient's history with mercury, pesticides or glutamates, or any other toxin for that matter, and may even give the patient a flu shot containing mercury on their way out.
In a 2009 "Neurological Review" Drs Lim, Fox and Lang state: "...it has become increasingly apparent that the neuropathologic changes of PD extend well beyond the nigrostriatal system. Even components of the early core motor symptoms may not be exclusively related to nigrostriatal dopamine deficiency." They go on to say that "most of the disability brought on by advancing PD relates to the emergence of symptoms that responds poorly, if at all, to levodopa or modern surgical therapies."
In fact, they say, "Increasing evidence suggests that in most cases the first neurons affected in PD are nondopaminergic.153
Taking L-dopa advances the progression of Parkinson's at a much faster pace than not taking L-dopa . This has lead researchers to believe L-dopa is the problem. Of course some L-dopa becomes dopamine and seems to alleviate symptoms, but the rest oxidizes, and this is because the underlying disease process (damaged
mitochondria) is still raging.
The Parkinson's Brain Is Toxic To Dopamine
153 Shen-Yang Lim, et al Overview of the Extranigral Aspects of Parkinson's Disease Arch Neurol Vol. 66 (No.2) Feb 2009 Pg 167-172.
"...a thorough understanding of the role of anti-Parkinson medications, such as L-dopa, dopamine (DA) agonists, catechol-O-methyltransferase (COMT) inhibitors, and monoamine oxidase (MAO) inhibitors, is needed. As health care providers become more proficient in the use of these drugs, the prevalence of late complications, or highly advanced PD, is increasing. Before the development of L-dopa, 30% of patients were described as having severe disease, but with the genesis of successful anti-PD therapies, severe disability if reported in 53% of Parkinson's patients 4 years after the diagnosis."
[Mark Stacy, MD. Managing Late Complications of Parkinson's Disease. Parkinson's Disease And Parkinsonian Syndromes. Vol. 83, No. 2. March 1999.]
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Prior to 1960 doctors didn't even know that Parkinson's had anything to do with dopamine. It was Ehringer and Hornykiewicz who described Parkinson's disease as a "dopamine deficiency" disease154, and patients were given the first dose of
Levodopa (L-dopa) in 1961.155 While drugs to increase dopamine production or block its oxidation are also often prescribed, L-dopa is the drug against which all other drugs are compared, said to be the most effective dopaminergic treatment for Parkinson's aka The Gold Standard.
But why L-dopa? Why not give dopamine? L-dopa can cross the blood brain barrier, and once in the brain is converted into dopamine. Conversely, dopamine doesn't cross the blood-brain barrier, and if given as a drug would build up and be toxic to the rest of the body. In fact, Carbidopa is now routinely combined with L-dopa. Carbidopa is a drug that restricts L-dopa's conversion to dopamine outside of the brain (to prevent peripheral toxicity). Carbidopa inhibits an enzyme
(aromatic-L-amino acid decarboxylase) which is important in the conversion of L-dopa to dopamine, thus preventing L-dopa from becoming Dopamine prior to reaching the brain. Since Carbidopa cannot cross the blood-brain barrier, once L-dopa crosses, it can form L-dopamine unrestrained.
Over the years L-dopa has been shown to have many drawbacks. The side-effect of nausea and vomiting, caused by L-dopamine's conversion to Dopamine
peripherally, is generally offset by use of Carbidopa. But this leaves the two most disconcerting side-effects of L-dopa use, which are motor complications that worsen year after year, and what is seen by researcher's as L-dopa's "potential to induce free radical-mediated damage and thereby induce and or accelerate nigral neuronal cell dysfunction and death."156 I'd like to explore that statement, because with what we now know about mitochondrial damage, we should be able to put past observations into current perspective.
154 H. Ehringer, O. Hornykiewicz. Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behaviour in diseases of the extrapyramidal system. Klin Wochenschr (1960) 38:1236-1239.
155 W Birkmayer, O. Hornykiewicz. The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia.
Wien Klin Wochenschr (1961) 73:787-788.
156 CW Olanow et al. Levodopa in the treatment of Parkinson's disease: current controversies. Mov Disord (2004) 19:997-1005.
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Much about dopamine toxicity was observed 40 or more years ago, and has not yet been "unlearned" by most who read those studies. I think we can show now that what we have blamed dopamine for doing all these years is not being done by dopamine, but to dopamine, by the reactive oxygen species generated from damaged mitochondria.
Consider the next paragraph. Many of these observations are from studies done in the 1970's and 80's. Most are done in a lab (in vitro) not in humans or even
"primates" (in vivo). These studies note that all of their observations are "poorly understood, inconclusive, that mechanisms have not been elucidated, and results are confounded by the in vitro environment being nothing like the in vivo
environment". These and more "disclaimers" continue even as recently as 2009.157 As you consider the next paragraph, note that if you insert that reactive oxygen species is being generated by damaged mitochondria as that which is actually oxidizing dopamine, causing it to become a part of the problem instead of the solution, much of the mystery is solved.
Dopamine undergoes autoxidation, semiquinone formation and polymerization with the production of radical species.158,159 Dopamine can be metabolized by monoamine oxidase to produce hydrogen peroxide (H2O2)160 The H2O2 produced by dopamine, in the presence of iron (Fenton reaction) produces the highly reactive hydroxyl radical. Yet, you can find these in scientific literature as being
associated with mitochondria as well.
Non-physiological release of synaptic dopamine (such as when excitatory
glutamate causes the release of dopamine161,162) is thought to play a major role in
157 Arnar Astradsson et al. The Blood-brain barrier is intact after levodopa-induced dyskinesias in parkinsonian primates-Evidence from in vivo neuroimaging studies. Neurobiology of Disease 35 (2009) 348-351.
158 PG Jenner, DG Graham. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol (1978) 14:633-643.
159 DC Tse et al. Potential oxidative pathways of brain catecholamines J Med Chem (1976) 19:37-40.
160 RN Adams et al. 6-Hydroxydopamine, a new oxidation mechanism. Eur J Pharmacol (1972) 17:287-292.
161 H. Mount et al. Glutamate Stimulation of 3H Dopamine Release from Dissociated Cell Cultures of Rat Ventral Mesencephalon. Journal of Neurochemistry Vol 52 (April 1989) Issue 4. 1300-1310.
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dyskinesia (diminishing ability to voluntarily move muscles, and an increasing presence of involuntary movements like tics and tremors).163 Researchers once suggested that the dyskinesia might have to do with a disrupted blood-brain barrier.164 But Astradsson et al found the blood-brain barrier in parkinsonian primates exhibiting L-dopa-induced dyskinesia to be intact.165
In 2009 researchers found that calcium homeostasis is dysregulated in Parkinson's patients with "L-Dopa-induced dyskinesias". They found a depressed Ca2+ rise in response to mitogen-induced activation (which means a chemical substance
encourages a cell to begin cell division). This defect was more pronounced in L-Dopa-induced dyskinesia patients. They conclude that "second messenger levels (like cAMP and free intracellular Ca2+) are altered in the peripheral blood
lymphocytes of Parkinson's patients treated with dopaminergic agents", and this results in further alterations in Ca2+ homeostasis. 166
Along with dopamine toxicity, researchers say they have observed mitochondrial dysfunction, specifically complex I deficiency.167 Here's a case of the cart pulling the horse.
On the one hand, research shows that L-dopa can act as a pro-oxidant at high
levels, while conversely, at more normal levels, acts as an antioxidant, inducing the upregulation of glutathione and other neuroprotective molecules possibly because
162 N.V. Kulagina et al. Glutamate regulates the spontaneous and evoked release of dopamine in the rat striatum. Neuroscience Vol 102 Issue 1 (January 2001) 121-128.
163 JA Obeso et al. Pathophysiology of levodopa-induced dyskinesias. Ann Neurol 47. (2000) S22-S32.
164 JE Westin et al. Endothelial proliferation and increased blood-brain barrier permeability in the basal ganglia in a rat model of 3,4-dihydroxyphenyl-L-alanine-induced dyskinesia. J Neurosci 26 (2006) 9448-9461.
165 Arnar Astradsson et al. The blood-brain barrier is intact after levodopa-induced dyskinesias in parkinsonian primates-Evidence from in vivo neuroimaging studies. Neurobiology of Disease 34 (2009) 348-351.
166 Fabio Blandini MD et al. Calcium HOmeostasis is Dysregulated in Parkinsonian Patients with L-Dopa-induced Dyskinesias. Clinical Neuropharmacology (May/June 2009) Vol 32, No 3. 133-139.
167 AH Schapira et al. Mitochondrial complex I deficiency in Parkinson's disease. Lancet (1989) 1:1269.
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the drug acts as a "minimal stressor", enhancing the production of these protective molecules.168,169
Perhaps most importantly is that more recent researchers have cautioned against placing much relevance upon observations of L-dopa toxicity in vitro culture because the culture is missing the high ascorbate found in tissues. Thus much of the in vitro evidence for a toxic effect by dopamine on neuronal cells may very well be "artifactual" and not the same as would be observed within the body.170 In addition, many studies that have demonstrated L-dopa toxicity in culture, used rather high concentrations of L-dopa, that is, >50μM/L compared to the typical 10-20 μM/L given to patients, of which only about 12% actually shows up in the cerebrospinal fluid.171
Scientists have noted that when glial cells (the brain's "immune system") and ascorbate have been added to cultures testing for L-dopa toxicity, because this becomes a scenario more like that found in the substantia nigra, L-dopa toxicity was significantly diminished or even abolished altogether!172,173
It seems extreme measures have to be taken to induce L-dopa toxicity in rats. High levels of L-dopa were injected into them in the presence of iron to cause toxicity.174
168 C Mytilineou et al. Toxic and protective effects of Levodopa on mesencephalic cell cultures. J Neurochem (1993) 61:1470-1478.
169 MA Mena et al. Neurotrophic effects of L-dopa in postnatal midbrain dopamine neuron/cortical astrocyte cocultures. J Neurochem (1997) 69:1398-1408.
170 MV Clement et al. The cytotoxicity of dopamine may be an artefact of cell culture. J Neurochem (2002) 81:414-421.
171 CW Olanow et al. Temporal relationships between plasma and cerebrospinal fluid pharmacokinetics of levodopa and clinical effect in Parkinson's disease. Ann Neurol (1991) 29:556-559.
172 MA Mena et al. Glia protect fetal midbrain dopamine neurons in culture from L-dopa toxicity through multiple mechanisms. J Neural Transm (1997) 104:317-328.
173 C. Mytilineou et al. Levodopa is toxic to dopamine neurons in an in vitro but not an in vivo model of oxidative stress. J Pham Exp Ther (2003) 304:792-800.
174 H Maharaj et al. Levodopa administration enhances 6-hydroxydopamine generation. Brain Res (2005) 1063:180-186.
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On the other hand, in normal rodents and primates, administration of large quantities of L-dopa caused no toxicity.175,176
It's what Dr. Schapira says after the quote above that returns us nicely to the mitochondria: "Finally, clinical studies have failed to support the concept of L-dopa toxicity, but imaging studies do not permit this concept to be completely excluded." Indeed! Because what we are seeing is dopamine being oxidized by reactive oxygen species generated from damaged mitochondria, not some
mysterious "auto" oxidation of dopamine.
That said, of course we do need to understand that the bottom line in Parkinson's
That said, of course we do need to understand that the bottom line in Parkinson's