Subject: iron/parkinsons/alzheimer/oxidation

   
   Free Radic Res 2000 Feb;32(2):103-14
   
Time-course of oxidation of lipids in human cerebrospinal fluid in vitro.

    Arlt S, Finckh B, Beisiegel U, Kontush A
    
   Medical Clinic, University Hospital Eppendorf, Hamburg, Germany.
   
   Oxidative mechanisms play an important role in the pathogenesis of
   Alzheimer's disease, Parkinson's disease and other neurodegenerative
   diseases. To assess whether the oxidation of brain lipoproteins plays
   a role in the development of these pathologies, we investigated
   whether the lipoproteins of human cerebrospinal fluid (CSF) are
   susceptible to oxidative modification in vitro. We studied oxidation
   time-course for up to 100 h of human CSF in the absence
   (autooxidation) or presence of exogenous oxidants. Autooxidation of
   diluted CSF was found to result in a slow accumulation of lipid
   peroxidation products. The time-course of lipid hydroperoxide
   accumulation revealed three consecutive phases, lag-phase, propagation
   phase and plateau phase. Qualitatively similar time-course has been
   typically found in human plasma and plasma lipoproteins. Autooxidation
   of CSF was accelerated by adding exogenous oxidants, delayed by adding
   antioxidants and completely inhibited by adding a chelator of
   transition metal ions. Autooxidation of CSF also resulted in the
   consumption of endogenous ascorbate, alpha-tocopherol, urate and
   linoleic and arachidonic acids. Taking into account that (i) lipid
   peroxidation products measured in our study are known to be derived
   from fatty acids, and (ii) lipophilic antioxidants and fatty acids
   present in CSF are likely to be located in CSF lipoproteins, we
   conclude that lipoproteins of human CSF are modified in vitro during
   its autooxidation. This autooxidation appears to be catalyzed by
   transition metal ions, such as Cu(II) and Fe(III), which are present
   in native CSF. These data suggest that the oxidation of CSF
   lipoproteins might occur in vivo and play a role in the pathogenesis
   of neurodegenerative diseases.
   
   PMID: 10653481, UI: 20117206
     _________________________________________________________________
   
 _________________________________________________________________

Subject: parkinsons/glutamate/oxidation

   
   Drugs Aging 1999 Feb;14(2):115-40
   
The role of iron in neurodegeneration: prospects for pharmacotherapy of
Parkinson's disease.

    Jellinger KA
    
   Ludwig Boltzmann Institute of Clinical Neurobiology, Vienna, Austria.
   kurt.jellinger@univie.ac.at
   
   Although the aetiology of Parkinson's disease (PD) and related
   neurodegenerative disorders is still unknown, recent evidence from
   human and experimental animal models suggests that a misregulation of
   iron metabolism, iron-induced oxidative stress and free radical
   formation are major pathogenic factors. These factors trigger a
   cascade of deleterious events leading to neuronal death and the
   ensuing biochemical disturbances of clinical relevance. A review of
   the available data in PD provides the following evidence in support of
   this hypothesis: (i) an increase of iron in the brain, which in PD
   selectively involves neuromelanin in substantia nigra (SN) neurons;
   (ii) decreased availability of glutathione (GSH) and other antioxidant
   substances; (iii) increase of lipid peroxidation products and reactive
   oxygen (O2)species (ROS); and (iv) impaired mitochondrial electron
   transport mechanisms. Most of these changes appear to be closely
   related to interactions between iron and neuromelanin, which result in
   accumulation of iron and a continuous production of cytotoxic species
   leading to neuronal death. Some of these findings have been reproduced
   in animal models using 6-hydroxydopamine,
   N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), iron loading and
   beta-carbolines, although none of them is an accurate model for PD in
   humans. Although it is not clear whether iron accumulation and
   oxidative stress are the initial events causing cell death or
   consequences of the disease process, therapeutic efforts aimed at
   preventing or at least delaying disease progression by reducing the
   overload of iron and generation of ROS may be beneficial in PD and
   related neurodegenerative disorders. Current pharmacotherapy of PD, in
   addition to symptomatic levodopa treatment, includes 'neuroprotective'
   strategies with dopamine agonists, monoamine oxidase-B inhibitors
   (MAO-B), glutamate antagonists, catechol O-methyltransferase
   inhibitors and other antioxidants or free radical scavengers. In the
   future, these agents could be used in combination with, or partly
   replaced by, iron chelators and lazaroids that prevent iron-induced
   generation of deleterious substances. Although experimental and
   preclinical data suggest the therapeutic potential of these drugs,
   their clinical applicability will be a major challenge for future
   research.
   
   Publication Types:
     * Review
     * Review, academic
       
   PMID: 10084365, UI: 99181856
     _________________________________________________________________
   
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     _________________________________________________________________



Subject: parkinsons



              Iron in the brains of Parkinson's disease sufferers
     _________________________________________________________________
   
   Studying the mechanism of iron storage in the brain will help to
   understand the disease process. 
     _________________________________________________________________
   
   The accumulation of metals in brain tissue has frequently been
   associated with neurological disorders - Alzheimer's disease is linked
   to aluminium, Wilson's disease to copper and Hallervorden-Spatz
   disease to iron. It has been known for some time that sufferers of
   Parkinson's disease also have abnormally high levels of iron in the
   brain. Paul Griffiths of Newcastle General Hospital Department of
   Neuroradiology, in collaboration with Barry Dobson and Gareth Jones at
   Daresbury Laboratory, have used the SRS to investigate how iron is
   stored in the brain in both healthy and Parkinson's diseased tissue.
   Now, for the first time, definite conclusions have been drawn about
   the method of iron storage.
   
   Iron is stored throughout the brain, accumulating rapidly during
   adolescence and early adulthood. The areas containing most iron are at
   the base of the brain - the substantia nigra and the globus pallidus -
   and these areas are also thought to be affected most in degenerative
   diseases. The presence of iron is perfectly normal; a healthy adult
   brain might contain 50 mg of iron per gram of tissue. However, in
   Parkinson's sufferers, this figure can rise to 250 mg per gram of
   tissue. Examining tissue from healthy brains and from Parkinson's
   sufferers, shows the similarities and differences in the iron
   deposits.
   
   [INLINE]
   
   Figure 1.35: The XAFS spectrum is shown in the upper graph of this
   figure, whilst the Fourier transform of the data (i.e. the radial
   distribution around the iron atoms) is shown below. Both graphs
   include the experimental data (blue) and a theoretically calculated
   model fit (red).
   
   A common method of iron storage in the body is via a protein called
   ferritin. Ferritin is a large protein, like a molecular football, that
   can hold 30 or 40 iron atoms inside. The iron is inert when it is
   stored inside the ferritin. A technique called X-ray Absorption Fine
   Structure (or XAFS) Spectroscopy has been used to study the brain
   tissue (figure 1.35). XAFS 'homes in' on particular atoms in a sample,
   and then identifies the position and type of their nearest neighbours.
   Using this technique the environment of the iron atoms in the brain
   can be studied in detail, clearly showing the signature of ferritin in
   both healthy and diseased tissue. The brain iron can now be posi (HOME) tively
   identified as ferritin.
   
                                      
   Figure 1.36: Cryo electron microscopy images of: (a) A solution of
   horse spleen ferratin. The inset shows an enlargement in which the
   ferratin cores are clearly visible. (b) A microtomal section of brain
   tissue from a Parkinson's sufferer. The inset shows a number of
   heavily laden cores. (c) A microtomal section of tissue from a
   non-diseased brain. The inset shows ferratin with a much lower loading
   than (b).
   
   In addition to characterising the iron deposits with XAFS, the core
   centres can be imaged using cryo electron microscopy.
   
   Ferritin cores in the brain tissue show up clearly as dark spots on
   the image (figure 1.36). The microscopy not only shows the location of
   the cores, but also indicates their density. Here a clear difference
   is seen between normal and Parkinson's tissue, with the ferritin
   'footballs' in diseased brains being more heavily loaded with iron.
   
   The role of iron in Parkinson's disease is not yet fully understood.
   However, these experiments have given the first conclusive results of
   the method of iron storage in the brain. This knowledge may improve
   our understanding of the degenerative processes involved in
   Parkinson's disease.
     _________________________________________________________________
   
   For more information contact: Dr B.R. Dobson 
   
   Tel: 01925 603323 e-mail: b.r.dobson@dl.ac.uk
     _________________________________________________________________
   


Subject: parkinsons



                     Role of Iron in Parkinsons disease
                                      
   Parkinsons disease involves the specific degeneration of dopaminergic
   neurons in the substantia nigra (1). An increase in levels of iron
   have been found in the substantia nigra of severely affected patients.
   This is accompanied by a decrease in levels of the major iron binding
   protein ferritin (2-3) .
   
   Superoxide and hydrogen peroxide are compounds produced as by products
   of normal metabolism, primarily during formation of high energy
   compounds like ATP during mitochondrial respiration. The brain is
   particularly susceptible to free radical damage due to high levels of
   oxygen metabolism and unique composition of its cellular membranes
   which contain large amounts of oxidant- sensitive polyunsaturated
   fatty acids (5-6). It is also relatively deficient in free radical
   scavenging enzymes (glutathione peroxidase and catalase) and
   antioxidant molecules (eg. glutathione, vitamin E)
   
   Dopaminergic neurons of the substantia nigra may be at risk for free
   radical damage due to oxidation of dopamine by the mitochondrial
   enzyme monoamine oxidase or by auto-oxidation. Both reactions produce
   hydrogen peroxide as a by-product. Free iron catalyzes the conversion
   of hydrogen peroxide to highly reactive hydroxyl radicals which can
   degrade DNA, proteins and membrane lipids leading to cellular
   degeneration (4).
   
   Preliminary experiments in our laboratory have indicated that over
   expression of ferritin may be toxic (since it removes all the iron
   needed for important biochemical reactions).We are now trying to
   conditionally express ferritin using the tetracycline inducible system
   .
   
Methodology

   1) Permanent PC-12 (Pheochromocytoma) cells containing the
   tranactivator plasmid have already been made in the lab (rTta 24A).
   
   2) Construction of response plasmid containing ferritin and a marker
   gene (lac Z).
   
   3) Transforming the rTta 24A cells with the ferritin containing
   response plasmid and checking for Lac-Z expression.
   
   4) Varying levels of ferritin expression (by varying tetracycline
   concentration) and assaying experimental and control cells for signs
   of free radical damage in the presence and absence of free radical
   inducing agents.
   
   5) Transgenic mice containing the ferritin gene (driven by tyrosine
   hydroxylase promoter) have been made in our lab.We are currently
   trying to characterize these animals by Southern blotting and
   immunohistochemical analysis.
   
References

     1.Gibb. et al. (1991) J. Neurol. Neuro. Surg. Psych. 54:388-396
   
     2.Dexter et al. (1989) J. Neurochem , 52:381-389
   
     3.Dexter et al. (1990) J. Neurochem, 55:16-20
   
     4.Haber et al. (1934) Proc. R. Soc. Lond. 147:332
   
     5.Ben-Shacher et al. (1991) J. Neurochem. 57:1609-1614
   
     6.Zaleska et al. (1989) Neurochem. Res. 14:597-605



http://www.drkoop.com/news/stories/2001/jan/hs/31_parkinsons.html?nl=dkc&sct=top&dt=020601

Iron Problems May Lead to Parkinson's
Mouse Study Shows Direct Link 

Jan 31 2001 11:24:12
Julia McNamee Neenan
HealthScout 

Genetic engineering that knocks out an iron-regulating protein caused Parkinson-like disabilities in mice, researchers announced today. 
The finding is key to understanding development of brain diseases that affect movement, said senior study investigator Dr. Tracey A. Rouault, chief of the section on human iron metabolism at the National Institute of Child Health and Human Development. While scientists had long observed that patients with these diseases built up iron deposits in the brain, no one was sure whether the deposits caused the diseases or were a byproduct of cell death that resulted from the diseases, Rouault said. 

"We demonstrated that an inherited iron regulation protein mutation can be the cause of deterioration of the brain in animals. The mistake in iron metabolism causes physical degeneration, and the iron accumulation is a sign of that mistake," Rouault said. 

The study, published in today's Nature Genetics, used genetically engineered mice that lacked one of two important regulators of iron, a protein called IRP2. The mice progressively deteriorated, showing difficulties moving, and accumulated damaging iron deposits in the brain and elsewhere. 

The brain damage in the mice parallels damage observed in Parkinson-like diseases in humans, particularly Parkinson's Plus, Rouault said. Also called Multiple System Atrophy (MSA), Parkinson's Plus affects up to 10 percent of the 1.5 million Americans with Parkinson's. 

Statistics pinpointing the incidence of MSA are hard to come by because the disease so often is misdiagnosed, said Donna Gruetzmacher, National Ataxia Foundation executive director. People with the disease typically lack coordinated movement, while other body areas or systems, such as blood pressure or sleep patterns, also break down. MSA typically is diagnosed in middle age, she said. 

Mice generally live 18 months to a year, but the mice lacking IRP2 developed problems within six months, Rouault said. 

"They had a tremor that could be quite severe. Their gait, or how they walked, was very uncoordinated. When they fell over, they couldn't right themselves. It progressed to the point where they couldn't get food or water because movement was so sacrificed. It really is a profound disease at that moment," Rouault said. 

The absence of IRP2 also caused measurable changes in iron levels in the liver and part of the intestine, the study showed. For instance, liver iron in the control mice was 947 parts per million at eight months, compared with 1,623 parts per million in the mutated mice. 

Researchers detected significant amounts of abnormal iron deposits in the cerebellum and the basal ganglia, both brain parts involved in movement. And by killing mice at various stages of development, the researchers saw that the iron deposits preceded brain damage, Rouault said. 

"The cell bodies of neurons condensed and lost the appropriate shape of their structures, and their axons degenerated," Rouault said. 

So far, the damage matches what's been seen in humans with Parkinson's Plus, which also is characterized by tremors and uncoordinated gait, Rouault said. The researchers are looking into whether the damage is like that seen in people with Parkinson's itself. 

The earliest and most extreme damage occurred in mice missing both copies of IRP2-carrying genes, but those with just one copy of the mutated gene also showed damage and physiological changes, which might explain why some didn't show signs of brain disease until much later in life, Rouault said. 

Gene therapy is a definite possibility in the future, but for now, researchers are looking for people with Parkinson-type diseases to study whether the gene coding for IRP2 has been mutated in some way, Rouault said. 

"We think there's a good chance some humans will have mutations in this gene, and we'd like to find them," Rouault said. 


SOURCES: Interviews with Tracey A. Rouault, M.D., chief of the section on human iron metabolism at the National Institute of Child and Health and Human Development; Donna Gruetzmacher, executive director, National Ataxia Foundation; February 2001 Nature Genetics 

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