Treating Multiple Neurodegenerative Diseases
ironjustice
Tricyclic pyrone compounds prevent aggregation and reverse cellular
phenotypes caused by expression of mutant huntingtin protein in
striatal neurons
Eugenia Trushina1 , Sandeep Rana2 , Cynthia T McMurray1,3 and Duy H
Hua2
1 Department of Molecular Pharmacology and Experimental Therapeutics,
Mayo Clinic, 200 First St. SW, Rochester, Minnesota 55905, USA
2 Department of Chemistry, CBC Building, Kansas State University,
Manhattan, KS 66506, USA
3 Department of Biochemistry and Molecular Biology, Mayo Clinic, 200
First St. SW, Rochester, Minnesota 55905, USA
BMC Neuroscience 2009, 10:73doi:10.1186/1471-2202-10-73
The electronic version of this article is the complete one and can be
found online at: http://www.biomedcentral.com/1471-2202/10/73
Received: 18 March 2009
Accepted: 8 July 2009
Published: 8 July 2009
Abstract
Background
Huntington's disease (HD) is a progressive neurodegenerative
disorder caused by a CAG repeat expansion mutation in the
coding region of a novel gene.
The mechanism of HD is unknown.
Most data suggest that polyglutamine-mediated aggregation
associated with expression of mutant huntingtin protein
(mhtt) contributes to the pathology.
However, recent studies have identified early cellular
dysfunctions that preclude aggregate formation.
Suppression of aggregation is accepted as one of the markers
of successful therapeutic approaches.
Previously, we demonstrated that tricyclic pyrone (TP) compounds
efficiently inhibited formation of amyloid-β (Aβ) aggregates in
cell and mouse models representing Alzheimer's Disease (AD).
In the present study, we aimed to determine whether TP compounds
could prevent aggregation and restore early cellular defects in
primary embryonic striatal neurons from animal model representing
HD.
Results
TP compounds effectively inhibit aggregation caused by mhtt in
neurons and glial cells.
Treatment with TP compounds also alleviated cholesterol
accumulation and restored clathrin-independent endocytosis in
HD neurons.
Conclusion
We have found that TP compounds not only blocked mhtt-induced
aggregation, but also alleviated early cellular dysfunctions
that preclude aggregate formation.
Our data suggest TP molecules may be used as lead compounds
for prevention or treatment of multiple neurodegenerative
diseases including HD and AD.
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The pyrones, 3-hydroxy-2-methyl-4-pyrone (maltol) and 3-hydroxy-2-
ethyl-4-pyrone (ethyl maltol) chelate iron with a high affinity and
selectivity.
http://www.ncbi.nlm.nih.gov/pubmed/2883285
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Maltol is a natural iron-chelating sugar found in your food ..
"Maltol a sugar used as a common food additive"
Comparative study of iron mobilization from haemosiderin, ferritin
and iron(III) precipitates by chelators.
Kontoghiorghes GJ, Chambers S, Hoffbrand AV.
The heteroaromatic chelators 1,2-dimethyl-3-hydroxypyrid-4-one,
MALTOL , mimosine and 2,4-dihydroxypyridine-N-oxide, have been shown
to
mobilize iron from human spleen haemosiderin, ferritin and also from
iron(III) precipitates, all containing equal amounts of iron, at
physiological pH.
In the case of almost every chelator, the least-solubilized
polynuclear iron form was ferritin, whereas haemosiderin was more
soluble and the iron(III) precipitate the most soluble of all.
Most of the chelators were more efficient than desferrioxamine at
releasing iron from ferritin, but less efficient in the removal of
iron from the other two polynuclear iron forms.
It is suggested that the chelator differences in iron mobilization
may be related to variations in the chelator molecular structure, the
protein structure, iron forms and in the mechanism of iron release.
PMID: 3566714
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"Chelators of synthetic or plant origin may carry less risk"
The effect of synthetic iron chelators on bacterial growth in human
serum
J.H. Brock a , Joan Licéaga a G.J. Kontoghiorghes b
a University Department of Bacteriology and Immunology, Western
Infirmary, Glasgow, USA b Department of Haematology, Royal Free
Hospital, London, U.K.
Correspondence to: Dr. J.H. Brock, Dept. of Bacteriology and
Immunology, Western Ifirmary, Glasgow, G11 6NT, Scotland, U.K.
ABSTRACT
Abstract The effect of synthetic iron chelators of the 1-alkyl-3-
hydroxy-2-methylpyrid-4-one class (the L1 series) and 1-
hydroxypyrid-2- one (L4) on bacterial growth in human serum was
compared with those of the plant iron chelators mimosine and maltol
and of the microbial siderophore desferrioxamine.
None of the synthetic chelators enhanced growth of 3 Gram-negative
organisms (Yersinia enterocolitica, Escherichia coli and Pseudomonas
aeruginosa); in some cases they were even inhibitory. L4 strongly
stimulated growth of Staphylococcus epidermidis, but the L1 series
had only a marginal effect.
Maltol was mildly inhibitory to all 4 bacterial species, while
mimosine enhanced the growth of S. epidermidis and Y. enterocolitica
but had little effect on E. coli or P. aeruginosa.
Desferrioxamine enhanced the growth.
Chelators of synthetic or plant origin may carry less risk of
increasing susceptibility to bacterial infection in patients
undergoing chelation therapy for iron overload than does
desferrioxamine, the drug currently in clinical use.
Copyright 1988 Federation of European Microbiological Societies
KEYWORDS
Iron * Chelator * Bacterial growth * Infection
FEMS Microbiology Letters
Volume 47 Issue 1, Pages 55 - 60
Published Online: 27 Mar 2006
by Blackwell Publishing Ltd. All rights reserved
Received 23 September 1987, Accepted 4 November 1987
DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1574-6968.1988.tb02490.x About DOI
---------------------------
http://www.jbc.org/cgi/reprint/184/1/131.pdf
The formation of maltol upon heating certain aqueous
carbohydrate glycine systems has been investigated.
Carbohydrates used in the experiment included starch,
cellulose, sucrose, lactose, maltose, glucose, galactose,
and methyl a-n-glucopyranoside.
Of these, maltol was obtained from only lactose and maltose.
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The Concise Encyclopedia of Foods & Nutrition
Formation and Occurence of Maltol
Chemists have demonstrated that maltol may be formed by heating
maltose at 375 degrees F for 1 hour ( note the similaritiies of these
conditions to those in baking), or by heating mixtures of sugars ,
such as maltose and lactose with amino acids , such as glycine (the
latter procedure is known as nonenzymatic browning reaction of the
Maillard type).
Maltol is found in roasted materials which have a moderate to high
carbohydrate content, such as bread crusts, cocoa beans , cellulose ,
cereals , chicory , coffee beans , diastatic flour doughs ( where
some
of the starch has been convertd by enzyme action to maltose), malt
products, soft woods , and soybeans.
It is also found in heated products which contain moderate amounts of
both sugars and amino acids, such as condensed and dried milks, dried
whey , and soy sauce.
Apparently heating is not always required for the production of
maltol, since it also occurs in larch bark and the dry needles of
cone- bearing evergreen trees.
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