Subject: MD/chelator/iron
______________
Med Hypotheses 13: 153-60 (1984)[84190712]
Proposed treatment of Duchenne muscular dystrophy with desferrioxamine.
I. A. Clark
The primary disturbance in Duchenne muscular dystrophy (DMD) appears
to affect membrane function, and changes characteristic of
oxidant-induced damage occur in skeletal muscle and erythrocytes.
There is recent evidence that DMD is a functional tocopherol
deficiency, with reduced levels of the lipoprotein required to carry
tocopherol to tissues. This may explain the parallels between DMD and
dietary tocopherol deficiency. Thus DMD should follow the usual
experience of other examples of oxidative pathology, where the balance
between tocopherol, the main antioxidant in membrane lipids, and non
protein-bound iron, an important catalyst of reactions which produce
oxidizing free radicals, largely determines whether or not tissue
damage occurs. Desferrioxamine prevents oxidant damage in vitro and in
vivo by removing this iron, and may therefore be able to reverse the
muscle damage of DMD. Recent experience with this drug in long term
dialysis patients is consistent with this suggestion.
MeSH Terms:
* Animal
* Deferoxamine/therapeutic use
* Genes, Recessive
* Human
* Iron/metabolism
* Linkage (Genetics)
* Membrane Lipids/metabolism
* Muscles/metabolism
* Muscular Dystrophy/drug therapy
* Muscular Dystrophy/etiology
* Muscular Dystrophy/genetics
* Muscular Dystrophy, Animal/metabolism
* Oxidation-Reduction
* Support, Non-U.S. Gov't
* Vitamin E/metabolism
* Vitamin E Deficiency/complications
Substances:
* Iron
* Vitamin E
* Membrane Lipids
* Deferoxamine
_________________________________________________________________
Subject: ataxia
Int J Mol Med 2001 Jun;7(6):581-9
Friedreich's ataxia and frataxin: Molecular genetics, evolution and
pathogenesis (Review).
Palau F
Instituto de Biomedicina de Valencia, CSIC, 46010 Valencia, Spain.
[Medline record in process]
Friedreich's ataxia is an autosomal recessive neuro-degenerative
disorder involving both central and peripheral nervous system.
Patients also show a systemic clinical picture presenting heart
disease and diabetes mellitus or glucose intolerance. The disease is
caused by mutations in the FRDA gene mapped on chromosome 9q13. The
product of the gene is frataxin, an 18 kDa soluble mitochondrial
protein with 210 amino acids. Crystal structure suggests a new, not
previously reported, protein fold. The most frequent mutation is the
expansion of a GAA trinucleotide repeat located within the first
intron of the gene, and represents 98% of the mutations. Point
mutations are described in compound heterozygous subjects with one
expanded allele. A two-step model of GAA normal alleles towards
premutation alleles, which might generate further full expanded
mutations in the population with Indo-European ancestry, has been
postulated. Clinical phenotype is variable and an inverse correlation
with the GAA expansion size has been observed. Analysis of the GAA
triplet is a strong molecular tool for clinical diagnosis, genetic
counselling and prenatal diagnosis. Friedreich's ataxia patho-genesis
is not solved yet. Substantial data from organism models, such the S.
cerevisae yeast and more recently conditioned knock-outs in mouse, and
studies in heart biopsies and fibroblast cultures from patients
suggest an important role of mitochondrial iron in the development of
the disease. Iron is accumulated in the mitochondrial matrix of both
the yeast frataxin deficient mutant and the patient fibroblasts. It
has been postulated that iron-induced oxygen radical affects the
oxidative phosphorylation in frataxin deficiency states favouring the
disease pathology. A second hypothesis postulates a direct role of
frataxin in the mitochondrial energy activation and oxidative
phosphorylation. Iron chelator drugs and antioxidant drugs have been
postulated for Friedreich's treatment. No results from clinical trials
are available yet, but idebenone, a short-chain quinone, seems to
reduce the size of hypertrophic cardiomyopathy and levels of oxidative
stress molecules in patients.
PMID: 11351269, UI: 21248737
_________________________________________________________________
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_________________________________________________________________
Subject: dystrophy/Q10
_________________________________________________________________
Biochim Biophys Acta 1271: 281-286 (1995)[95322488]
Two successful double-blind trials with coenzyme Q10 (vitamin Q10) on muscular
dystrophies and neurogenic atrophies.
K. Folkers & R. Simonsen
Institute for Biomedical Research, University of Texas at Austin
78705, USA.
Coenzyme Q10 (vitamin Q10) is biosynthesized in the human body and is
functional in bioenergetics, anti-oxidation reactions, and in growth
control, etc. It is indispensable to health and survival. The first
double-blind trial was with twelve patients, ranging from 7-69 years
of age, having diseases including the Duchenne, Becker, and the
limb-girdle dystrophies, myotonic dystrophy. Charcot-Marie-Tooth
disease, and the Welander disease. The control coenzyme Q10 (CoQ10)
blood level was low and ranged from 0.5-0.84 microgram/ml. They were
treated for three months with 100 mg daily of CoQ10 and a matching
placebo. The second double-blind trial was similar with fifteen
patients having the same categories of disease. Since cardiac disease
is established to be associated with these muscle diseases, cardiac
function was blindly monitored, and not one mistake was made in
assigning CoQ10 and placebo to the patients in both trials. Definitely
improved physical performance was recorded. In retrospect, a dosage of
100 mg was too low although effective and safe. Patients suffering
from these muscle dystrophies and the like, should be treated with
vitamin Q10 indefinitely.
MeSH Terms:
* Adolescence
* Adult
* Aged
* Charcot-Marie Disease/drug therapy
* Child
* Comparative Study
* Double-Blind Method
* Female
* Human
* Male
* Middle Age
* Muscular Atrophy/drug therapy
* Muscular Dystrophy/drug therapy
* Myotonia Atrophica/drug therapy
* Ubiquinone/analogs & derivatives
* Ubiquinone/therapeutic use
Substances:
* Ubiquinone
* coenzyme Q10
_________________________________________________________________
Subject: oxidation/dystrophy/Veteran Affairs
Rando, Thomas A. OXIDATIVE STRESS AND MUSCULAR DYSTROPHIES
VA Medical Center
Palo Alto, CA 94304
Rando, Thomas A., M.D., Ph.D.
Department of Veterans Affairs: Medical Research
Report Date: 04/16/96
Title: Oxidative Stress and Muscular Dystrophies
Abstract:
OBJECTIVES: To identify the cause of muscle cell necrosis in muscular
dystrophies, to test the hypothesis that this necrosis occurs as a
result of free radical injury to the muscle cells, and to attempt to
prevent muscle necrosis by enhancing the antioxidant defenses of the
cells.
RESEARCH PLAN: The most common forms of muscular dystrophy are due to
defects in the gene for the protein dystrophin. Dystrophin is a
cytoskeletal protein that links the intracellular cytoskeleton with
the extracellular matrix through a series of membrane proteins and
glycoproteins. When dystrophin is completely absent from the cell, as
occurs in the human disease Duchenne muscular dystrophy or in the mdx
mouse, widespread muscle necrosis occurs. Similar pathologic changes
are seen in other myopathic conditions, such as muscle ischemia and
vitamin E deficiency, in which the(HOME) major cause of cellular injury is
free radical induced damage. The primary hypothesis of our work is
that muscle necrosis is due to free radical damage to muscle cell
membranes. The membrane instability caused by dystrophin deficiency
leads to an increased susceptibility to such injury. We propose to
study muscle cell necrosis and free radical injury, and to study the
susceptibility to such injury in a muscle cell culture model in vitro
and in the mdx mouse in vivo.
METHODS: In vitro, primary cultures of differentiated muscle cells
from normal and mdx mice will be subjected to oxidative stress by
adding pro-oxidants (e.g. H2O2, menadione) to the culture medium. We
will then examine the susceptibility of the cells by measuring cell
survival and biochemical indices of free radical damage to the
membranes (lipid peroxidation) as well as the oxidative state of the
cells (glutathione levels). Finally, we will attempt to prevent free
radical injury and cell death by the addition of antioxidants (e.g.
alpha-tocopherol, Nacetylcysteine) to the culture medium. In all these
assays, we expect to see an increased susceptibility to injury and
death in the dystrophic cells.
In vivo, we will examine the muscle at different ages leading up to
the onset of muscle degeneration, especially between age 2 weeks, when
the muscle is nolmal histologically, and 4 weeks, when widespread
necrosis is occurring. We will test for an increase in free radical
damage to the cells (lipid peroxidation) preceding the onset of the
necrosis as would be expected if oxidative stress is the final cause
of the cellular- injury. We will also test for changes in the
oxidative state of the cells (glutathiolle levels) as measures of free
radical metabolic activity, and for differences in cellular
antioxidant machinery (superoxide dismutase, glutathione peroxidase,
catalase) that might contribute to differential susceptibility. For
all of these studies, we will use the non-dystrophic parental mouse
strain to control for age-related changes.
FINDINGS: Using cells in culture, we have provided evidence that mdx
muscle cells are more susceptible to oxidative injury than normal
muscle cells, but not more susceptible to other forms of metabolic
injury. In vivo, we have demonstrated that lipid peroxidation is
greater in mdx muscle than in normal muscle during the prenecrotic
state. Thus, even before there is any evidence of active disease, we
have shown that there is ongoing injury to the cells. We have
determined the level of expression of antioxidant enzymes in nolmal
and dystrophic mice during the same ages, and it appears that there
are actually lower levels of expression in the mdx mice, perhaps
accounting for the increased susceptibility to oxidative injury.
CLINICAL RELEVANCE: We are directly studying the pathogenesis and
treatment of a disease that leads to progressive muscular weakness,
muscle wasting, and premature death in children and adults alike.
Furthermore, we are studying a disease process, namely free radical
damage to cells, that has been postulated to contribute to the
morbidity of a wide range of diseases including stroke, Parkinson's
disease, and cancer, and to the process of aging itself. Increased
understanding of the cause and prevention of this disease process
could lead to dramatic advances in treatment of some of the major
causes of morbidity and mortality in the aging population we serve.
MeSH Keywords:
OXIDATIVE STRESS
MUSCULAR DYSTROPHY
LIPID PEROXIDATION
.
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