Subject: Q10/dystrophies
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: night blindness/dystrophy/vitamin A
Nature Genetics
September 1995
Night blindness in Sorsby's fundus dystrophy reversed by vitamin A
By Samuel G. Jacobson et al.
Night blindness in Sorsby's fundus dystrophy reversed by vitamin A
Samuel G. Jacobson, Artur V. Cideciyan, Gopalakrishnan Regunath,
Francisco J. Rodriguez, Kimberlie Vandenburgh, Val C. Sheffield and
Edwin M. Stone
Sorsby's fundus dystrophy (SFD) is an autosomal dominant retinal
degeneration caused by mutations in the tissue inhibitor of
metalloproteinases-3 (_TIMP3_) gene. Mechanisms of the visual loss in
SFD, however, remain unknown. In a SFD family with a novel _TIMP3_
point mutation, we tested a hypothesis that their night blindness is
due to a chronic deprivation of vitamin A at the level of the
photoreceptors caused by a thickened membrane barrier between the
photoreceptor layer and its blood supply. Vitamin A at 50,000 IU/d was
administered orally. Within a wee, the night blindness disappeared in
patients at early stages of disease. Nutritional night blindness is
thus part of the pathophysiology of this genetic disease and vitamin A
supplementation can lead to dramatic restoration of photoreceptor
function.
Subject: DYSTROPHIES/OXIDATIVE STRESS
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 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-toeopherol, 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 (HOME) serve.
MeSH Keywords:
OXIDATIVE STRESS
MUSCULAR DYSTROPHY
LIPID PEROXIDATION
.
Subject: Ataxia/tocopherol
______________
J Am Coll Nutr 6: 151-6 (1987)[87223597]
Changes in vitamin E concentration in red blood cells and plasma of patients
with olivopontocerebellar ataxia within the Schut-Swier kindred.
G. T. Vatassery & L. J. Schut
Many reports have documented the importance of vitamin E for the
function of the nervous system, especially of the cerebellum.
Therefore, we studied the concentrations of vitamin E in the blood
plasma and red blood cells of patients with a hereditary form of
olivopontocerebellar ataxia. The concentrations of alpha tocopherol
(the principal biologically-active form of vitamin E) in the plasma
and red cells of the ataxic subjects were significantly lower than
those of unaffected, close relatives as well as unrelated control
subjects. Total lipids, cholesterol, triglycerides and lipoproteins in
the serum of the ataxia group were all within normal range. The
results suggest that this specific type of familial ataxia is
associated with a rare and isolated abnormality in vitamin E and/or
antioxidant metabolism. The vast majority of previous reports of lower
blood concentrations or deficiency of vitamin E in children or adults
were also associated with deficits in the absorption of lipids or
abnormalities in serum lipids and lipoproteins.
MeSH Terms:
* Adult
* Erythrocytes/metabolism
* Female
* Genes, Dominant
* Human
* Male
* Olivopontocerebellar Atrophy/blood
* Olivopontocerebellar Atrophy/genetics
* Pedigree
* Spinocerebellar Degeneration/genetics
* Support, Non-U.S. Gov't
* Support, U.S. Gov't, Non-P.H.S.
* Vitamin E/blood
Substances:
* Vitamin E
_________________________________________________________________
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: Spinal Muscle Atrophy/vitamin e/tocopherol
_________________________________________________________________
Equine Vet J 26: 409-415 (1994)[95080231]
Equine motor neuron disease: findings in 28 horses and proposal of a
pathophysiological mechanism for the disease [see comments]
T. J. Divers, H. O. Mohammed, J. F. Cummings, B. A. Valentine, A. De
Lahunta, C. A. Jackson & B. A. Summers
Department of Clinical Sciences, New York State College of Veterinary
Medicine, Cornell University, Ithaca 14853-6401.
Over a three and one-half year period, 28 adult horses were diagnosed
with equine motor neuron disease (EMND). The most commonly identified
environmental risk factors for a horse having EMND were absence of
grazing for more than a year and provision of poor quality hay.
Quarter Horses were 5.4 times more at risk than other breeds but this
was thought to be an epiphenomenon related to the frequency of Quarter
Horses at boarding stables. Weight loss, excessive recumbency and/or
trembling were the first signs noted. Other clinical diagnostic signs
included: constant shifting of the weight in the rear limbs,
abnormally low head carriage and muscle fasciculations. Excellent to
ravenous appetites were present in all cases and marked coprophagia in
some cases. Abnormally high serum concentration of muscle-derived
enzymes was the only consistent serum chemistry abnormality found.
Abnormal glucose absorption, increased cerebrospinal fluid total
protein and intrathecal production of IgG were identified in a number
of cases. Euthanasia was performed on 5 horses within 4 days of
hospital admission, because of inability to stand or respiratory
distress, and on 18 horses after the diagnosis had been completed.
Five affected horses were maintained for observational purposes for
periods of 9 months to over 2 years after the onset of clinical signs.
They were given access to pasture and 2 were given supplemental
vitamin E as the only therapy. Marked clinical improvement occurred in
the 4 more acutely affected horses. Pathological findings, preference
of type 1 muscle fibre atrophy and lipopigment accumulation within the
capillary endothelium of the spinal cord of all cases, supported the
hypothesis of EMND being an oxidative disease.(ABSTRACT TRUNCATED AT
250 WORDS)
MeSH Terms:
* Animal
* Animal Feed
* Breeding
* Electromyography/veterinary
* Female
* Horse Diseases/epidemiology
* Horse Diseases/etiology
* Horse Diseases/physiopathology
* Horses
* Male
* Motor Neuron Disease/epidemiology
* Motor Neuron Disease/etiology
* Motor Neuron Disease/physiopathology
* Motor Neuron Disease/veterinary
* Prospective Studies
* Risk Factors
* Vitamin E/blood
Substances:
* Vitamin E
_________________________________________________________________
Subject: Vitamin E and Iron
Vitamin e decreases the hepatic levels of aldehyde-derived
peroxidation products in rats with iron overload. Parkkila, Seppo,
Onni Niemel[umlaut]a, Robert S. Britton, Kyle E. Brown, Seppo
Yl[umlaut]a-Herttuala, Rosemary O'neill, and Bruce R. Bacon.
Departments of Anatomy, University of Oulu, and Clinical Chemistry,
University of Helsinki, and AIV Institute, University of Kuopio,
Finland; Division of Gastroenterology and Hepatology, Department of
Internal Medicine, Saint Louis University School of Medicine, St.
Louis, MO 63110
_________________________________________________________________
APStracts 2:0187G, 1995.
_________________________________________________________________
Hepatic iron overload can cause lipid peroxidation with the formation
of aldehydic products, hepatocellular injury and fibrosis. Vitamin E
([alpha]-tocopherol) may prevent peroxidation-induced hepatic damage.
We used confocal laser scanning microscopy, digital image analysis,
and immunohistochemical methods to quantitate aldehyde-derived
peroxidation products in the liver of rats with experimental iron
overload with and without supplemental vitamin E. A strong
autofluorescent reaction co-localizing with iron deposits was present
in the livers of iron-loaded rats. Fluorescent granules were unevenly
distributed in the cytosol of both hepatocytes and Kupffer cells in
the periportal regions. Immunohistochemical studies revealed the
presence of malondialdehyde adducts in the periportal regions of the
iron-loaded rats. Vitamin E supplementation markedly reduced the
fluorescence intensity and the amount of aldehyde-derived peroxidation
products and changed the distribution of stainable iron and
iron-associated peroxidation products such that their levels were much
decreased in Kupffer cells. These results indicate that
aldehyde-derived covalent chemical addition products are formed in the
liver in iron overload. Vitamin E supplementation markedly reduces the
amount of these compounds and changes their cellular distribution.
These findings should be implicated in the role of antioxidant therapy
in conditions causing iron overload and lipid peroxidation.
Received 30 May 1995; accepted in final form 31 August 1995.
APS Manuscript Number G232-5.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 September 1995.
Subject: muscular dystrophy/mice/tocopherol
Pediatr Res 1996 Sep;40(3):444-9
Wheat kernel ingestion protects from progression of muscle weakness in mdx
mice, an animal model of Duchenne muscular dystrophy.
Hubner C, Lehr HA, Bodlaj R, Finckh B, Oexle K, Marklund SL, Freudenberg K,
Kontush A, Speer A, Terwolbeck K, Voit T, Kohlschutter A
Department of Neuropediatrics, Virchow Medical Center, Humboldt
University, Berlin, Germany.
A simple, reproducible test was used to quantify muscle weakness in
mdx mice, an animal model of Duchenne muscular dystrophy. The effect
of bedding on wheat kernels and of dietary supplementation of
alpha-tocopherol on the progression of muscle weakness was
investigated in mdx mice. When measured during the first 200 d of
life, mdx mice developed muscle weakness, irrespective of bedding and
diet. When kept on wood shavings and fed a conventional rodent diet,
mdx mice showed progressive muscle weakness over the consecutive 200
d, and eventually showed a significant weight loss during the next
200-d observation period. Progression of muscle weakness and weight
loss were almost completely prevented in mdx mice that were kept on
wheat kernel bedding. In contrast, only incomplete maintenance of
muscle strength and body weight was observed in mdx mice kept on wood
shavings and fed the alpha-tocopherol-supplemented diet. It is
concluded from these experiments that a component of wheat kernels
other than alpha-tocopherol is essential to prevent the progression of
muscle weakness in mdx mice.
PMID: 8865282, UI: 97018666
_________________________________________________________________
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