Dear Listfriends,
The topic of CoQ10 comes up frequently, and I thought you might be
interested in the following report, posted by Dr. Lieberman, on the NPF
list:
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Mitochondrial Function and Coenzyme Q10
in Parkinson's Disease
By Cliff Shults, M.D., Professor of Neurosciences, University of
California, San Diego; Chief, Neurology Services, Veterans Affairs San
Diego, Healthcare System; and Director, National Parkinson Foundation
Center of Excellence at University of California, San Diego/Salk
Institute


3-dimentional reconstruction of
a mitochondrion in a neuron in the brain
The study of mitochondrial function in Parkinson's disease (PD) was
stimulated by Dr. William Langston's discovery of a group of intravenous
drug users who had acutely developed the tremor; rigidity; and slowness
typical of Parkinson's disease after using a designer narcotic. Dr.
Langston and his colleagues determined that the chemical in the designer
narcotic responsible for the development of Parkinson's disease was
methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). To be toxic to the
dopamine-producing nerve cells in the substantia nigra (the brain cells
that are lost in PD) MPTP must first be converted in the brain to the
actual toxin, MPP+. The nerve cells in the substantia nigra are
selectively
damaged by MPP+ because the MPP+ is actively transported into those
cells.
Once inside the dopamine-producing nerve cells, the MPP+ is taken up
into
the mitochondrion, which is the part of the cells that makes energy.
MPP+
interferes with a certain step in energy production, complex I. Through
interference with energy production and a resultant increase in the
production of oxygen free radicals, chemicals which are toxic to cells,
the
MPP+ causes damage and death of the dopamine-producing nerve cells.

The observation that MPTP is toxic to nerve cells through interference
with
mitochondrial function led to studies of mitochondrial function in the
brains from patients with PD. Dr. Tony Schapira, working with Drs. Peter
Jenner and David Marsden in London, found that complex I activity was
selectively reduced in the substantia nigra of patients with PD. At
about
the same time, Dr. Davis Parker, who is now at the University of
Virginia,
reported a significant reduction in complex I activity in platelets from
patients with PD. Platelets are the cells in blood that cause it to
clot.
Platelets may seem an unusual tissue in which to study brain function,
but
many of the biochemical processes that occur in the brain also occur in
platelets. For example, platelets have been shown to take up dopamine,
and
they contain monoamine oxidase B (the enzyme inhibited by selegiline)
and
synuclein (the molecule involved in certain cases of familial PD). The
reports of Schapira and Parker have been subsequently confirmed by other
investigators.

Although the studies of Schapira and Parker indicated that mitochondrial
function is reduced in the brain and platelets from Parkinson's disease
patients, the possibility remained that the reduction was due to factors
other than PD. One possible confounding factor was the level of
debilitation. It was conceivable that debilitation associated with
advanced
PD might result in reduction in platelet mitochondrial activity in a
fashion akin to the anemia caused by chronic disease. A second possible
confounding factor was drug therapy. In the studies of mitochondrial
function described above, most patients studied were receiving treatment
with levodopa. This may be of significance because Dr. Serge Przedborski
and his colleagues at Columbia University have reported that chronic
treatment of rats with levodopa caused a reversible reduction of complex
I
activity in the substantia nigra.

Dr. Richard Haas and I at the University of California, San Diego,
reasoned
that if the reduction in complex I activity found in PD is part of the
process that results in death of dopamine-producing nerve cells in the
substantia nigra, then it should be found early in the course of the
illness. On the other hand, if the impairment in complex I activity is
due
to debilitation or medication for PD, then the activity should not be
reduced in patients with early, untreated disease. To address this
question, our group carried out two studies. First, we evaluated
mitochondrial function in platelets from a group of patients with
Parkinson's disease who had early disease and were not on medication for
PD, and from two control groups, age/sex-matched controls and spouses.
The
spouses acted as controls for the home environment. We studied
mitochondrial function in platelets from 18 PD subjects, 18
age/sex-matched
controls and 13 spouses. We found that the activity of complex I was
significantly lower in the PD patients than in either age/sex-matched
controls or spouses.

The first part of this study clearly showed that the reduction in the
activity of complex I defect found in platelets from patients with PD is
not due to debilitation or the effect of medication for PD. Our finding
further suggests that impaired complex I function may be part of, or the
result of, the processes that cause death of the nigral neurons.

To evaluate the possible effects of medications that are commonly used
to
treat PD on mitochondrial function, we evaluated platelet mitochondrial
function a second time in 11 patients after the patients had received
carbidopa/ levodopa (Sinemet 25/100, one tablet three times each day)
for
one month, and a third time after the patients had received
carbidopa/levodopa and selegiline (Eldepryl, 5 mg twice each day) for an
additional month. We found that treatment with carbidopa/levodopa and
selegiline did not affect mitochondrial function in platelets.

A goal of our research is to develop better treatments for PD
Mitochondria
produce energy in useful forms for the cells by transferring electrons
between molecules. The electron acceptor for complex I in the
mitochondria
in humans is a molecule named coenzyme Q10. Coenzyme Q10, also known as
ubiquinone, also appears to play an important role as an anitoxidant.
Antioxidants are molecules that are able to eliminate free radicals, the
molecules mentioned above that can damage cells. Coenzyme Q10's dual
functions as an integral member of the mitochondrial electron transport
chain and as an anitioxidant make it potentially important in the
treatment
of PD because evidence has accumulated that both mitochondrial
dysfunction
and damage to nerve cells in the substantia nigra due to oxidative free
radicals occur in PD.

To further explore the possible causes of the reduction in mitochondrial
function in the Parkinson's patients, Dr. Haas, Dr. Flint Beal (formerly
of
Massachusetts General Hospital, now the Chair of the Neurology
Department
at Cornell/New York Hospital), and I measured the levels of coenzyme Q10
in
the platelet mitochondria that have been isolated in our original study.
We
found that the level of coenzyme Q10 was significantly lower in the PD
subjects than in the control subjects, who had been matched for age and
sex.

Dr. Beal and I next investigated whether oral administration of coenzyme
Q10 could reduce the damage caused by MPTP in one-year-old mice. As
mentioned above, MPTP is the compound discovered by Dr. Langston that
selectively injures the dopamine-producing nerve cells in the substantia
nigra. Four groups of one-year-old mice received either a standard diet
or
a diet supplemented with coenzyme Q10 for five weeks. After four weeks,
one
group that had received the standard diet and one group that had the
coenzyme Q10 supplemented diet were treated with MPTP. The four groups
continued on their assigned diets for an additional week. We found that
treatment with coenzyme Q10 did not significantly affect the levels of
dopamine in the striatum in animals that did not receive MPTP. The
striatum
is the area of the brain that the dopamine-producing nerve cells in the
substantia nigra send fibers to. In animals that received MPTP, animals
fed
coenzyme Q10 had significantly greater preservation of dopamine in the
striatum when compared to animals that received a standard diet without
coenzyme Q10. We also found that the dopaminergic nerve fibers were
significantly preserved in animals that received coenzyme Q10. Because
coenzyme Q10 had not been systematically studied in PD patients, we next
undertook a pilot study in 15 Parkinson's patients of the effects of one
month of oral coenzyme Q10 (200 mg + vitamin E 400 I two, three, or four
times/day; five subjects at each dose). We evaluated adverse events,
plasma
levels of coenzyme Q10, signs of PD, and complex I activity in platelet
mitochondria. Oral coenzyme Q10 caused a significant increase in the
plasma
level at each dose studied. Coenzyme Q10 was well tolerated, but two
subjects at the highest dose had mild changes in the urine at the end of
the study. These changes did not persist and were of uncertain clinical
significance. In 12 subjects (four subjects at each dose), the activity
of
complex I was determined at both the baseline and final visits. When the
data from all 12 subjects were analyzed together, there was a trend
toward
an increase in the activity of complex I.

The above work stimulated development of a study to evaluate the effects
of
coenzyme Q10 in patients with early, untreated PD. Development of the
study
was a collaborative effort of Dr. Karl Kieburtz, Dr. David Oakes, Dr.
Ira
Shoulson and Sandra Plumb of the University of Rochester, Dr. Jay Nutt
of
Oregon Health Sciences University, Dr. Jorge Juncos of Emory University,
Dr. Beal, Dr. Haas, and myself. The study is supported by the National
Institute of Neurological Disorders and Stroke (NINDS), which is part of
the National Institutes of Health (NIH), under a new program to carry
out
pilot clinical trials of novel therapies for PD and other neurological
diseases. Drs. Mike Walker and Gene Oliver of NINDS have played
instrumental roles in the development of this new program, which
promises
to be very useful in bringing promising new treatments for PD into
clinical
trials.

The study will be carried out by investigators at 12 medical centers,
all
of whom are members of the Parkinson Study Group. The Parkinson Study
Group
is a consortium of over 50 of the leading clinical centers in PD in
North
America. Persons with early PD, who do not require treatment of their PD
with levodopa or other medication, will be eligible to participate in
the
study. Patients will receive one of three doses of coenzyme Q10 (300,
600
or 1200 mg per day) or placebo, so each subject will have a three in
four
chance of receiving coenzyme Q10. Each patient will be followed for up
to
17 months. Our study should indicate whether there is evidence that
coenzyme Q10 can slow the worsening that PD patients typically
experience.

This line of research began with the clinical observation that a then
unidentified chemical (MPTP) could cause a parkinsonian syndrome, then
progressed through the research efforts of many laboratories, and has
emerged into a clinical trial of a potentially protective treatment for
PD.
The support of the National Parkinson Foundation has been very valuable
to
our group and many other groups working in this area.

For further details regarding the study, please contact:

Sandy Plumb
Clincal Trials Coordination Center
1351 Hope Avenue, Suite 220, Rochester, NY 14620
Phone: 716-275-7311



--
Kathrynne Holden, MS, RD
Author: "Eat well, stay well with Parkinson's disease"
"Constipation and Parkinson's" --  audiocassette & guidebook
"Guidelines for Medical Nutrition Therapy for Parkinson's
disease" & Risk Assessment Tools
"Risk for malnutrition and bone fracture in Parkinson's
disease," J Nutr Elderly. V18:3;1999.
http://www.nutritionucanlivewith.com/

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