4-Jul-2006 (News-Medical Alert) - In preliminary results,
researchers have shown that a drug which mimics the effects of the
nerve-signaling chemical dopamine causes new neurons to develop in
the part of the brain where cells are lost in Parkinson's disease
The drug also led to long-lasting recovery of function in an animal
model of PD.

The findings may lead to new ways of treating PD and other
neurodegenerative diseases. The study was funded in part by the
NIH's National Institute of Neurological Disorders and Stroke
(NINDS).

The study suggests that drugs that affect dopamine D3 receptors
might trigger new neurons to grow in humans with the disease. Some
of these drugs are commonly used to treat PD. The finding also
suggests a way to develop new treatments for PD. The results appear
in the July 5, 2006, issue of The Journal of Neuroscience.

Parkinson's disease, a progressive neurodegenerative disorder that
causes tremors, stiffness, slow movements, and impaired balance and
coordination, results from the loss of dopamine-producing neurons in
part of the brain called the substantia nigra. While many drugs are
available to treat these symptoms during the early stages of the
disease, the treatments become less effective with time. There are
no treatments proven to slow or halt the course of PD. However, many
researchers have been trying to find ways of replacing the lost
neurons. One possible way to do this would be to transplant new
neurons that are grown from embryonic stem cells or neural
progenitor cells. However, this type of treatment is very difficult
for technical reasons.

The new study, conducted by Christopher Eckman, Ph.D., and Jackalina
Van Kampen, Ph.D., at the Mayo Clinic College of Medicine in
Jacksonville, Florida, focused on a second possible way to restore
function - prompting stem cells that normally remain dormant in the
adult brain to develop into neurons. While most researchers
previously believed the adult brain could not develop new neurons,
recent studies have shown that the brain contains stem cells and
that new neurons can develop in some regions. Studies by Dr. Van
Kampen and others also have shown that drugs which affect dopamine
D3 receptors can trigger development of new neurons (a process
called neurogenesis) in the brains of adult rats. Until now,
however, no one had shown that the newly developed neurons could
connect with other parts of the brain and restore function.

"This is the first study to show that endogenous neurogenesis
[development of new neurons from cells already in the brain] can
lead to recovery of function in an animal model of Parkinson's
disease," says Dr. Eckman.

The researchers gave either 2-, 4-, or 8-week continuous infusions
of a drug called 7-OH-DPAT, which increases the activity of dopamine
D3 receptors, into the brain ventricles of adult rats with neuron
loss in the substantia nigra and symptoms similar to human PD on one
side of the body. 7-OH-DPAT is not used in humans, but its effects
on dopamine receptors are similar to the drugs pramipexole and
ropinirole, which are approved to treat PD. The rats also received
injections of a chemical called bromodeoxyuridine (BrdU), which
marks proliferating cells, and infusions of a substance that
fluorescently "traces" how neurons connect. The animals were tested
before and 3 days after receiving the treatment to see how well they
could walk and reach to retrieve food pellets with their paws. A
subset of the rats was tested again 2 and 4 months following the
treatment.

Rats treated with 7-OH-DPAT had more than twice as many
proliferating cells in the substantia nigra as rats that were
treated with saline, the researchers found. Many of the newly
generated cells appeared to develop into mature neurons, and
approximately 28 percent of them appeared to be dopamine neurons by
8 weeks after treatment. Animals treated for 8 weeks also developed
almost 75 percent of the normal number of neuronal connections with
other parts of the brain and showed an approximately 80 percent
improvement in their movements and a significantly improved ability
to retrieve food pellets. These effects lasted for at least 4 months
after the treatment ended.

"There was a profound behavioral effect of the treatment, even after
it 'washed out' of the system," Dr. Eckman notes. "This shows that
the treatment affects the underlying pathology."

Several previous studies point to the possibility that drugs like
pramipexole and ropinirole might modify the course of PD, but this
effect is difficult to test and has never been proven, says Dr.
Eckman. While these drugs are useful in treating the symptoms of PD,
they have not been designed to prompt development of new neurons, he
adds. Altering how the current drugs work or developing new
compounds to enhance neurogenesis could provide an entirely new
avenue for treating this disease.

"These findings are very exciting for several reasons. Being able to
stimulate endogenous stem cells in patients would alleviate the need
for transplantation of engineered cells, and as a drug therapy, it
would be also easy to administer to patients. Moreover, given that
similar drugs exist, medicinal chemistry to maximize this effect
could be achieved quickly," says Diane Murphy, Ph.D., the NINDS
program director for the grant that funded this research.

Dr. Eckman and Dr. Van Kampen are now looking at how different doses
of pramipexole and similar drugs affect neurogenesis. Once they
identify the most effective doses in animals, researchers might be
able to test comparable doses in humans. They are also carrying out
experiments to learn if using drugs that act on other kinds of
receptors might stimulate neurogenesis in Alzheimer's disease and
other neurodegenerative diseases.