|Dopamine Drug Leads to New Neurons and Recovery of Function
in Rat Model of Parkinson's Disease
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 (PD). 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 which 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
“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
The NINDS is a component of the National Institutes of Health (NIH) within
the Department of Health and Human Services and is the nation’s primary supporter
of biomedical research on the brain and nervous system. The NINDS mission is
to reduce the burden of neurological disease. Go to http://www.ninds.nih.gov/ for
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov.