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 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.

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 more information.

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 http://www.nih.gov.


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* Van Kampen JM and Eckman CB. "Dopamine D3 Receptor Agonist Delivery to a 
Model of Parkinson's Disease Restores the Nigrostriatal Pathway and 
Improves Locomotor Behavior." The Journal of Neuroscience, July 5, 2006, 
Vol. 26, No. 27, pp. 7272-7280. 

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