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Dopamine drug leads to new neurons and recovery of function in rat model of Parkinson's
July 05, 2006In 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 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.
NIH/National Institute of Neurological Disorders and Stroke
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.
NIH/National Institute of Neurological Disorders and Stroke
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