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.
The drug requires continual infusion.
"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.
Similar drugs exist and the researchers are examining the effects of other drugs in rats as a prelude to trying therapies in human sufferers of Parkinson's. This result could turn out to yield an effective therapy without the need to solve the many problems involved with the development of adult or embryonic stem cells grown outside of the body.
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