Dopamine drug leads to neuronal replacement: a cure for Parkinson's Disease?

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 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 focussed on finding 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 and faces numerous regulatory hurdles not to mention the cost of such a therapy.

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 potentially available for neuronal differentiation. Studies by Dr. Van Kampen and others also have shown that drugs which affect dopamine D3 receptors can trigger 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.

The researchers gave either 2-, 4-, or 8-week continuous infusions of a drug 7-OH-DPAT, a dopamine D2/D3 receptor agonist 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 bromodeoxyuridine (BrdU), which marks proliferating cells, and infusions of a fluorescent tracer to map neuronal connections. 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.

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.

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.

Message posted by: Simon Chandler