Research offers hope to patients with Parkinson's disease

New drugs and surgical procedures are already being tested in the laboratory - treatments that hold real promise for those who suffer from this disorder.

"Research on Parkinson's is exploding," said Joseph Jankovic, MD, director of the Parkinson's Disease and Movement Disorders Clinic at Baylor College of Medicine. The clinic was established in 1977 and has been recognized by the National Parkinson's Foundation as a center of excellence since 1992. "We are currently doing dozens of studies just here at Baylor on the disease."

For years, treatment for Parkinson's disease remained fairly static. Parkinson's patients could take the prescription drug levodopa to relieve symptoms such as rigidity and tremor, but the drug's effectiveness was limited by side effects. As symptoms increased, the dosage also had to be increased, making it more likely that patients would suffer side effects such as severe nausea, vomiting, unpredictable fluctuations in their condition, and uncontrollable jerking movements called dyskinesia. Eventually, the side effects of levodopa become worse than the disease itself.

In the past, patients could undergo a surgical procedure called a pallidotomy, which destroyed the globus pallidus, part of the brain believed to cause tremor, stiffness and slowness in Parkinson's patients. Or they could have a thalamotomy, a surgical procedure that removed part of the thalamus, another area of the brain that controls tremor. Both procedures produced only partial benefit and carried significant risk.

An estimated 1 million people in the United States have Parkinson's, which is caused when the brain is deficient in a substance called dopamine. What causes the deficiency is not fully understood, but a potential breakthrough occurred recently when Weidong Le, MD, PhD, associate professor of neurology at Baylor, identified a defect in the Nurr1 gene as a risk factor for Parkinson's disease in some patients. The Nurr1 gene is essential for the development and maintenance of the brain's dopamine system, a finding originally reported by Orla Conneely, PhD, a professor of cellular and molecular biology at Baylor.

"From our study of familial Parkinson patients from the Houston area and other states, we found that almost 10 percent of the study participants, who were Caucasians, had the Nurr1 gene defect," Le said.

Using the defective gene, Le is trying to develop cell and animal models that can mimic pathological and biochemical changes seen in human Parkinson's disease. Unlike current animal models for Parkinson's, Baylor's animal model degenerates as time progresses, mimicking part of the disease process of Parkinson's in humans.

The discovery of the Nurr1 gene defect and the development of an animal model may shed light on how dopamine levels degenerate in Parkinson's and provide useful information for developing treatment for this disease. Le works with Jankovic and other scientists to learn more about the cause of cell death in Parkinson's disease and how to prevent it with various neuroprotective therapies.

Treating the symptoms

Besides levodopa, Parkinson's disease is most often treated with drugs called dopamine agonists, which stimulate the brain's dopamine receptors directly without the need for dopamine. New dopamine agonists are more effective and have fewer side effects than traditional dopamine agonists and medications such as levodopa. The Parkinson's Disease Center is studying several experimental new dopamine agonists and other anti-Parkinson's drugs in its Experimental Therapeutics Center and investigating different and novel ways to deliver Parkinson's drugs. One such alternative method is the transdermal patch. By delivering the drug continuously through the skin, the patch provides a more constant stimulus to the brain and may help reduce side effects like nausea and vomiting, common with oral drugs.

Another new class of drug under investigation at Baylor, called an adenosine A2 receptor antagonist, may help treat or prevent dyskinesia experienced by persons taking levodopa. Neuroprotective drugs that block biochemical pathways that lead to cell death hold tremendous promise as a method of halting or at least slowing down or delaying the progression of the disease.

Deep brain stimulation, which Baylor neurosurgeon Richard Simpson, MD, and Jankovic helped pioneer, is a newer surgical option for Parkinson's patients and patients with severe disabling tremor who don't respond well to drugs. When the appropriate brain target is selected, such as the subthalamic nucleus, this procedure can also improve other Parkinson's symptoms and Levodopa related side effects. The surgeon implants an electrode in the thalamus or the subthalamic nucleus, which is connected to a stimulator implanted under the skin in the upper chest. The stimulator generates electrical impulses that block the tremors, dyskinesias and dramatically improve response to levodopa. This procedure is similar to the thalamotomy and pallidotomy but it does not cause a permanent lesion in the brain and more importantly it allows the treating neurologist to adjust the stimulating parameters and tailor the treatment to the specific needs of the patient.

Recent improvements in neuroimaging and microelectrode recordings have also helped make these procedures safer and more effective.

Jankovic also frequently prescribes injections of botulinum toxin, commonly known as Botox, to patients with Parkinson's and other tremors as well as other involuntary movements caused by abnormal muscle spasms. While Botox is now best known for its cosmetic use, it was actually first approved to treat blepharospasm, a movement disorder that causes the eye to spasm. Jankovic conducted the initial clinical trial of Botox that led to its FDA approval as a treatment for blepharospasm. Since then, the drug has become as essential tool to treat movement disorders.

Putting on the brakes

While researchers have made great strides developing drugs and other treatments to help improve the symptoms of Parkinson's, there are currently no neuroprotective treatments that halt the progression of the disease. Le is working on that by genetically reengineering adult bone stem cells in hopes that they will turn into neurons that produce dopamine, and halt or reverse the progression of the disease. His long-term strategy is to introduce a foreign gene and a regulator gene into the stem cell to control the amount of dopamine expressed. The reengineered stem cells would then be injected directly into the brain of the patient. The theory is that the patient would not reject the stem cells because they would come from his or her own bone marrow.

"Our research is still in the beginning stages," Le said. "First we have to prove that the cells make the dopamine. Then if we find the cell has dopamine, we have to be sure that the cell releases it. After that we have to see whether the cells can regenerate in the brain."

Using bone marrow stem cells to generate other types of cells is a controversial process. Recent research reported in the journal Science by David Shine, PhD, an associate professor of neurosurgery, and other researchers at Baylor, showed special experimental conditions might be necessary to induce adult bone marrow stem cells to produce the kinds of cells found in the brain.

"That's why genetically altering the stem cells is a key element of our research," Le said. "Our preliminary study results suggest that it is possible for adult stem cells to differentiate into neuronal cells under certain conditions."

Looking for causes in the environment

Environmental factors, such as pollution, also may be a cause of Parkinson's.

"Pesticides, used in the early 60s or 70s to kill insects in fish ponds have been shown to be a possible cause of Parkinson's," Le said. "The agent rotenone in certain types of pesticides is toxic to dopamine neurons. We administered this agent in our mouse model to see how and why it affects the dopamine neurons."

Mice who received the rotenone lost more than half of their neurons in two months. Le found that the toxin damaged the dopamine cells by inhibiting the action of mitochondria, which produced energy for the cells, and by inducing nitric oxide to produce free radical damage. Researchers at Baylor are continuing to try to determine exactly why this happens. The hope is that someday, they may use their knowledge to develop a compound that will protect people who are frequently exposed to hazardous materials containing rotenone or other pesticides. So far, several compounds tested in cell cultures and animal models have been successful protecting dopamine neurons.

Anticipating the future

Both Jankovic and Le have spent decades unraveling the mysteries of Parkinson's, in hope of one day finding a cure. Le is hopeful that researchers may find it in his lifetime.

"Compared to other neurodegenerative diseases, Parkinson's is easier to understand," Le said. "We know that we are dealing with the dopamine system and that the way to improve the symptoms is through the dopamine system. Of course we also need to pay attention to other systems. With effort from physicians, scientists and neurosurgeons, we can find a way to cure this disease."