"If you could get to patients as early as possible after diagnosis and provide a neuroprotective therapy, you might be able to stop or dramatically slow further loss of nerve cells, effectively maintaining the disease in its early stages," says Jay Schneider, Ph.D., professor of pathology, anatomy and cell biology and neurology and Director of the Parkinson's Disease Research Unit at Jefferson Medical College of Thomas Jefferson University in Philadelphia, who led the work. Dr. Schneider and his co-workers report their results June 29 in the journal Brain Research.
The drug, pramipexole (PPX), belongs to a class of drugs called dopamine agonists, which act directly on dopamine receptors, simulating the activity of dopamine. Parkinson's disease results from a lack of dopamine-producing cells. PPX is frequently given to early-stage patients in the hope of improving symptoms and delaying the need for another anti-Parkinson's drug, levodopa. The researchers studied both young and old mice that had been given a neurotoxin that in turn caused a Parkinson's-like condition.
To assess the neuroprotective properties of PPX, some mice were given the drug at the same time they were given the toxin. Some of these animals continued to receive PPX for several days while others received the drug for as much as two weeks. Others did not receive the drug.
The effect of the drug was "dramatic," Dr. Schneider says, and more pronounced in the younger animals. "We were able to prevent nearly 100 percent of the brain cells from dying, which is amazing. It seems like the greatest effect came when giving both the toxin and drug at the same time and then continuing the drug for another two weeks," he says.
Dr. Schneider and his co-workers think that PPX may somehow interfere with apoptosis, or programmed cell death, and perhaps other early death-related mechanisms set into motion early in the cell death process.
Dr. Schneider's team also found that the size of the dopamine cells was significantly greater in the animals who received the toxin and treatment simultaneously and continued to have the treatment for 14 days, suggesting that "in addition to its possible anti-apoptotic effects, the drug may work directly or indirectly as a neurotrophic factor - it may actually enhance the cells," he says.
Dr. Schneider says that although the way in which PPX exerts its neuroprotective effect is not known, he and his colleagues believe that the neuroprotective effects of the drug are not related to its ability to act on dopamine receptors. Researchers don't know the drug's long-term effects or how much it might help slow the progression of the disease, he notes.
Some patients show symptomatic benefit from the medication. But it has side effects, such as excessive daytime sleepiness, and rarely, sudden onset of sleepiness. "One of the problems in showing a neuroprotective effect in patients is knowing how much of a dose to give," he says. "The neuroprotective dose in a mouse may be higher than the highest tolerable dose in a human.
The scientists currently are doing studies to try to understand the mechanisms behind the drug's neuroprotective effects. A key will be to first understand the way in which cells die after exposure to the neurotoxin, Dr. Schneider says.
In related work, Dr. Schneider's group is looking for patients to help them find out whether a promising, drug, GM1 ganglioside, can improve symptoms, delay disease progression, and in some cases actually restore damaged brain cells in Parkinson's disease patients.
Dr. Schneider is leading a five-year study involving 150 patients. The researchers want to compare the effectiveness of GM1 ganglioside - a naturally occurring substance that plays an important role in cell growth, development, and repair - to standard Parkinson's disease treatments, which improve symptoms but do not affect the disease process. For more information, call 1-800-JEFF-NOW.
Contact:Steve Benowitz or Phyllis Fisher at 215-955-6300. After Hours: 215-955-6060.
Journal
Brain Research