NO PARKINSON'S ZONE

NO PARKINSON'S ZONE

Treatments for Parkinson's disease have progressed dramatically, leading to ane asing of symptoms and increased optimism among many patients.
by Jon Nalick
n a frightening betrayal by their own bodies, people with Parkinson’s disease often find themselves reduced to the role of spectators of their own limbs. And with minds that remain unaffected by the disease, dealing with these uncontrolled movements can be as socially awkward as it is physically challenging.
The understanding of the disease is growing rapidly, with effective treatments available that can ease or eliminate symptoms. With medical advances coming soon, patients will be able to live with Parkinson’s without letting the disease take over their lives.
Mark Lew, M.D., associate professor of neurology and director of the division of movement disorders at the Keck School of Medicine, says, “When I started treating Parkinson’s patients 10 years ago, I used to lose sleep when a young patient came into my office because I knew that person would have to live a long time dealing with the disease—and with treatments that can have significant side effects.
“But in the last five years, treatments have changed dramatically, with new classes of drugs becoming available and research that suggests new mechanisms to fight the disease. I’d say that in five to 10 years, if we don’t have a cure, we will have radically more effective treatments. There is just tremendous optimism for patients today.”
That hope stems, in part, from research and clinical studies that Lew and his colleagues are performing at USC—potential treatments that may one day regenerate and restore function to portions of the brain that deteriorate in those people with the disease.
First described in 1817 by British physician James Parkinson as “the shaking palsy,” the disease occurs when nerve cells that produce a crucial neurotransmitter called dopamine die or function aberrantly.
With diminished dopamine, individuals can develop alarming symptoms. Often the first symptom of the disease is a tremor of a limb or hand on one side of the body, especially when the patient is at rest. Other common symptoms include rigidity or stiffness of the limbs and trunk; bradykinesia, or slowed movement; speech impairments; and postural instability or impaired balance and coordination. People with Parkinson’s often show reduced facial expressions and speak in a soft voice.
The disease, which typically grows worse over time, directly affects the body. No matter how difficult movement becomes, the patient’s mind continues to function normally, except for a small group of patients who may develop dementia. The stress and challenge of fighting with one’s own body can lead to problems including depression, sleep disturbances and sexual dysfunction. Researchers suspect that Parkinson’s disease is triggered by a combination of environmental and genetic factors—although the disease is not directly linked to heredity as is, for example, eye color.
While the cause remains unknown, the effects and course of the disease are well documented.
Symptoms first appear when 80 to 85 percent of the dopamine-secreting cells located in the center of the brain die. The remaining cells attempt to compensate by ramping up production of the chemical, which is vital for coordinating the body’s movements, but can only muster 40 to 60 percent of the amount needed.
As more of the dopamine-producing cells die, symptoms worsen—usually slowly and gradually. But symptoms vary considerably among individuals, Lew says.
“There are people who have the disease for 15 years who remain completely functional, while others who have it for three to five years who are completely disabled. At worst, you can have a profound loss of balance and be wheelchair-bound, although that usually occurs much later in the disease,” he says.
Parkinson’s usually strikes people age 50 and older; it affects one percent of all those over 65. It occurs infrequently in younger adults and juveniles. More than one million Americans suffer from the disease.
Early treatments for Parkinson’s disease came from extracts of the belladonna plant that helped relax stiff muscles and calm tremors. These were replaced following World War II, when other drugs that achieved the same effect came into use. By the 1960s, researchers discovered the link between dopamine deficiencies and Parkinson’s disease, opening new avenues for treatment, Lew says.
By 1970, physicians began prescribing Levodopa, or L-dopa, a drug that the brain quickly converts into dopamine, relieving symptoms, but also eliciting undesirable side effects that prompted many to reduce or discontinue its use. Five years later, Levodopa was combined with another drug that mitigated the side effects, to create a drug called Sinemet. Bromocriptine, which also helps stimulate production of dopamine, became available at about the same time.
Lew says that even though drug therapy is effective, as the disease progresses, it requires larger doses to get the same results, making side effects more likely and more severe. Common side effects of the drugs used to treat Parkinson’s include involuntary movements of the face and limbs, called dyskinesias, and changes in muscle tone, called dystonias. And sometimes, after long periods of treatment, the drugs may temporarily cease to work without warning. The challenge for physicians has been to maximize the beneficial effects of medication while minimizing potential side effects that can be as distressing as the disease.
Lew says that for more than two decades, the medical community provided few significant improvements in treatment. But that changed in 1997 when the U.S. Food and Drug Administration (FDA) approved four new drugs: Mirapex, Requip, Tasmar and Comtron.
According to an FDA report, Mirapex and Requip directly stimulate dopamine receptors in the brain and allow patients to improve mobility. In clinical trials, patients taking Mirapex alone saw as much as a 30 percent improvement in symptoms. Com-bining Mirapex with L-dopa drugs allowed patients with advanced Parkinson’s to reduce doses of L-dopa by as much as 25 percent. Requip trials showed similar benefits, allowing patients to reduce L-dopa doses by about 31 percent.
Tasmar and Comtron are new drugs called COMT inhibitors, which need to be used with L-dopa to improve Parkinson’s symptoms. Initially in clinical trials, patients with a stable response to L-dopa drugs who took Tasmar experienced significant im-provements in daily activities such as talking, writing, walking and dressing. But Tasmar is rarely used now because of the risk of sudden and severe liver failure. Comtron was FDA-approved shortly after Tasmar. Comtron is well tolerated and offers improvement of symptoms without liver function problems.
Lew says that the new drugs offer physicians a greater number of tools with which to tailor an individual’s therapy—which is important, because younger patients may respond differently than older patients to a similar regimen of drugs.
Parallel to the development of drug therapies, brain surgery has been used to control tremors by destroying specific areas that promote them, but its use declined rapidly several decades ago with the advent of L-dopa.
However, surgery has seen a resurgence of popularity due to refinement of new technologies, Lew says. Deep brain stimulation uses an electrical implant, similar to a cardiac pacemaker, to regulate activity of target areas of the brain. This technique was recently approved by the FDA for Parkinson’s disease.
Lew cautions that although the surgical procedures may bring dramatic relief for 10 years or more, they are not a cure and do not slow the progression of the disease.
Meanwhile, scientists continue to explore the causes of the disease in hope of hastening a cure.
Armed with a $2 million grant from the National Institute of Environmental Health Sciences, Enrique Cadenas, M.D., Ph.D., professor and chair of the Department of Molecular Pharmacology and Toxicology at the USC School of Pharmacy, is investigating whether a process known as oxidative stress plays a key role in triggering Parkinson’s.
Cadenas is trying to determine whether elevated levels of nitric oxide can essentially knock over the first domino in a chain of molecular events that destroy dopamine- producing cells.
He hypothesizes that nitric oxide—a highly reactive molecule with an unpaired electron—encourages the production of oxygen free radicals, which are capable of doing extensive damage to the dopamine-producing cells’ mitochondria. Mitochondria provide the energy cells need to survive, and if they fail, the cells die.
Jean Shih, Ph.D., the Boyd and Elsie Welin Professor at the USC School of Phar-macy, studies a brain enzyme called mono-amine oxidase that breaks down dopamine.
In her research, she uses mice that are missing a gene that codes for one form of the enzyme. She has found that those mice metabolize certain neurotoxins differently than normal mice and are protected from acquiring Parkinson’s disease. That finding may hold a key to protecting people in the future.
Michael Jakowec, Ph.D., assistant professor of neurology at the Keck School of Medicine, is engaged in a flurry of experiments aimed at showing how vulnerable or sick brain cells can be strengthened, replaced or protected from injury.
His research focuses on “neuroplasticity,” basically the brain’s ability to alter itself at a molecular level—for example, in response to new experiences, chemical stimuli or damage. These molecular self-alterations can be positive, such as when they aid needed nerve growth, or negative, as when they prompt nerves to fire in an uncontrolled fashion.
In his work, Jakowec examines mice that have been exposed to a chemical known as MPTP, which appears to replicate Parkinson’s disease and its effects. He investigates how gene and protein expression may mitigate damage, how certain chemicals help the brain repair itself and how brain cells respond to damage. These studies are already generating clues that may ultimately lead to better treatments, he says.
Jakowec and his colleagues are investigating how to coax remaining dopamine-producing cells to accelerate production of the chemical—and whether certain drugs can prevent damage to those cells in the first place.
Researchers are also interested in seeing if stem cells—primal cells that under certain conditions can differentiate into any tissue in the body—can be used as a potential treatment or cure.
“Stem cells are really coming into play as we learn more about them in the lab. The angle with stem cells is that they can potentially be turned into the cells that were lost and transplanted, and hopefully they’ll pick up the slack. Or they may carry important molecular factors that promote the brain’s intrinsic ability to heal itself,” Jakowec says.
He says that stem cell research may ultimately prove to be a useful, but temporary, stepping stone to a better treatment or cure. For example, once researchers discover the specific mechanism stem cells use to heal the brain, they may be able to exploit that mechanism more precisely with tailor-made molecules or therapies.
Jakowec recently received a $1 million, four-year grant from the National Institutes of Health to study the role of the neurotransmitter glutamate as a regulator of dopamine activity. The research may eventually help pave the way for new classes of drugs to alleviate Parkinson’s.
Jakowec is also participating in an inter-disciplinary collaboration with researchers in the Department of Biokinesiology and Physical Therapy to determine whether
exercise can help alleviate symptoms of Parkinson’s. The research, prompted by studies in mice that have a Parkinson’s-like illness, shows that an hour of exercise on a treadmill can promote significant, measurable improvement in symptoms.
Giselle Petzinger, M.D., assistant professor of neurology, says that kind of research, which draws from information coming from basic science labs to design potentially useful clinical experiments, is USC’s strong suit.
“We’re always thinking about how the research translates into human terms,” says Petzinger, who divides her time between performing basic science experiments and treating patients.
“Dealing with patients on a day-to-day
basis, you want to bring hope—and you can do that just by sharing information about the current research with them. And every day we’re understanding the disease better and better, and that can clearly lead to better treatments,” she says.
“We cannot guarantee that we can cure the disease in five years, but we can say that because of the research that’s going on now, the way we will manage the disease in five years will be dramatically different,” she adds.
“Things are changing that fast.”
For more information about the research and treatment of Parkinson’s disease, or to learn more about The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273).

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