[lou_lou]

THE SEARCH FOR THE PERMANENT OFF SWITCH




Category: Neurochemistry
Term Paper Code: 916


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THE SEARCH FOR THE PERMANENT OFF SWITCH

Keywords: Tremor, substantia nigra, neurotransmitter, neural grafting



MCB 165

DAVID PRESTI



ABSTRACT



Parkinson's Disease has affected many individuals, and their families. The disease and its symptoms have been around for over 4,000 years. Many of the traits that are associated with Parkinson's have been identified. These traits are centered with the destruction of a particular part of the brain, the substantia nigra. The loss of dopamine, and the imbalance of other neurotransmitters, led to many of the disease's symptoms. The cause of the disease is still unknown. Some ideas such as genetic inheritance, and free radicals are thought to play a serious role. Though no cure has been made, there are specific drugs that are able to delay certain parkinsonian traits. These groups of drugs, when taken simultaneously prove to be successful. However, the drugs, though initially very effective, eventually give way. New research has provided surgical methods to further delay the onset of those traits. Even with the new drugs and on going research, 1.5 million individuals still struggle daily with the disease. It is through their eyes that one can see the on/off struggle they face every day with Parkinson's. One can only hope that the day will come when science will find the permanent "off" to Parkinson's





When summer vacations began back when I was in junior high, I didn't go off to camp, or hang out with my friends. I would spend the majority of my vacation at my grandfather's house. My parents would wake me up every morning, and take me to grandpas on their way to work. I would say hello to my grandmother, then immediately head towards the back yard. There, my grandfather would have started our work for the day. Each day was filled with different activities. From weeding, to putting up a basketball hoop, there was always something to be done at my grandfather's house.

As the years went on, the work never stopped. I was in high school now, and I continued to go to my grandfather's house for the summers. But as time went on, I began to notice a difference. Now, I was doing the majority of the work. My grandfather played more of a coach, telling me exactly what to do. I also noticed that things that would have taken only hours for my grandfather to do, now took a whole day. Many chores that once seemed second nature, now were left for me to finish. My grandfather was noticeably slowing down in his everyday functions.

Nearing the end of my grandfather's life, one could never believe that the man sitting in his chair, with a mask-like expression, was a man of strength and determination. A man, who taught me how to fix anything, now relies on me to push him around in a wheelchair. The land my grandfather once loved, has now, after every fall, become a hated enemy. From that point, until the end of his life, my grandfather struggled with Parkinson's disease.

So naturally, when I heard that we could do a report on any topic that related to out Neuro class, I decided I would write about Parkinson's disease. A disease that so many people, like my grandfather, struggled with in their daily life. In this paper I will talk about the history of the disease, it's symptoms, and various treatments. I will also talk about various experiments that are being done this present day to further understand and treat Parkinson's.

As we have learned in class, Parkinson's disease (PD) was first diagnosed by James Parkinson in 1817. But, descriptions of the symptoms of PD have gone back for more than 4,000 years ago. Hieroglyphs in Egypt, and the Bible have described individuals with tremor, posture, and off balanced walk that typify the disease. Although many of the symptoms are known, the cause of the disease is still a mystery. No sure diagnosis is available. The best forms of diagnosis are neurological examinations, and even those are only 80-90 percent accurate.

PD occurs in every part of the world, and affects both men and women equally. In the world today, approximately 1.5 million suffer from PD. Parkinson's is usually associated with people over the age of 50. Upon diagnosis, PD progression is very gradual. This makes it very hard for a physician to realize if a patient truly has Parkinson's or not. Abraham N. Lieberman, and his book Parkinson's Disease: The Complete Guide for Patients and Caregivers, describes some of the "cardinal signs" of PD. One of the major signs is tremor. Tremor is experienced by more than half of all pakinsonians. The tremor can vary due to the time of day, or various emotional stresses. Another sign of PD is rigidity. Rigidity is defined as when the muscles are constantly tensed, or always contracted. This rigidity is what leads to a mask-like stare that so many parkinsonians have. Another sign that parkinsonians have, which is closely related to rigidity, would be bradykinesia. This is where a person takes a seemingly long time to do regular activities, such as walking, or sitting down. Another cardinal sign of PD is postural instability. Traits involved would be the inability to stand up straight, picking up ones feet, swinging of the arms, or to balance oneself after being bumped. These traits make it hard for a person with PD to do things that were once instinctively done.

There are also secondary signs of PD. Many individuals who are in the early stages of the disease may not display major traits, as described earlier, but go through a number or secondary signs. Some examples of this are feelings of being in a "rush". Some even stand in a stooped fashion, like a sprinter trying to propel themselves forward. Others shuffle their feet, which often lead to dangerous falls. Another secondary sign is the lowering of one's coordination. Such examples would be the inability to unbutton ones shirt, non-legible handwriting, or a decrease in the ability to play one's favorite sport. Many times the lowering of coordination skills are accompanied by speech and swallowing dysfunction. Many parkinsonians also experience a decrease in blood pressure. This may occur when sympathetic nerves, which control the heart and blood vessels, are damaged due to PD. Many people who have this trait often complain of dizziness or lightheadedness when they quickly stand up.

Perhaps one of the more disturbing secondary traits that may accompany PD would be dementia. Dementia is defined as the progressive loss of memory and other intellectual functions. Often, changes in personality and behavior often accompany dementia. Parkinsonian dementia often is associated with older patients. About 300f the people diagnosed with PD eventually become demented. One form of dementia, Alzheimer's Disease, is often occurs in concurrence to PD. The fact that dementia only occurs in the elderly has led researcher to believe that two separate diseases may exist. In the younger patients, the disease tends to be more motory oriented, while the elderly experience the same motory problems, but those problems are accompanied by problems in cognition and emotion.

Although many symptoms of Parkinson's disease were known, very little was known why those symptoms occurred. The motor problems usually associated with PD could be targeted to the brain. This is because human movement is controlled from many different brain centers. The origins of movement impulses are believed to begin from the cerebral cortex and basal ganglia in the brain. The most studied, and most understood part of the basal ganglia would be the corpus striatum. Being one of the body's motor control centers, the striatum receives information on body position and movement from other parts of the brain. The striatum then fine tunes the information and initiates the movement command. After the command is set, the striatum then sends impulses to the rest of the brain's motor control system, and eventually throughout the body. As we learned in class, the substantia nigra is located just below the striatum in the midbrain. In the 1920s, it was here that scientists discovered one of the hallmarks of PD. As we had learned in lecture, in the 1920s, many researchers had discovered that patients suffering with PD had a large decline in the number of nerve cells in the substatia negra. From lecture, we know that the substantia negra nerve cells make dopamine. A healthy brain would produce enough dopamine to allow the brain to carry out the complicated activities. But, parkinsonians' dopamine-producing cells are diminished, and the brain cannot execute the millions of transmissions needed to maintain smooth voluntary movement, or good posture.

Dopamine is not the only neurotransmitter in the basal ganglia. Seratonin and acetylcholine play key roles in the brain's motor control. In excess, acetylcholine is known to have excitatory effects. This increase in acetylcholine results in an increased synaptic transmission within the basal ganglia. Over-stimulation of neurons can cause similar symptoms, as would a shortage of dopamine, such as tremor and rigidity. Scientists have concluded that an interaction between dopamine, acetylcholine, seratonin, and other neurotransmitters is of great importance. An imbalance of any one could produce drastic effects, effects that may lead to PD. This imbalance may be due to the presence of particular enzymes. One particular enzyme, monoamine oxidase B (MAO B), breaks down dopamine. Since the balance of neurotransmitters is so important, MAO B prevents the accumulation of dopamine within the neuron. As one ages, however, the amount of MAOB enzymes increases. With this increase, it is believed, that

MAO B is responsible for the release of free radicals (MPP+). These radicals may damage neurons and other healthy cells. There is much evidence that increased substantia negra damage due to free radicals (Schapira 1999). In a healthy brain, the substantia nigra produces another enzyme that breaks down and neutralizes free radicals. But, in PD patients, the enzyme is drastically depleted. Thus, some cells in the substantia nigra may be destroyed by free radicals.

The processes in which cells die due to free radicals are either from apoptosis or necrosis. Necrosis is the disintegration of a cell and all its organelles, in order to prepare it for phagocytosis. Necrosis often involves the swelling of the cell, and possible harm to neighboring cells. Apoptosis, another way a cell can die, is kinder to the surroundings. Apoptosis only affect only the targeted cell. Each individual cell contains apoptotic genes in its genome. These genes are triggered when the cells are exposed to environmental stressors, such as free radicals. Apoptosis is completed when serine markers accumulate on the cell membrane, and signal microphages to phagocytize it.

Schapira (1999) points out that there is now evidence that shows apoptotic cell death in the brain of patients with PD at their time of death. As previously mentioned, apoptosis is usually quick. If this is true, many brain cells in parkinsonian patients may be in the pre-apoptotic stage. If that is true, researcher could discover a way to save those cells from apoptosis.

Right now, there is no cure for PD. The symptoms each individual experiences will worsen over time. Physicians do not even know the exact speed, or to what extent the disease will progress. The truth is, the disease is different, and varies within each individual. This unpredictability is what frustrates many that have the disease. Many physicians use a rough scale to identify where their patients lie. One such scale is called the Hoehn-Yahr Scale. This scale consists of five stages: 1) no visible disease 2) disease involves one side of the body 3) disease involves both sides of the body, but does not impair balance 4) disease markedly impairs balance or walking 5) disease results in complete immobility. There are drugs that can slow the progression of these stages.

Although there are drugs capable of controlling the progression of PD, many live by the motto "less is best". Many of the drugs are powerful, have strong side effects, and cost a lot of money. The side effects range from cramping to hallucinations and confusion. Another downfall of parkinsonian drugs is the ability for the body to build up tolerance over time. Balancing the benefits and the side effects often becomes the main challenge in Parkinson's treatment. Right now there are four main categories of parkinsonian drugs, anticholinergic therapy, replacement therapy, dopamine agonists, and MAO B inhibitors.

The first treatment, anticholinergics, block the action of acetylcholine. If you remember earlier, the lowering of dopamine due to PD causes acetylcholine to produce an excitatory effect causes parkinsonian symptoms. The blocking action of anticholinergics reduces those symptoms. A French neurologist, Jean-Martin Charcot, discovered that certain plant extracts were in fact anticholinergics. Scientists later discovered that the two active ingredients in most anticholinergics were hyoscine and atropine. Some side effects of anticholinergics are blurry vision, dizziness, and urinary retention. Anticholinergics are one of the initial drugs used to treat early parkinsonian patients.

The next group of drugs were known as replacement therapy for drastically low amounts of dopamine in the brain. The main problem was the insertion of dopamine itself into the brain. We learned in class that dopamine is unable to cross the blood-brain barrier. A pre-cursor to dopamine, L-dopa, can cross the barrier (BBB). L-dopa was first used by W. Birkenmayer in 1960. This did not prove too successful. Many of Birkinmayer's patients experienced profound nausea and hypotension. The reason for this would be that only 100f the administered L-dopa actually reached the brain. The 90% were converted to dopamine in the body. Such a conversion is what produced the strong side effects. In order for L-dopa to be considered as a successful therapy for PD one more step was needed. This step occurred in the mid 1970s. A new drug, carbidopa, blocked the conversion of L-dopa outside the brain. Since carbidopa could not cross the BBB, cannot stop the conversion of L-dopa to dopamine inside of the brain. Thus a new drug containing both L-dopa and carbidopa, Sinamet, was put into the market. Today, Sinemet is the single most effective drug available to treat PD. Most patients are able to control their symptoms for many years, with very few side effects. The fact is, however, that Sinamet does loose its potency after a period of time.

The next group of drugs greatly stimulated the effects of dopamine. Dopamine agosinsts stimulated dopamine receptors in the striatum. At first these agonists were too toxic to provide reliable relief from parkinsonian symptoms. Over time a drug called bromocriptine was used by D. Calne, to stimulate striatal receptors (D2). Although these agonists produce similar side effects as Sinemet, they are often less severe. Often, the agonist is taken together with Sinemet.

The final group of drugs MAO inhibitors was discovered in the 1960s. MAO, if you recall, is involved in the creation of MPP+. MPP+ destroys substantia nigra cells. Early in MAO inhibitor studies, the drugs inhibition of dopamine breakdown was not observed exclusively in the brain, but also caused damage in the liver. However, in the early 1960s, Joseph Knoll created a drug called selegiline which inhibited the breakdown of dopamine only in the brain. Using sinemet, combined with this inhibitor, it was discovered to increase the effectiveness of the sinemet for over a year. These four classes of drugs, some function best when combined with others, have proven to be essential in the treatment of PD.

One of the other major procedures in treating PD is neural transplantation. Isao Date and Takashi Ohmoto (1999) performed experiments on various types of donor tissue. To start, Date and Ohmoto used two types of animal models for transplantation studies. The first is the 6-Hydroxydopamine Model (6-OHDA). 6-OHDA is a neurotoxin, and is injected directly into the substantia nigra of a rat. The second animal model is an injection of MPTP into a monkeys or mice to produce parkinsonian effects. With the MPTP model, dopamine count significantly decreased with older mice, while no significant changes were seen with the young. Old mice were more sensitive to MPTP than the young mice were.

Now that that the parkinsonian traits were established in the mice, the first of the series of neural transplants could begin. The first transplant would be that of a fetal substantia negra. In order for the graft to be accepted into the brain, the hosts were immunosuppressed with 15-deoxyspergualin (DSG). In order to find out whether or not the dopaminergic neurons survived, the graft was stained with tyrosine hydroxylase. After four weeks the majority of the DSG treated mice showed surviving neurons. All the grafts without DSG were rejected.

Another procedure for neural grafting was the idea of transplanting preserved donor tissue. Date and Ohmoto experimented with two ways of storage. The first was cool storage and the second freeze storage. For the cool storage, fetal rat ventral mesencephalons were kept in a buffer solution kept at 4 degrees Celsius. Tissues that had been cooled for 16 hours or less still proved to survive fairly well. For the freeze storage, the graft was stored in liquid nitrogen for 7 days. For a control, grafts were transplanted immediately after dissection. The results showed that only 150f the preserved grafts survived when compared to the control. The surviving grafts, however, did not show any difference to the number of surviving neurons.

Date and Ohmoto also experimented with the injection of acidic fibroblast growth factor into the striatum of MPTP treated mice could renew the host nigrostriatal dopaminergic system. This renewal was only observed in young mice though. One final experiment was to try and avoid problems of immunological rejection of the grafts. In order to do this an application of a polymer encapsulation that permits dopamine secretion, oxygen, glucose, and nutrition entry, but not immunocytes or antibodies. One month after transplantation a large number had survived, and began producing dopamine.

All this time we have looked at experiments in which antiparkinson effects can be obtained by dopaminergic pathways. But, in addition to the loss of dopamine, a series of changes occur in the basal ganglia as well. One example is the increased activity of the globus padillus. This is one of the main aspects in the neural mechanisms that produce parkinsonian symptoms. One reason for this could be the activation of striatal NMDA receptors. This is backed when NMDA is injected in rodents, and produces parkinsonian effects. Since striatal NMDA receptors may have different properties, selective targeting by specific antagonists could produce antiparkinsonian effects (Nash, Hill, and Brotchie 1999). There have been a series of experiments to show this.

To start, rats were injected with reserpine, and placed into an arena surrounded by infrared beams. The beams would measure their activity while in the box. Each rat was injected with either ifenprodil, eliprodil, or a placebo (both ifenprodil and eliprodil are NMDA antagonists). After the test, the results showed that both ifenprodil and eliprodil produced an increase in locomotor activity, 1026% and 553% respectively. Also, the side effects associated with the Central Nervous System were not observed, confirming the belief of a specific NMDA receptor in the striata. It was also concluded that there was a dose dependent relationship with both ifenprodil and eliprodil. The larger the dose of each antagonist, the greater the antiparkinson effect.

All this research and treatment of PD is very encouraging. The future in the treatment and perhaps the cure for PD looks to be headed in the right place. But what about the people who suffer with PD, and do not respond to the medication? How do they feel? Margaret Bourke-White described what it was like to suffer from PD:



"To understand what parkinsonism is like under modern treatment, you must also experience the euphoria that comes each time your medicine does work to relieve your stiffness. You must experience the tickle of ecstasy that travels through your spine as your frozen-stiff body seems to thaw out...And to know what it is like to be parkinsonian, you must know how it feels when, a few minutes later, a young child notices your increasing dykinesia and calls our 'Mister, why are you walking so funny?'"



Parkinson's Disease is a slow killer. Due to modern drugs and surgical procedures, one is able to switch off many of its symptoms for a short period of time. Inevitably, the drugs and the surgery wear off, and the switch of symptoms is turned to the on position once again. Only time will tell whether or not a permanent off switch will emerge. Until then, many individuals will have to deal with the frustrations of the constant struggles between on and off; and families will continue to watch their loved ones loose control of their lives.



BIBLIOGRAPHY



1. Biziere, E. Kathleen & Kurth, C. Matthias. Living With Parkinson's Disease,

DemosVermande, New York, 1997.



2. Brotchie, J.M., Hill, M.P. & Nash, J.E. Antiparkinsonian Actions of Blockade of

NR2B-Containing NMDA Receptors in the Reserpine-Treated Rat. Experimental Neurology 42-48 (March 1999)



3. Date, I. & Ohmoto, T. Neural Transplantation for Parkinson's Disease Cellular and

Molecular Neurobiology 67-76 (March 1999)



4. Dorrows, Sidney Parkinson's: A Patient's View Seven Locks Press, INC.

Cabin John, Md (1981)



5. Lieberman, A.N. & Williams F. L. Parkinson's Disease: The Complete Guide for

Patients and Caregivers Phillip Lief Group, INC, New York, 1993.





6. McGoon, D.C. The Parkinson's Handbook W. W. Norton & Company, New York,

1990.





7. Schapira, A.H.V. Science, Medicine, and the Future: Parkinson's disease BMJ

311-314 (January 1999)

[GregD]

TenaLouise,
If I may ask? Where did you find this?


David Presti did an execellent job writing this paper. One thing I would add is according to The National Parkinson Foundation and the American Parkinson Disease Association, about 10%-20% of those diagnosed with Parkinson's disease are under age 50, and about half of those are diagnosed before age 40.

GregD

[Virginia Therese]

TenaLouise...and very comprehensive. Though some of the information was somewhat technical, still, it was presented in a way that it was easy enough to read and comprehend...thank you for posting....

Therese